Sonneveld, P.

A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma (Article)

2013-05-01T00:00:00Z

Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory multiple myeloma who had ≥2 prior lines of therapy, one of which had to be bortezomib-based. Fourteen initial patients received siltuximab alone, 10 of whom had dexamethasone added for suboptimal response; 39 subsequent patients were treated with concurrent siltuximab and dexamethasone. Patients received a median of four prior lines of therapy, 83% were relapsed and refractory, and 70% refractory to their last dexamethasone-containing regimen. Suppression of serum C-reactive protein levels, a surrogate marker of IL6 inhibition, was demonstrated. There were no responses to siltuximab but combination therapy yielded a partial (17%) + minimal (6%) response rate of 23%, with responses seen in dexamethasone-refractory disease. The median time to progression, progression-free survival and overall survival for combination therapy was 4·4, 3·7 and 20·4 months respectively. Haematological toxicity was common but manageable. Infections occurred in 57% of combination-treated patients, including ≥grade 3 infections in 18%. Further study of siltuximab in modern corticosteroid-containing myeloma regimens is warranted, with special attention to infection-related toxicity.

High-dose imatinib versus high-dose imatinib in combination with intermediate-dose cytarabine in patients with first chronic phase myeloid leukemia: a randomized phase III trial of the Dutch-Belgian HOVON study group (Article)

2013-04-10T00:00:00Z

Despite the revolutionary change in the prognosis of chronic myeloid leukemia (CML) patients with the introduction of imatinib, patients with resistant disease still pose a considerable problem. In this multicenter, randomized phase III trial, we investigate whether the combination of high-dose imatinib and intermediate-dose cytarabine compared to high-dose imatinib alone, improves the rate of major molecular response (MMR) in newly diagnosed CML patients. This study was closed prematurely because of declining inclusion due to the introduction of second generation tyrosine kinase inhibitors and only one third of the initially required patients were accrued. One hundred nine patients aged 18-65 years were randomly assigned to either imatinib 800 mg (n = 55) or to imatinib 800 mg in combination with two successive cycles of cytarabine 200 mg/m2for 7 days (n = 54). After a median follow-up of 41 months, 67 % of patients were still on protocol treatment. The MMR rate at 12 months was 56 % in the imatinib arm and 48 % in the combination arm (p = 0.39). Progression-free survival was 96 % after 1 year and 89 % after 4 years. Four-year overall survival was 97 %. Adverse events grades 3 and 4 were more common in the combination arm. The addition of intermediate-dose of cytarabine to imatinib did not improve the MMR rate at 12 months. However, the underpowering of the study precludes any definitive conclusions. This trial is registered at www.trialregister.nl (NTR674).

Plasma cell leukemia: Consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group (Article)

2013-04-01T00:00:00Z

Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥20%) and absolute number (≥2 × 10 9/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL.

Real-world health care costs of relapsed/refractory multiple myeloma during the era of novel cancer agents (Article)

2013-02-01T00:00:00Z

What is known and objective: High costs of novel agents increasingly put pressure on limited healthcare budgets. Demonstration of their real-world costs and cost-effectiveness is often required for reimbursement. However, few published economic evaluations of novel agents for multiple myeloma exist. Moreover, existing cost analyses were heavily based on conventionally treated patients. We investigated real-world health care costs of relapsed/refractory multiple myeloma in Dutch daily practice. Methods: A retrospective medical chart review was conducted for 139 patients treated between January 2001 and May 2009. Total monthly costs attributable to each cost component were described across all regimens and for bortezomib-, thalidomide- and lenalidomide-based treatment regimens. Results: Mean monthly total costs (€3,981) varied depending on the sequence of therapy (range: €442-€31,318). Significant cost drivers across all regimens included costs of therapy and hospital admissions. The acquisition costs for novel agents in particular accounted for 32% of mean total monthly costs. Prognostic factors associated with increased mean total monthly costs in multivariate regression analysis included low platelet counts (P = 0·01) and worsening performance status (P < 0·001). Mean total monthly costs of bortezomib- and lenalidomide-based regimens were significantly higher than those for thalidomide-based regimens in second, third and fourth treatment line. What is new and conclusions: Real-world costs during treatment of relapsed/refractory multiple myeloma vary greatly. Cost drivers include hospital admissions and acquisition costs of novel agents. Costs also vary by prognostic factors and treatment-related resource use. Future studies assessing the costs of combination therapy consisting of two or more novel agents are encouraged.

Disease control in patients with relapsed and/or refractory multiple myeloma: What is the optimal duration of therapy? (Article)

2012-11-01T00:00:00Z

Novel agents such as thalidomide, bortezomib, and lenalidomide have improved outcomes and extended survival in patients with relapsed and/or refractory multiple myeloma (RRMM). These agents appear to be most effective when used at first relapse rather than later in the treatment sequence; however, the optimal duration of therapy has not been defined. Continuous therapy from relapse to disease progression may be able to maintain suppression of residual disease, thereby extending overall survival. This article reviews the currently available data on treatments, including novel agents for patients with RRMM, focusing on the duration of therapy required to improve clinical outcomes.

Health-related quality of life and disease-specific complaints among multiple myeloma patients up to 10 yr after diagnosis: Results from a population-based study using the PROFILES registry (Article)

2012-10-01T00:00:00Z

Background: This prospective population-based study describes health-related quality of life (HRQOL) and disease-specific complaints of patients with multiple myeloma (MM) up to 10 yr post-diagnosis. Methods: The Eindhoven Cancer Registry was used to select all patients diagnosed with MM from 1999 to 2010. Patients with MM completed the EORTC QLQ-C30 and EORTC QLQ-MY20 questionnaires at baseline (n = 156; 74% response rate) and 1 yr later (n = 80). The EORTC QLQ-C30 was also completed by an age- and sex-matched normative population (n = 500). Results: Patients with MM reported statistically significant and clinically relevant worse scores on all EORTC QLQ-C30 scales (all P's at least < 0.01) compared to the norm. Also, patients with MM reported a mean decrease (e.g., worsening) between baseline and 1-yr follow-up scores for: quality of life (mean, 68 vs. 55, respectively, P < 0.001; 74% of patients had a deteriorated score), fatigue (33 vs. 39, P < 0.05; 50%), nausea and vomiting (6.3 vs. 13, P < 0.05; 71%), pain (33 vs. 43, P < 0.05; 59%), and dyspnea (17 vs. 33, P < 0.001; 66%). The most bothering symptoms during the past week were tingling hands/feet (32%), back pain (28%), bone aches/pain (26%), pain in arm/shoulder (19%), and feeling drowsy (18%). Also, 37% worried about their future health, 34% thought about their disease, and 21% worried about dying. Conclusion: Patients with MM experience a very high symptom burden and low HRQOL. Future studies should focus on possible mechanisms that can predict low HRQOL and high symptom burden in patients with MM and should investigate optimal ways to alleviate these.

Health-related quality of life and disease-specific complaints among multiple myeloma patients up to 10 yr after diagnosis: Results from a population-based study using the PROFILES registry (Article)

2012-10-01T00:00:00Z

Novel anticancer agents for multiple myeloma: A review of the evidence for their therapeutic and economic value (Article)

2012-06-01T00:00:00Z

Recent advances in oncology treatment have improved patient outcomes at the expense of increasing healthcare costs. The indication multiple myeloma is especially characterized by a recent and continuing flood of expensive novel agents. A review encompassing all elements necessary to perform an economic evaluation of novel agents for multiple myeloma was conducted for thalidomide, bortezomib and lenalidomide. Improvements in efficacy have led to a switch from conventional therapy to novel agents as standard therapy. Incremental cost-effectiveness ratios for novel agents alone or in combination with conventional agents were generally regarded to be within acceptable ranges. Conflicting results were reported for the incremental cost-effectiveness of bortezomib versus lenalidomide, as unresolved questions remain regarding their comparative effectiveness. Future economic evaluations will require an assessment of the cost-effectiveness of these agents in terms of sequence within the treatment paradigm and in combination with one another.

How to manage neutropenia in multiple myeloma (Article)

2012-02-01T00:00:00Z

Neutropenia is a hematologic adverse event characterized by an absolute neutrophil count (ANC) lower than 1500 cells/mL. This reduction may be due to decreased neutrophil production, accelerated use, a shift in compartments of neutrophils, or a combination of these factors. Neutropenia is often associated with infections, which are major causes of morbidity and mortality in patients with cancer. In patients with multiple myeloma, the novel agents thalidomide, lenalidomide, and bortezomib have improved outcome, but chemotherapy-related neutropenia should be carefully considered. Chemotherapy-related high-risk factors for severe neutropenia include regimens with an expected neutropenia rate of > 50%, such as the 3-drug combinations including lenalidomide plus alkylating agents or doxorubicin, whereas low-risk regimens include combinations of the novel agents with dexamethasone alone. Patient characteristics, disease stage, type of current and previous treatment, and ANC < 1000 cells/mL at baseline are additional factors that define the risk of severe neutropenia. Granulocyte-colony stimulating factor (G-CSF) should be used to manage chemotherapy-related neutropenia so that patients may stay on treatment for a longer time and benefit from it. Primary G-CSF prophylaxis should be used when high-risk regimens are administered or when low/intermediate-risk regimens are used and additional risk factors are present. Reactive G-CSF treatment is indicated when patients undergoing low-risk chemotherapy experience grade 3/4 neutropenia. If ANC restores to > 1000 cells/mL, therapy can be resumed with no dose modifications. In case of persistence of severe neutropenia, treatment should be delayed until ANC reaches > 1000 cells/mL, and dose reductions are necessary.

Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p (Article)

2012-01-26T00:00:00Z

In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For all analyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P < .28) or OS (P < .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as IS-RCTN64455289.

Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study (Article)

2012-01-01T00:00:00Z

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T0). The median age at diagnosis was 58 years, and time from diagnosis to T0was 3.3 years. Following T0, 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0-8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T0in 94 patients (44%) including ≥partial response in 69 (32%). The median overall survival and event-free survival from T0were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.

Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients (Article)

2011-11-01T00:00:00Z

Bortezomib induced peripheral neuropathy is a dose-limiting side effect and a major concern in the treatment of multiple myeloma. To identify genetic risk factors associated with the development of this side effect in bortezomib treated multiple myeloma patients, a pharmacogenetic association study was performed using a discovery set (IFM 2005-01; n=238) and a validation set (HOVON65/GMMG-HD4 and a Czech dataset; n=231). After multiplicity correction, none of the 2,149 single nucleotide polymorphisms tested revealed any significant association with bortezomib induced peripheral neuropathy. However, 56 single nucleotide polymorphisms demonstrated an association with bortezomib induced peripheral neuropathy with pointwise, uncorrected significance. Pathway analysis of these polymorphisms demonstrated involvement of neurological disease (FDR <20%). Also a clear enrichment of major bortezomib metabolizing genes was found. Univariate evaluation of these 56 polymorphisms in the validation set demonstrated one single nucleotide polymorphism with pointwise significance: rs619824 in CYP17A1.

Cancer testis antigens in newly diagnosed and relapse multiple myeloma: Prognostic markers and potential targets for immunotherapy (Article)

2011-11-01T00:00:00Z

Background In multiple myeloma, expression of cancer testis antigens may provide prognostic markers and potential targets for immunotherapy. Expression at relapse has not yet been evaluated for a large panel of cancer testis antigens which can be classified by varying expression in normal tissue: restricted to testis, expressed in testis and brain and not restricted but selectively expressed in testis. Design and Methods Evaluation of cancer testis antigen expression was made in newly diagnosed multiple myeloma cases (HOVON-65/GMMG-HD4 trial; n=320) and in relapse cases (APEX, SUMMIT, CREST trials; n=264). Presence of expression using Affymetrix GeneChips was determined for 123 cancer testis antigens. Of these 87 had a frequency of more than 5% in the newly diagnosed and relapsed patients, and were evaluated in detail. Results Tissue restriction was known for 58 out of 87 cancer testis antigens. A significantly lower frequency of presence calls in the relapsed compared to newly diagnosed cases was found for 3 out of 13 testis restricted genes, 2 out of 7 testis/brain restricted genes, and 7 out of 38 testis selective genes. MAGEC1, MAGEB2 and SSX1 were the most frequent testis-restricted cancer testis antigens in both data sets. Multivariate analysis demonstrated that presence of MAGEA6 and CDCA1 were clearly associated with shorter progression free survival, and presence of MAGEA9 with shorter overall survival in the set of newly diagnosed cases. In the set of relapse cases, presence of CTAG2 was associated with shorter progression free survival and presence of SSX1 with shorter overall survival. Conclusions Relapsed multiple myeloma reveals extensive cancer testis antigen expression. Cancer testis antigens are confirmed as useful prognostic markers in newly diagnosed multiple myeloma patients and in relapsed multiple myeloma patients.

MicroRNA signatures characterize multiple myeloma patients (Article)

2011-11-01T00:00:00Z

Personalized therapy in multiple myeloma according to patient age and vulnerability: A report of the European Myeloma Network (EMN) (Article)

2011-10-27T00:00:00Z

Most patients with newly diagnosed multiple myeloma (MM) are aged > 65 years with 30% aged > 75 years. Many elderly patients are also vulnerable because of comorbidities that complicate the management of MM. The prevalence of MM is expected to rise over time because of an aging population. Most elderly patients with MM are ineligible for autologous transplantation, and the standard treatment has, until recently, been melphalan plus prednisone. The introduction of novel agents, such as thalidomide, bortezomib, and lenalidomide, has improved outcomes; however, elderly patients withMM are more susceptible to side effects and are often unable to tolerate full drug doses. For these patients, lower-dose-intensity regimens improve the safety profile and thus optimize treatment outcome. Further research into the best treatment strategies for vulnerable elderly patients is urgently needed. Appropriate screening for vulnerability and an assessment of cardiac, pulmonary, renal, hepatic, and neurologic functions, as well as age > 75 years, at the start of therapy allows treatment strategies to be individualized and drug doses to be tailored to improve tolerability and optimize efficacy. Similarly, occurrence of serious nonhematologic adverse events during treatment should be carefully taken into account to adjust doses and optimize outcomes.

Lenalidomide maintenance after nonmyeloablative allogeneic stem cell transplantation in multiple myeloma is not feasible: Results of the HOVON 76 Trial (Article)

2011-09-01T00:00:00Z

To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in multiple myeloma as part of first-line treatment, we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started maintenance 1 to 6 months after nonmyeloablative allo-SCT. Lenalidomide was dosed 10 mg on days 1 to 21 of a 28-day schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty-five eligible patients were enrolled, and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because of the development of acute graft versus host disease (GVHD). In total, 13 patients (43%) stopped treatment because of development of GVHD, 5 patients (17%) because of other adverse events, and 5 patients (17%) because of progression. Responses improved in 37% of patients, and the estimated 1-year progression-free survival from start of maintenance was 69% (90% confidence interval, 53%-81%). Lenalidomide increased the frequency of human leukocyte antigen-DR+T cells and regulatory T cells, without correlation with clinical parameters. In conclusion, lenalidomide maintenance 10 mg daily after nonmyeloablative allo-SCT with unmanipulated graft in multiple myeloma patients is not feasible, mainly because of the induction of acute GVHD. This trial was registered at www.trialregister.nl as #NTR1645.

Screening for gastrointestinal malignancy in patients with iron deficiency anemia by general practitioners: An observational study (Article)

2011-09-01T00:00:00Z

Background. The prevalence of iron deficiency anemia (IDA) is 25% in men and postmenopausal women in the developed world. IDA is commonly caused by chronic gastrointestinal blood loss, and a thorough examination of the gastrointestinal tract must be standard practice. Objective. To retrospectively study endoscopic evaluations of patients from general practitioners diagnosed with IDA in a peripheral hospital laboratory in order to determine the cause of IDA and the number of gastrointestinal malignancies. Material and methods. We retrospectively evaluated all patients with IDA diagnosed in a peripheral hospital laboratory by the general practitioner in the region of our hospital from 1 January 2004 until 31 December 2005. We included women older than 50 and men 18 years and older without a history of IDA in the previous 2 years. Results. In 2 years, 287 patients were newly diagnosed with IDA in our hospital laboratory. Only 90 (31%) patients were endoscopically evaluated within 4 months. Gastrointestinal endoscopy revealed at least one lesion potentially responsible for blood loss in 41 of 90 (46%) patients. The most common lesions identified by gastroduodenal endoscopy were erosive esophagitis, gastritis and duodenitis (14%). Cancer was the most commonly detected lesion in the colon, accounting for 17 of 21 colonic lesions explaining IDA. In total, gastrointestinal malignancy was diagnosed in 2% of screened patients. Factors determining the decision for endoscopic screening were lower hemoglobin level, lower ferritin level and male gender. Conclusion. In our retrospective study of patients with IDA, only 31% received any form of endoscopic evaluation. In general practice, IDA is investigated suboptimally, and interventions other than the issuing of guidelines are needed to change practice.

Rapid early monoclonal protein reduction after therapy with bortezomib or bortezomib and pegylated liposomal doxorubicin in relapsed/refractory myeloma is associated with a longer time to progression (Article)

2011-08-15T00:00:00Z

BACKGROUND: A rapid and early monoclonal (M) protein response during initial therapy in patients with multiple myeloma had been identified as a predictor of superior long-term outcome in some-but not all-studies. METHODS: To determine if the parameter of M protein reduction was of value in the relapsed and/or refractory setting, retrospective landmark analyses were performed at the end of cycles 2 and 4 of a phase 3 study, which randomized such patients to receive bortezomib alone or pegylated liposomal doxorubicin (PLD) with bortezomib. RESULTS: Compared with a <25% reduction in M protein at the landmark time point, patients with a 50% to <75% reduction after cycle 2 had a significantly lower hazard ratio (HR) for time to progression (HR = 0.41; 95% confidence interval [CI], 0.26-0.64; P <.001), as did those with a ≥75% reduction (HR = 0.26; 95% CI, 0.15-0.45; P <.001). In all of these groups, PLD + bortezomib provided superior outcomes to bortezomib alone, and did so without an increase in the risk of adverse events overall and with a predictable toxicity profile. CONCLUSIONS: These analyses supported the possibility that a robust early M protein response is a good prognostic factor for long-term outcome of myeloma patients with relapsed and/or refractory disease receiving bortezomib or PLD + bortezomib.

Critical review of economic evaluations in multiple myeloma: An overview of the economic evidence and quality of the methodology (Article)

2011-07-01T00:00:00Z

Continued expansion in the availability of costly alternative therapies in multiple myeloma will enhance the role of economic evaluations in reimbursement decisions and amendments to the treatment guidelines. The quality of economic evaluations should be taken into account by clinicians involved in decision-making. A systematic review and critique of the methodology was performed to assess the trends and quality in economic evaluations in multiple myeloma to date. A literature search was conducted to identify full economic evaluations in multiple myeloma as of December 2009. Details of the economic evaluation methods applied were extracted. Each study underwent a quality assessment based on the Drummond checklist for appraisal of high-quality economic evaluations in health care. Eighteen published economic evaluations were identified. Stem cell transplantation in combination with intensive chemotherapy has been demonstrated to be cost-effective, while interferon alpha is generally ineffective at additional costs. Evaluations have become less frequent in the last decade, especially for newer therapies despite their important contribution to improvements in outcomes. The quality of the methodology applied and its documentation can be improved in many aspects. As users of the results of economic evaluations, clinicians involved in guiding decision-making should be critical of the quality of economic evaluations in multiple myeloma. To ensure access to and identification of high-quality studies, researchers conducting economic evaluations of future advances should strive towards evaluations that fulfil the Drummond criteria and are properly documented.

International myeloma working group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation (Article)

2011-06-09T00:00:00Z

The role of high-dose therapy followed by autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional chemotherapy to newer regimens incorporating the immunomodulatory derivatives thalidomide or lenalidomide and the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various doublet, triplet, and quadruplet regimens. Up-front use of these induction treatments, in particular 3-drug combinations, has affected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the depth of response, a gain that translates into extended progression-free survival and, potentially, overall survival. High activity shown by immunomodulatory derivatives and bortezomib before ASCT has recently led to their use as consolidation and maintenance therapies after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This article reviews the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current management of younger, transplantation-eligible MM patients.

Treatment of relapsed and refractory multiple myeloma in the era of novel agents (Article)

2011-06-01T00:00:00Z

The introduction of the Immunomodulatory drugs (IMiDs) and proteasome inhibitors, used either as a single-agent or combined with classic anti-myeloma therapies, has improved the outcome for patients with relapsed myeloma. However, there is currently no generally accepted standard treatment for relapsed/refractory myeloma patients, partly because of the absence of trials comparing the efficacy of the novel agents in relapsed/refractory myeloma. Choice of a new treatment regimen depends on both patient and disease-specific characteristics. A lenalidomide-based regimen is the first choice in patients with neuropathy, while bortezomib has the highest efficacy in patients with renal insufficiency and is not associated with increased risk of thromboembolism. A second autologous stem cell transplantation (auto-SCT) can be applied in patients with a progression-free period of ≥18-24. months after the first auto-SCT. In high-risk relapse such as occurring early after auto-SCT consolidation with allogeneic SCT can be considered. In this review we provide an overview of the various salvage regimens and give recommendations for treatment of patients with relapsed/refractory myeloma in different clinical settings.

The expression of the peripheral cannabinoid receptor CB2 has no effect on clinical outcome in diffuse large B-cell lymphomas (Article)

2011-06-01T00:00:00Z

Background: The peripheral cannabinoid receptor (CB2) is mainly detected on B cells in the germinal centers (GCs) of the immune system, using an antibody directed against the extra cellular N-terminal domain of the receptor. We retrospectively investigated the CB2 receptor expression in diffuse large B-cell lymphomas (DLBCL) and its clinical relevance for treatment outcome. Patients and methods: We have constructed a tissue micro-array (TMA) using lymphoma tissue of a large cohort of patients with DLBCL (N=104) who were treated with CHOP. Results: Forty-five out of 79 evaluable cases (57%) were CB2 positive. The expression of CB2 receptors was variably present in both the germinal center B cell (GCB) (n=31) and the non-GCB/activated B-cell (ABC) (n=43) DLBCL subtypes. CB2 positivity was not associated with a different outcome in this patient cohort (CR; P=0.87, EFS; P=0.32, DFS; P=0.06 and OS; P=0.18). Implementation of CB2 expression in the Hans algorithm using the markers CD10, BCL6, and MUM1 did not result in added prognostic value (all P-values >0.1). Conclusions: We hypothesize that although CB2 is normally expressed in GCs, the expression in one of the malignant counterparts such as DLBCL is aberrant. This may be an explanation for the absence of prognostic relevance for the expression of this protein.

Multiple myeloma treatment strategies with novel agents in 2011: A European perspective (Article)

2011-05-06T00:00:00Z

The arrival of the novel agents thalidomide, bortezomib, and lenalidomide has significantly changed our approach to the management of multiple myeloma and, importantly, patient outcomes have improved. These agents have been investigated intensively in different treatment settings, providing us with data to make evidence-based decisions regarding the optimal management of patients. This review is an update to a previous summary of European treatment practices that examines new data that have been published or presented at congresses up to the end of 2010 and assesses their impact on treatment practices.

Consensus recommendations for risk stratification in multiple myeloma: Report of the International Myeloma Workshop Consensus Panel 2 (Article)

2011-05-05T00:00:00Z

A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serumβ2-microglobulin level and International Staging System stages II and III, incorporating high β2-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.

Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: Consensus statement (Article)

2011-05-01T00:00:00Z

An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma.

Effect of thalidomide with melphalan and prednisone on health-related quality of life (HRQoL) in elderly patients with newly diagnosed multiple myeloma: a prospective analysis in a randomized trial (Article)

2011-04-07T00:00:00Z

Thalidomide with melphalan/prednisone (MPT) was defined as standard treatment in elderly patients with multiple myeloma (MM) based on five randomized trials. In one of these trials, HOVON49, a prospective health-related quality-of-life (HRQoL) study was initiated in order to assess the impact of thalidomide on QoL. Patients aged >65 years with newly diagnosed MM were randomized to receive melphalan plus prednisone (MP) or MPT, followed by thalidomide maintenance in the MPT arm. Two hundred eighty-four patients were included in this side study (MP, n = 149; MPT n = 135). HRQoL was assessed with the EORTC Core QoL Questionnaire (QLQ-C30) and the myeloma-specific module (QLQ-MY24) at baseline and at predetermined intervals during treatment. The QLQ-C30 subscales physical function (P = 0.044) and constipation (P < 0.001) showed an improvement during induction in favour of the MP arm. During thalidomide maintenance, the scores for the QLQ-MY24 paraesthesia became significantly higher in the MPT arm (P<0.001). The QLQ-C30 subscales pain (P = 0.12), insomnia (P = 0.068), appetite loss (P = 0.074) and the QLQ-MY24 item sick (P = 0.086) scored marginally better during thalidomide maintenance. The overall QoL-scale QLQ-C30-HRQoL showed a significant time trend towards more favourable mean values during protocol treatment without differences between MP and MPT. For the QLQ-C30 subscales emotional function and future perspectives, difference in favour of the MPT arm from the start of treatment was observed (P = 0.018 and P = 0.045, respectively) with no significant 'time × arm' interaction, indicating a persistent better patient perspective with MPT treatment. This study shows that the higher frequency of toxicity associated with MPT does not translate into a negative effect on HRQoL and that MPT holds a better patient perspective.

Cytarabine dose for acute myeloid leukemia (Article)

2011-03-17T00:00:00Z

BACKGROUND: Cytarabine (ara-C) is an important drug in the treatment of acute myeloid leukemia (AML). High-dose cytarabine (2000 to 3000 mg per square meter of body-surface area) is toxic but results in higher rates of relapse-free survival than does the conventional dose of 100 to 400 mg per square meter. Intermediate dose levels have not been thoroughly evaluated. METHODS: We compared two induction regimens in patients 18 to 60 years of age (median, 49) who had newly diagnosed AML. The intermediate-dose group, totaling 431 patients, received cytarabine at a dose of 200 mg per square meter given by continuous intravenous infusion for 24 hours during cycle 1 of induction therapy and 1000 mg per square meter by infusion for 3 hours twice daily during cycle 2 of induction therapy. The high-dose group, totaling 429 patients, received a dose-escalated regimen of 1000 mg of cytarabine per square meter every 12 hours in cycle 1 and 2000 mg per square meter twice daily in cycle 2. Patients with a complete response did not receive additional cytarabine but received consolidation therapy in a third cycle of chemotherapy (mitoxantrone-etoposide) or underwent autologous or allogeneic stem-cell transplantation. Complete remission rates, survival rates, and toxic effects were assessed for each treatment group. RESULTS: At a median follow-up of 5 years, no significant differences were noted between the intermediate-dose group and the high-dose group with respect to complete remission rates (80% and 82%, respectively), probability of relapse, event-free survival at 5 years (34% and 35%), or overall survival (40% and 42%). High-dose cytarabine provided no clear advantage in any prognostic subgroup. The high-dose treatment resulted in higher incidences of grade 3 and grade 4 toxic effects (in cycle 1), prolonged hospitalization, and delayed neutrophil recovery (in cycle 2) and platelet recovery (in cycles 2 and 3). CONCLUSIONS: Induction therapy with cytarabine at the lower dose already produced maximal antileukemic effects for all response end points, suggesting a plateau in the dose-response relationship above this dose level. High-dose cytarabine results in excessive toxic effects without therapeutic benefit. (Netherlands Trial Register number, NTR230.). Copyright

Complete response correlates with long-term progression-free and overall survival in elderly myeloma treated with novel agents: Analysis of 1175 patients (Article)

2011-03-17T00:00:00Z

Complete response (CR) was an uncommon event in elderly myeloma patients until novel agents were combined with standard oral melphalan-prednisone. This analysis assesses the impact of treatment response on progression-free survival (PFS) and overall survival (OS). We retrospectively analyzed 1175 newly diagnosed myeloma patients, enrolled in 3 multicenter trials, treated with melphalanprednisone alone (n = 332), melphalan-prednisone-thalidomide (n = 332), melphalanprednisone-bortezomib (n = 257), or melphalan-prednisone-bortezomib- thalidomide (n = 254). After a median follow-up of 29 months, the 3-year PFS andOSwere 67% and 27% (hazard ratio = 0.16; P < .001), and 91% and 70% (hazard ratio = 0.15; P < .001) in patients who obtained CR and in those who achieved very good partial response, respectively. Similar results were observed in patients older than 75 years. Multivariate analysis confirmed that the achievement of CR was an independent predictor of longer PFS and OS, regardless of age, International Staging System stage, and treatment. These findings highlight a significant association between the achievement of CR and long-term outcome, and support the use of novel agents to achieve maximal response in elderly patients, including those more than 75 years. This trial was registered at www.clinicaltrials.gov as #NCT00232934, #ISRCTN 90692740, and #NCT01063179.

Bortezomib-induced peripheral neuropathy: Facts and genes - Authors' reply (Article)

2011-02-01T00:00:00Z

Microparticle-associated tissue factor activity and venous thrombosis in multiple myeloma (Article)

2011-01-01T00:00:00Z

Multiple myeloma (MM) is associated with an increased risk of venous thromboembolic (VTE) complications. Aim of this study was to measure microparticle-associated tissue factor (MP-TF) activity in patients with newly diagnosed MM before and after chemotherapy and to investigate whether MP-TF activity is associated with VTE. MP-TF activity was assessed in 122 newly diagnosed MM patients who were eligible for combination chemotherapy. MP-TF activity levels (17.6 fM Xa/min [8.6-33.2] (median [IQR]) were higher in untreated MM patients compared to normal healthy volunteers (4.1 fM Xa/min [2.3-6.6], p <0.001). MP-TF activity prior to the start of treatment was not different between patients who developed a VTE during follow-up (n=15) and those who did not (n=107). In 75 patients in whom plasma was obtained before and after chemotherapy, MP-TF activity decreased significantly (from 17.4 [10.2-32.8] to 12.0 [7.0-18.5] fM Xa/min, P=0.006). MP-TF activity remained, however, elevated in patients who developed VTE (15.1 [10.3-25.2]), in contrast to patients not developing VTE (11.4 [7.0-25.2], P<0.001). In conclusion, MP-TF activity is increased in patients with MM. Whether MP-TF activity has a pathogenetic role in VTE in MM patients remains to be established in future studies.

Polymorphisms in the multidrug resistance gene MDR1 (ABCB1) predict for molecular resistance in patients with newly diagnosed chronic myeloid leukemia receiving high-dose imatinib (Article)

2010-12-23T00:00:00Z

Treatment-related peripheral neuropathy in multiple myeloma: the challenge continues (Article)

2010-11-01T00:00:00Z

Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib. © 2010 Elsevier Ltd.

Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial (Article)

2010-11-01T00:00:00Z

Background: Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity in patients with multiple myeloma, often requiring adjustment of treatment and affecting quality of life. We investigated the molecular profiles of early-onset (within one treatment cycle) versus late-onset (after two or three treatment cycles) bortezomib-induced peripheral neuropathy and compared them with those of vincristine-induced peripheral neuropathy during the induction phase of a prospective phase 3 trial. Methods: In the induction phase of the HOVON-65/GMMG-HD4 trial, patients (aged 18-65 years) with newly diagnosed Salmon and Durie stage 2 or 3 multiple myeloma were randomly assigned to three cycles of bortezomib-based or vincristine-based induction treatment. We analysed the gene expression profiles and single-nucleotide polymorphisms (SNPs) of pretreatment samples of myeloma plasma cells and peripheral blood, respectively. This study is registered, number ISRCTN64455289. Findings: We analysed gene expression profiles of myeloma plasma cells from 329 (39%) of 833 patients at diagnosis, and SNPs in DNA samples from 369 (44%) patients. Early-onset bortezomib-induced peripheral neuropathy was noted in 20 (8%) patients, and 63 (25%) developed the late-onset type. Early-onset and late-onset vincristine-induced peripheral neuropathy was noted in 11 (4%) and 17 (7%) patients, respectively. Significant genes in myeloma plasma cells from patients that were associated with early-onset bortezomib-induced peripheral neuropathy were the enzyme coding genes RHOBTB2 (upregulated by 1·59 times; p=4·5×10-5), involved in drug-induced apoptosis, CPT1C (1·44 times; p=2·9×10-7), involved in mitochondrial dysfunction, and SOX8 (1·68 times; p=4·28×10-13), involved in development of peripheral nervous system. Significant SNPs in the same patients included those located in the apoptosis gene caspase 9 (odds ratio [OR] 3·59, 95% CI 1·59-8·14; p=2·9×10-3), ALOX12 (3·50, 1·47-8·32; p=3·8×10-3), and IGF1R (0·22, 0·07-0·77; p=8·3×10-3). In late-onset bortezomib-induced peripheral neuropathy, the significant genes were SOD2 (upregulated by 1·18 times; p=9·6×10-3) and MYO5A (1·93 times; p=3·2×10-2), involved in development and function of the nervous system. Significant SNPs were noted in inflammatory genes MBL2 (OR 0·49, 95% CI 0·26-0·94; p=3·0×10-2) and PPARD (0·35, 0·15-0·83; p=9·1×10-3), and DNA repair genes ERCC4 (2·74, 1·56-4·84; p=1·0×10-3) and ERCC3 (1·26, 0·75-2·12; p=3·3×10-3). By contrast, early-onset vincristine-induced peripheral neuropathy was characterised by upregulation of genes involved in cell cycle and proliferation, including AURKA (3·31 times; p=1·04×10-2) and MKI67 (3·66 times; p=1·82×10-3), and the presence of SNPs in genes involved in these processes-eg, GLI1 (rs2228224 [0·13, 0·02-0·97, p=1·18×10-2] and rs2242578 [0·14, 0·02-1·12, p=3·00×10-2]). Late-onset vincristine-induced peripheral neuropathy was associated with the presence of SNPs in genes involved in absorption, distribution, metabolism, and excretion-eg, rs1413239 in DPYD (3·29, 1·47-7·37, 5·40×10-3) and rs3887412 in ABCC1 (3·36, 1·47-7·67, p=5·70×10-3). Interpretation: Our results strongly suggest an interaction between myeloma-related factors and the patient's genetic background in the development of treatment-induced peripheral neuropathy, with different molecular pathways being implicated in bortezomib-induced and vincristine-induced peripheral neuropathy. Funding: German Federal Ministry of Education and Research, Dutch Cancer Foundation Queen Wilhelmina, European Hematology Association, International Myeloma Foundation, Erasmus MC, and Janssen-Cilag Orthobiotech.

Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin (Article)

2010-11-01T00:00:00Z

Single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and P-glycoprotein 1 (MDR1) genes modulate their ability to mediate drug resistance. We therefore sought to retrospectively evaluate their influence on outcomes in relapsed and/or refractory myeloma patients treated with bortezomib or bortezomib with pegylated liposomal doxorubicin (PLD). The MRP1/R723Q polymorphism was found in five subjects among the 279 patient study population, all of whom received PLD∈+∈bortezomib. Its presence was associated with a longer time to progression (TTP; median 330 vs. 129 days; p∈=∈0.0008), progression-free survival (PFS; median 338 vs. 129 days; p∈=∈0.0006), and overall survival (p∈=∈0.0045). MDR1/3435(C∈>∈T), which was in Hardy-Weinberg equilibrium, showed a trend of association with PFS (p∈=∈0.0578), response rate (p∈=∈0.0782) and TTP (p∈=∈0.0923) in PLD∈+∈ bortezomib patients, though no correlation was found in the bortezomib arm. In a recessive genetic model, MDR1/3435 T was significantly associated with a better TTP (p∈=∈0.0405) and PFS (p∈=∈0.0186) in PLD∈+∈bortezomib patients. These findings suggest a potential role for MRP1 and MDR1 SNPs in modulating the long-term outcome of relapsed and/or refractory myeloma patients treated with PLD∈+∈bortezomib. Moreover, they support prospective studies to determine if such data could be used to tailor therapy to the genetic makeup of individual patients.

European Myeloma Network: The 3rd Trialist Forum Consensus Statement from the European experts meeting on multiple myeloma (Article)

2010-11-01T00:00:00Z

Over the past two decades, not only treatment options, but also the diagnosis, staging, and risk assessment of multiple myeloma (MM), have undergone significant development, partially due to a deeper understanding of MM pathogenesis. Conventional cytogenetics and fluorescence in situ hybridization are routinely assessed in MM, and when combined with ISS stage may attain an even better predictive potential. In order to achieve even more effective and individualized therapies, one crucial goal is the identification of genes and gene combinations that predict for response or resistance to chemotherapy. High-dose chemotherapy with autologous stem cell transplant (SCT) still remains the standard therapy for younger patients, with novel agents now being included in both pre-transplant regimens and post-transplant consolidation/maintenance approaches. Similarly, novel agents are also being incorporated into allogeneic SCT for selected patients. In the treatment of elderly patients with MM, novel agents have been successfully incorporated into less intensive regimens, including melphalan/prednisone, low-dose dexamethasone, and cyclophosphamide/ dexamethasone. While second-generation proteasome inhibitors are currently being intensively investigated, the subcutaneous administration of bortezomib, being equivalent to the established i.v. route, is now entering clinical practice. Supportive care remains a crucial aspect in the management of MM. The European Myeloma Network Trialist Group aims to address these contemporary aspects in MM.

Phase I/II clinical study of Tosedostat, an inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia. (Article)

2010-10-01T00:00:00Z

PURPOSE: To identify the maximum-tolerated dose (MTD) and to evaluate the antileukemic activity of tosedostat (formerly CHR-2797), an orally bioavailable aminopeptidase inhibitor. PATIENTS AND METHODS: In phase I, the MTD of once daily oral doses of tosedostat in hematologic malignancies was defined. In phase II, the therapeutic activity of the maximum-acceptable dose (MAD) of tosedostat was evaluated in elderly and/or relapsing patients with acute myeloid leukemia (AML) or myelodysplastic syndrome. RESULTS: In phase I, 16 patients were treated in four cohorts with tosedostat (60 mg to 180 mg) for 28 days. Three patients reported dose-limiting toxicities: two with reversible thrombocytopenia (> 75% reduction in platelet count) at 180 mg (MTD) and one with a Common Toxicity Criteria (CTC) grade 3 ALT elevation at 130 mg (MAD). In phase II, 41 patients were treated with 130 mg tosedostat. In phases I and II, the most common severe (CTC grades 3 to 5) adverse event was a reduction in the platelet count. Of the 51 AML patients in this study, seven reached complete marrow response (< 5% marrow blasts), with three achieving complete remission, and a further seven patients reaching a partial marrow response (between 5% and 15% marrow blasts). The overall response rate was therefore 27%. All responders were age > 60 years, and 79% had either relapsed or refractory AML. CONCLUSION: This phase I/II study demonstrates that oral once daily dosing with 130 mg tosedostat is well tolerated and has significant antileukemic activity. The favorable risk-benefit profile suggests that further clinical trials are warranted.

The use of biochemical markers of bone remodeling in multiple myeloma: A report of the International Myeloma Working Group (Article)

2010-10-01T00:00:00Z

Lytic bone disease is a frequent complication of multiple myeloma (MM). Lytic lesions rarely heal and X-rays are of limited value in monitoring bone destruction during anti-myeloma or anti-resorptive treatment. Biochemical markers of bone resorption (amino- and carboxy-terminal cross-linking telopeptide of type I collagen (NTX and CTX, respectively) or CTX generated by matrix metalloproteinases (ICTP)) and bone formation provide information on bone dynamics and reflect disease activity in bone. These markers have been investigated as tools for evaluating the extent of bone disease, risk of skeletal morbidity and response to anti-resorptive treatment in MM. Urinary NTX, serum CTX and serum ICTP are elevated in myeloma patients with osteolytic lesions and correlate with advanced disease stage. Furthermore, urinary NTX and serum ICTP correlate with risk for skeletal complications, disease progression and overall survival. Bone markers have also been used for the early diagnosis of bone lesions. This International Myeloma Working Group report summarizes the existing data for the role of bone markers in assessing the extent of MM bone disease and in monitoring bone turnover during anti-myeloma therapies and provides information on novel markers that may be of particular interest in the near future.

High incidence of arterial thrombosis in young patients treated for multiple myeloma: Results of a prospective cohort study (Article)

2010-07-08T00:00:00Z

This prospective study evaluated the risk of arterial thrombosis in 195 consecutive patients aged 18 to 65 years with newly diagnosed multiple myeloma (MM). All patients were treated with 3 cycles of VAD (vincristine, doxorubicin, and dexamethasone) or TAD (thalidomide-AD) or PAD (bortezomib-AD) in national trials, followed by high-dose melphalan and autologous stem cell transplantation. For a period of 522 patient-years, 11 of the 195 patients (5.6%) developed arterial thrombosis. The highest incidence was seen during induction chemotherapy courses. Median age at onset of arterial thrombosis was 59 years (range, 43-65 years). Hypertension and smoking were significantly associated with arterial thrombosis with a relative risk of 11.7 (2.23-61.2) and 15.2 (1.78-130), respectively. Factor VIII levels (FVIII:C) correlated significantly with age (P = .02) and higher International Scoring System (ISS) stage (P = .001). A higher FVIII:C was associated with arterial thrombosis (hazard ratio [HR] = 1.85; 95% confidence interval [CI] = 0.99-3.47) after adjustment for age, ISS score, and assigned treatment arm. MM patients have an increased risk for arterial thrombotic events during and after induction chemotherapy. Hypertension, smoking, and high factor VIII levels, possibly reflecting disease activity, contribute to the risk of arterial thrombosis.

Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia (Article)

2010-06-01T00:00:00Z

Abstract. BACKGROUND: In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study. DESIGN AND METHODS: Having reported feasibility previously, we hereby report the efficacy of escalated imatinib (200 mg, 400 mg, 600 mg or 800 mg) in combination with two cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1 to 7) in 162 patients with chronic myeloid leukemia. RESULTS: With a median follow-up of 55 months, the 5-year cumulative incidences of complete cytogenetic response, major molecular response, and complete molecular response were 89%, 71%, and 53%, respectively. A higher Sokal risk score was inversely associated with complete cytogenetic response (hazard ratio of 0.63; 95% confidence interval, 0.50-0.79, P<0.001). A higher dose of imatinib and a higher dose of cytarabine were associated with increased complete molecular response with hazard ratios of 1.60 (95% confidence interval, 0.96-2.68, P=0.07) and 1.66 (95% confidence interval, 1.02-2.72, P=0.04), respectively. Progression-free survival and overall survival rates at 5 years were 92% and 96%, respectively. Achieving a major molecular response at 1 year was associated with complete absence of progression and a probability of achieving a complete molecular response of 89%. CONCLUSIONS: The addition of intravenous cytarabine to imatinib as upfront therapy for patients with chronic myeloid leukemia is associated with a high rate of complete molecular responses (Clinicaltrials.Gov Identifier: NCT00028847).

Micro-RNA-15a and micro-RNA-16 expression and chromosome 13 deletions in multiple myeloma (Article)

2010-05-01T00:00:00Z

We have used copy number variation (CNV) analysis with SNP mapping arrays for miRNA-15a and miRNA-16-1 expression analysis in patients with multiple myeloma (MM) with or without deletion of chromosome 13q14. MiRNA-15a and miRNA-16 display a range of expression patterns in MM patients, independent of the chromosome 13 status. These findings suggest that genes other than miR-15a and miR-16 may explain the prognostic significance of 13q14 deletions.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management (Article)

2010-04-22T00:00:00Z

Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months.Leukemia advance online publication, 22 April 2010; doi:10.1038/leu.2010.60.

Gemtuzumab ozogamicin as postremission treatment inAMLat 60 years of age or more: results of a multicenter phase 3 study (Article)

2010-04-01T00:00:00Z

Abstract: In older patients with acute myeloid leukemia (AML), the prevention of relapse has remained one of the major therapeutic challenges, with more than 75% relapses after complete remission. The anti-CD33 immunotoxin conjugate gemtuzumab ozogamicin (GO) has shown antileukemic remission induction activity in patients with relapsed AML. Patients with AML or refractory anemia with excess blasts in first complete remission attained after intensive induction chemotherapy were randomized between 3 cycles of GO (6 mg/m(2) every 4 weeks) or no postremission therapy (control) to assess whether GO would improve outcome. The 2 treatment groups (113 patients receiving GO vs 119 control patients) were comparable with regard to age (60-78 years, median 67 years), performance status, and cytogenetics. A total of 110 of 113 received at least 1 cycle of GO, and 65 of 113 patients completed the 3 cycles. Premature discontinuation was mainly attributable to incomplete hematologic recovery or intercurrent relapse. Median time to recovery of platelets 50 x 10(9)/L and neutrophils 0.5 x 10(9)/L after GO was 14 days and 20 days. Nonhematologic toxicities were mild overall, but there was 1 toxic death caused by liver failure. There were no significant differences between both treatment groups with regard to relapse probabilities, nonrelapse mortality, overall survival, or disease-free survival (17% vs 16% at 5 years). Postremission treatment with GO in older AML patients does not provide benefits regarding any clinical end points. The HOVON-43 study is registered at The Netherlands Trial Registry (number NTR212) and at http://www.controlled-trials.com as ISRCTN77039377.

A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma (Article)

2010-02-11T00:00:00Z

The phase 3 trial HOVON-50 was designed to evaluate the effect of thalidomide during induction treatment and as maintenance in patients with multiple myeloma who were transplant candidates. A total of 556 patients was randomly assigned to arm A: 3 cycles of vincristine, adriamycin, and dexamethasone, or to arm B: thalidomide 200 mg orally, days 1 to 28 plus adriamycin and dexamethasone. After induction therapy and stem cell mobilization, patients were to receive high-dose melphalan, 200 mg/m2, followed by maintenance with α-interferon (arm A) or thalidomide 50 mg daily (arm B). Thalidomide significantly improved overall response rate as well as quality of the response before and after high dose melphalan. Best overall response rate on protocol was 88% and 79% (P = .005), at least very good partial remission 66% and 54% (P = .005), and complete remission 31% and 23% (P = .04), respectively, in favor of the thalidomide arm. Thalidomide also significantly improved event-free survival from median 22 months to 34 months (P < .001), and prolonged progression free from median 25 months to 34 months (P < .001). Median survival was longer in the thalidomide arm, 73 versus 60 months; however, this difference was not significant (P = .77). Patients randomized to thalidomide had strongly reduced survival after relapse. This trial was registered on www.controlled-trials.com as ISRCTN06413384.

Current multiple myeloma treatment strategies with novel agents: A European perspective (Article)

2010-02-05T00:00:00Z

The treatment of multiple myeloma (MM) has undergone significant developments in recent years. The availability of the novel agents thalidomide, bortezomib, and lenalidomide has expanded treatment options and has improved the outcome of patients with MM. Following the introduction of these agents in the relapsed/refractory setting, they are also undergoing investigation in the initial treatment of MM. A number of phase III trials have demonstrated the efficacy of novel agent combinations in the transplant and nontransplant settings, and based on these results standard induction regimens are being challenged and replaced. In the transplant setting, a number of newer induction regimens are now available that have been shown to be superior to the vincristine, doxorubicin, and dexamethasone regimen. Similarly, in the front-line treatment of patients not eligible for transplantation, regimens incorporating novel agents have been found to be superior to the traditional melphalan plus prednisone regimen. Importantly, some of the novel agents appear to be active in patients with high-risk disease, such as adverse cytogenetic features, and certain comorbidities, such as renal impairment. This review presents an overview of the most recent data with these novel agents and summarizes European treatment practices incorporating the novel agents.

Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell collection following initial therapy with thalidomide-, lenalidomide-, or bortezomib-containing regimens (Article)

2009-11-20T00:00:00Z

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells.An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.

A new co-operative group: The European Myeloma Network Trialist Group (Article)

2009-11-11T00:00:00Z

Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma (Article)

2009-11-01T00:00:00Z

This subgroup analysis of the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial examined whether prior exposure to specific therapies affected the relative efficacy of bortezomib versus dexamethasone in relapsed/refractory myeloma. Time to progression and overall survival were superior with bortezomib in all subgroups, with no evidence of interaction between any prior therapies and assignment to study therapy. Patients with prior thalidomide exposure had worse outcomes overall, but neither prior thalidomide nor prior autologous stem cell transplantation affected the relative efficacy of bortezomib versus dexamethasone. These results confirm the superiority of bortezomib over dexamethasone, regardless of prior exposure to specific therapies (clinicaltrials.gov: NCT00048230).

Hematology: Lenalidomide plus dexamethasone is effective in multiple myeloma. (Article)

2009-10-26T00:00:00Z

A prospective subgroup analysis of two prospective, randomized, double-blind, placebo-controlled phase III clinical trials showed that the combination of lenalidomide plus dexamethasone is superior to dexamethasone alone in patients with relapsed or refractory multiple myeloma who had been previously treated with thalidomide; the implications for clinical practice are discussed.

The use of bisphosphonates in multiple myeloma: Recommendations of an expert panel on behalf of the European Myeloma Network (Article)

2009-10-01T00:00:00Z

Background: Bisphosphonates (BPs) prevent, reduce, and delay multiple myeloma (MM)-related skeletal complications. Intravenous pamidronate and zoledronic acid, and oral clodronate are used for the management of MM bone disease. The purpose of this paper is to review the current evidence for the use of BPs in MM and provide European Union-specific recommendations to support the clinical practice of treating myeloma bone disease. Design and methods: An interdisciplinary, expert panel of specialists on MM and myeloma-related bone disease convened for a face-to-face meeting to review and assess the evidence and develop the recommendations. The panel reviewed and graded the evidence available from randomized clinical trials, clinical practice guidelines, and the body of published literature. Where published data were weak or unavailable, the panel used their own clinical experience to put forward recommendations based solely on their expert opinions. Results: The panel recommends the use of BPs in MM patients suffering from lytic bone disease or severe osteoporosis. Intravenous administration may be preferable; however, oral administration can be considered for patients unable to make hospital visits. Dosing should follow approved indications with adjustments if necessary. In general, BPs are well tolerated, but preventive steps should be taken to avoid renal impairment and osteonecrosis of the jaw (ONJ). The panel agrees that BPs should be given for 2 years, but this may be extended if there is evidence of active myeloma bone disease. Initial therapy of ONJ should include discontinuation of BPs until healing occurs. BPs should be restarted if there is disease progression. Conclusions: BPs are an essential component of MM therapy for minimizing skeletal morbidity. Recent retrospective data indicate that a modified dosing regimen and preventive measures can greatly reduce the incidence of ONJ.

High-dose daunorubicin in older patients with acute myeloid leukemia (Article)

2009-09-24T00:00:00Z

BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P = 0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P = 0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.) Copyright

International myeloma working group (IMWG) consensus statement and guidelines regarding the current status of stem cell collection and high-dose therapy for multiple myeloma and the role of plerixafor (AMD 3100) (Article)

2009-06-26T00:00:00Z

Multiple myeloma is the most common indication for high-dose chemotherapy with autologous stem cell support (ASCT) in North America today. Stem cell procurement for ASCT has most commonly been performed with stem cell mobilization using colony-stimulating factors with or without prior chemotherapy. The target CD34+ cell dose to be collected as well as the number of apheresis performed varies throughout the country, but a minimum of 2 million CD34+ cells/kg has been traditionally used for the support of one cycle of high-dose therapy. With the advent of plerixafor (AMD3100) (a novel stem cell mobilization agent), it is pertinent to review the current status of stem cell mobilization for myeloma as well as the role of autologous stem cell transplantation in this disease. On June 1, 2008, a panel of experts was convened by the International Myeloma Foundation to address issues regarding stem cell mobilization and autologous transplantation in myeloma in the context of new therapies. The panel was asked to discuss a variety of issues regarding stem cell collection and transplantation in myeloma especially with the arrival of plerixafor. Herein, is a summary of their deliberations and conclusions.

International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation (Article)

2009-06-08T00:00:00Z

In 2005, the first guidelines were published on the management of patients with multiple myeloma (MM). An expert panel reviewed the currently available literature as the basis for a set of revised and updated consensus guidelines for the diagnosis and management of patients with MM who are not eligible for autologous stem cell transplantation. Here we present recommendations on the diagnosis, treatment of newly diagnosed non-transplant-eligible patients and the management of complications occurring during induction therapy among these patients. These guidelines will aid the physician in daily clinical practice and will ensure optimal care for patients with MM.

Reply to C.A. Dasanu et al (Article)

2009-05-01T00:00:00Z

Interstitial pneumonitis caused by pneumocystis jirovecii pneumonia (PCP) during bortezomib treatment (Article)

2009-04-01T00:00:00Z

Front-Line Treatment in Younger Patients With Multiple Myeloma (Article)

2009-04-01T00:00:00Z

The treatment of newly diagnosed myeloma has evolved rapidly. The choice of initial therapy depends on eligibility for stem cell transplantation, as well as baseline risk factors. Eligibility for transplantation is important since the choice of initial therapy is primarily melphalan-based in patients who are not candidates for transplant, while melphalan-containing regimens are avoided as induction therapy in transplant candidates. An assessment of risk based on independent prognostic markers is important mainly for prognosis but may have some value in choice of initial therapy. For example, bortezomib-based regimens may have particular value in patients with certain high-risk features. This review discusses the current status of front-line therapy in younger patients with myeloma who are candidates for stem cell transplantation.

Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: Impact of a dose-modification guideline (Article)

2009-03-01T00:00:00Z

The frequency, characteristics and reversibility of bortezomib-associated peripheral neuropathy were evaluated in the phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in patients with relapsed myeloma, and the impact of a dose-modification guideline on peripheral neuropathy severity and reversibility was assessed. Patients received bortezomib 1·3 mg/m2 (days 1, 4, 8, 11, eight 21-d cycles, then days 1, 8, 15, 22, three 35-d cycles); bortezomib was held, dose-reduced or discontinued depending on peripheral neuropathy severity, according to a protocol-specified dose-modification guideline. Overall, 124/331 patients (37%) had treatment-emergent peripheral neuropathy, including 30 (9%) with grade ≥3; incidence and severity were not affected by age, number/type of prior therapies, baseline glycosylated haemoglobin level, or diabetes history. Grade ≥3 incidence appeared lower versus phase II trials (13%) that did not specifically provide dose-modification guidelines. Of patients with grade ≥2 peripheral neuropathy, 58/91 (64%) experienced improvement or resolution to baseline at a median of 110 d, including 49/72 (68%) who had dose modification versus 9/19 (47%) who did not. Efficacy did not appear adversely affected by dose modification for grade ≥2 peripheral neuropathy. Bortezomib-associated peripheral neuropathy is manageable and reversible in most patients with relapsed myeloma. Dose modification using a specific guideline improves peripheral neuropathy management without adversely affecting outcome.

Lenalidomide in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma (Article)

2009-03-01T00:00:00Z

Recent studies have shown a clinical benefit of lenalidomide, an oral immunomodulatory drug, plus dexamethasone in patients with relapsed/refractory multiple myeloma (MM). The most common grade 3-4 adverse events were cytopenias, fatigue, muscle cramps, rash, infection, insomnia, and venous thromboembolism. Lenalidomide in combination with dexamethasone has been approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of patients with MM who have received at least one prior therapy. An expert panel reviewed the efficacy and toxicity of lenalidomide plus dexamethasone, and provided recommendations on the management of patients receiving this treatment. Patient selection is straightforward, as prognostic factors do not appear to heavily influence efficacy. In addition, the panel agreed on strategies for the management of side effects. The recommendations presented here will aid the safe administration of lenalidomide, and avoid unnecessary dose reduction and discontinuation, thus assuring the best efficacy of treatment.

Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: A prospective sibling donor versus no-donor comparison (Article)

2009-02-05T00:00:00Z

While commonly accepted in poor-risk acute lymphoblastic leukemia (ALL), the role of allogeneic hematopoietic stem cell transplantation (allo-SCT) is still disputed in adult patients with standard-risk ALL. We evaluated outcome of patients with ALL in first complete remission (CR1), according to a sibling donor versus no-donor comparison. Eligible patients (433) were entered in 2 consecutive, prospective studies, of whom 288 (67%) were younger than 55 years, in CR1, and eligible to receive consolidation by either an autologous SCT or an allo-SCT. Allo-SCT was performed in 91 of 96 patients with a compatible sibling donor. Cumulative incidences of relapse at 5 years were, respectively, 24 and 55% for patients with a donor versus those without a donor (hazard ratio [HR], 0.37; 0.23-0.60; P < .001). Nonrelapse mortality estimated 16% (± 4) at 5 years after allo-SCT. As a result, disease-free survival (DFS) at 5 years was significantly better in the donor group: 60 versus 42% in the no-donor group (HR: 0.60; 0.41-0.89; P= .01). After risk-group analysis, improved outcome was more pronounced in standard-risk patients with a donor, who experienced an overall survival of 69% at 5 years (P = .05). In conclusion, standard-risk ALL patients with a sibling donor may show favorable survival following SCT, due to both a strong reduction of relapse and a modest nonrelapse mortality. This trial is registered with http://www.trialregister.nl under trial ID NTR228.

International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders (Article)

2009-01-01T00:00:00Z

The serum immunoglobulin-free light chain (FLC) assay measures levels of free κ and λ immunoglobulin light chains. There are three major indications for the FLC assay in the evaluation and management of multiple myeloma and related plasma cell disorders (PCD). In the context of screening, the serum FLC assay in combination with serum protein electrophoresis (PEL) and immunofixation yields high sensitivity, and negates the need for 24-h urine studies for diagnoses other than light chain amyloidosis (AL). Second, the baseline FLC measurement is of major prognostic value in virtually every PCD. Third, the FLC assay allows for quantitative monitoring of patients with oligosecretory PCD, including AL, oligosecretory myeloma and nearly two-thirds of patients who had previously been deemed to have non-secretory myeloma. In AL patients, serial FLC measurements outperform PEL and immunofixation. In oligosecretory myeloma patients, although not formally validated, serial FLC measurements reduce the need for frequent bone marrow biopsies. In contrast, there are no data to support using FLC assay in place of 24-h urine PEL for monitoring or for serial measurements in PCD with measurable disease by serum or urine PEL. This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD.

Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping (Article)

2008-12-15T00:00:00Z

A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism isamajor concernin the treatment of patients with multiple myeloma with tha-lidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP) - based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in "functional regions" within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and side effects associated with myeloma therapy. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair, and cytokine balance. The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related micro-environment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332.

Pegylated liposomal doxorubicin plus bortezomib in relapsed or refractory multiple myeloma: Efficacy and safety in patients with renal function impairment (Article)

2008-12-01T00:00:00Z

A retrospective analysis was undertaken of patients (n = 193) with renal insufficiency (creatinine clearance [CrCl] < 60 mL/min) from a phase III trial comparing bortezomib ± pegylated liposomal doxorubicin (PLD) in relapsed/refractory myeloma (n = 646). The response rate (49% vs. 42%) and median time to disease progression (331 days vs. 199 days) were comparable or slightly better for patients with renal insufficiency treated with PLD/bortezomib compared with patients treated with bortezomib alone. There was a steady, clinically meaningful improvement in renal function for patients with renal insufficiency in both treatment arms. However, patients with impaired renal function were at a slightly increased risk of a drug-related serious adverse event (28% vs. 19% for CrCl < 60 and ≥ 60 mL/min, respectively).

Treatment of diffuse large B-cell lymphoma in the elderly: strategies integrating oncogeriatric themes. (Article)

2008-12-01T00:00:00Z

With an increasingly aged population, many patients will present with diffuse large B-cell lymphoma in their 70s and 80s. Recently, several randomized studies have confirmed the benefit of rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and showed a substantial improvement in the outcome of fit elderly patients. This article reviews the efficacy and toxicity of the current treatment regimens applied for the treatment of diffuse large B-cell lymphoma in elderly patients and provides practical recommendations for the management of these patients.

Bortezomib is associated with better health-related quality of life than high-dose dexamethasone in patients with relapsed multiple myeloma: Results from the APEX study (Article)

2008-11-01T00:00:00Z

Health-related quality of life (HRQL) was prospectively measured during the phase III APEX trial of bortezomib versus dexamethasone in relapsed multiple myeloma patients. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core (QLQ-C30) and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (NTX) side-effects questionnaires were administered at baseline and every 6 weeks up to 42 weeks. Patients receiving bortezomib (1.3 mg/m2, days 1, 4, 8 and 11 for eight 3-week cycles, then days 1, 8, 15 and 22 for three 5-week cycles; n = 296) demonstrated significantly better mean Global Health Status over the study versus patients receiving dexamethasone (40 mg/d, days 1-4, 9-12, and 17-20 for four 5-week cycles, then days 1-4 only for five 4-week cycles; n = 302), plus significantly better physical health, role, cognitive, and emotional functioning scores, lower dyspnoea and sleep symptom scores, and better NTX questionnaire score, using multiple imputation to account for missing data. Results were similar using available-data analyses. Sensitivity analyses suggested that improved HRQL with bortezomib is at least partially explained by improved survival. These results show that bortezomib was associated with significantly better multidimensional HRQL compared with dexamethasone, consistent with the better clinical outcomes seen with bortezomib.

Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma (Article)

2008-10-01T00:00:00Z

Haematological toxicities and thromboembolic (TE) events are common complications of myeloma therapy. TE risk may be elevated with combination regimens, notably thalidomide/lenalidomide plus high-dose dexamethasone; concomitant erythropoietin appears to further increase the risk with lenalidomide-dexamethasone. We characterised thrombocytopenia and neutropenia in the phase 3 APEX (Assessment of Proteasome Inhibition for Extending Remissions) study of bortezomib versus high-dose dexamethasone in relapsed myeloma, and calculated the incidences of deep-vein thrombosis (DVT)/pulmonary embolism (PE) with: bortezomib or dexamethasone ± erythropoietin in APEX; bortezomib ± dexamethasone ± erythropoietin in two phase 2 studies of relapsed/refractory myeloma. Bortezomib-associated thrombocytopenia and neutropenia were transient, predictable and manageable; mean platelet and neutrophil counts followed a cyclical pattern, and improved over the treatment course. Grade 3/4 thrombocytopenia incidence was higher with bortezomib versus dexamethasone (26%/4% vs. 5%/1%), but significant bleeding events were comparable (4% vs. 5%). DVT/PE incidence was low (≤3.1%) in all analyses; addition of dexamethasone/erythropoietin did not affect TE risk. In APEX, TE risk appeared lower with bortezomib versus dexamethasone. Bortezomib caused transient and cyclical thrombocytopenia and was not associated with elevated TE risk, alone or with dexamethasone ± erythropoietin. Preliminary data suggest bortezomib may reduce the thrombogenic potential of combination regimens via inhibition of platelet function or other mechanism-specific effects on coagulation.

The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma (Article)

2008-10-01T00:00:00Z

Quality of response is associated with prolonged overall survival (OS) in newly diagnosed multiple myeloma patients. This cohort study within the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of bortezomib versus dexamethasone in relapsed myeloma assessed the relationship between quality of response to bortezomib (n = 315) and clinical benefit. Treatment-free interval (TFI), time to alternative therapy (TTAT), time to progression (TTP) and OS were assessed in response-evaluable patients in the bortezomib arm in cohorts defined by achievement of complete response (CR; n = 27), very good partial response (VGPR; n = 31), partial response (PR; n = 77), minimal response (MR; n = 21) or non-response (NR, including stable and progressive disease; n = 159). CR was associated with significantly longer median TFI (24.1 vs. 6.9/6.4 months) and TTAT (27.1 vs. 13.6/14 months) versus VGPR/PR. Median TTP was similar in CR, VGPR and PR cohorts; median OS was not reached. Patients achieving MR appeared to have prolonged median TFI (3.8 vs. 2.3 months), TTAT (8.7 vs. 6.2 months), TTP (4.9 vs. 2.8 months) and OS (24.9 vs. 18.7 months) versus NR. In conclusion, bortezomib had substantial activity in relapsed myeloma patients; CR may be a surrogate marker for significant clinical benefit with bortezomib. MR appeared to be valid as a separate response category in this setting.

Gastrointestinal plasmacytomas: A rare finding with important consequences (Article)

2008-09-01T00:00:00Z

Prospective evaluation of coagulopathy in multiple myeloma patients before, during and after various chemotherapeutic regimens (Article)

2008-07-01T00:00:00Z

Background: Venous thromboembolism (VTE) occurs frequently in multiple myeloma patients, especially during induction treatment with thalidomide in combination with anthracyclines and/or dexamethasone. Several coagulation abnormalities have been described in untreated myeloma patients, but these have not been prospectively evaluated during and after treatment. Patients and methods: We performed a prospective study in 138 multiple myeloma patients in whom coagulation factor levels were evaluated longitudinally before, during induction and after intensification. Patients were randomized to induction treatment consisting of adriamycin and dexamethason, in combination with either vincristin (VAD), thalidomide (TAD), or bortezomib (PAD) followed by high-dose melphalan (HDM) and autologous stem cell transplant (ASCT). Results: Factor VIII:C (FVIII:C) and von Willebrand factor (VWF) were significantly elevated before treatment (median FVIII:C 2.26 U/ml, VWF:Ag 1.95 U/ml). Irrespective of the type of induction regimen, these variables increased strongly during induction therapy (FVIII:C 2.55 U/ml and VWF:Ag 2.96 U/ml). Fibrinogen also showed a significant increase after induction therapy (3.5 g/l pre-treatment and 4.0 g/l after treatment, respectively, P < 0.001). This was significantly higher in TAD than VAD treated patients. Three to six month after ASCT levels of VWF and FVIII:C had decreased to values lower than observed before treatment (1.71 and 1.67 U/ml respectively). There was no correlation between the increased levels at start and the response of multiple myeloma to treatment. High levels of VWF, fibrinogen and FVIII:C before start of treatment were significantly associated with mortality. Fourteen patients (10%) developed a venous thrombotic event (VTE). The coagulation factor abnormalities before and during treatment were not associated with the development of VTE. Conclusion: During induction treatment several changes in coagulation factor levels are observed, which may result in a prothrombotic state. Larger studies are required to establish whether the changes in these coagulation factors during induction treatment contribute to the increased risk of venous thromboembolism in multiple myeloma patients.

First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: Results of a phase 1/2 trial (Article)

2008-06-15T00:00:00Z

Ofatumumab is a unique monoclonal antibody that targets a distinct small loop epitope on the CD20 molecule. Preclinical data show that ofatumumab is active against B-cell lymphoma/chronic lymphocytic leukemia cells with low CD20-antigen density and high expression of complement inhibitory molecules. In a phase 1/2 trial evaluating safety and efficacy of ofatumumab in relapsed or refractory follicular non-Hodgkin lymphoma (FL) grade 1 or 2, 4 dose groups of 10 patients received 4 weekly infusions of 300, 500, 700, or 1000 mg. Patients had a median of 2 prior FL therapies and 13% had elevated lactate dehydrogenase. No safety concerns or maximum tolerated dose was identified. A total of 274 adverse events were reported; 190 were judged related to ofatumumab, most occurring on the first infusion day with Common Terminology Criteria grade 1 or 2. Eight related events were grade 3. Treatment caused immediate and profound B-cell depletion, and 65% of patients reverted to negative BCL2 status. Clinical response rates ranged from 20% to 63%. Median time to progression for all patients/ responders was 8.8/ 32.6 months, and median duration of response was 29.9 months at a median/ maximum follow-up of 9.2/38.6 months. Ofatumumab is currently being evaluated in patients with rituximab-refractory FL. This trial was registered at www.clinicaltrials.gov as #NCT00092274.

Lenalidomide: A new therapy for multiple myeloma (Article)

2008-05-01T00:00:00Z

The last decade has seen rapid evolution in the management of multiple myeloma. Cytogenetic, molecular, and proteomic techniques have led to a better understanding of the pathophysiology and prognostic markers of this heterogeneous malignancy. New immunomodulatory drugs, such as lenalidomide, which interrupt myeloma growth and survival pathways have entered into clinical usage. Combined with dexamethasone, oral lenalidomide has proved to be highly effective in patients whose disease has become resistant to conventional therapy. Currently, several clinical trials are ongoing in order to define the optimal use of this new agent and its combinations across the spectrum of patients with myeloma. Whether the ultimate outcome of future research will be a single-treatment solution for all patients, or whether treatments will become better-tailored to the individual (based on prognostic markers and pre-existing co-morbidities) has yet to be determined.

Thalidomide for treatment of multiple myeloma: 10 years later (Article)

2008-04-15T00:00:00Z

Thalidomide, bortezomib, and lenalidomide have recently changed the treatment paradigm of myeloma. In young, newly diagnosed patients, the combination of thalidomide and dexamethasone has been widely used as induction treatment before autologous stem cell transplantation (ASCT). In 2 randomized studies, consolidation or maintenance with low-dose thalidomide has extended both progression-free and overall survival in patients who underwent ASCT at diagnosis. In elderly, newly diagnosed patients, 3 independent randomized studies have reported that the oral combination of melphalan and prednisone plus thalidomide (MPT) is better than the standard melphalan and prednisone (MP). These studies have shown better progression-free survival, and 2 have shown improved overall survival for patients assigned to MPT. In refractory-relapsed disease, combinations including thalidomide with dexa-methasone, melphalan, doxorubicin, or cyclophosphamide have been extensively investigated. The risks of side effects are greater when thalidomide is used in combination with other drugs. Thromboembo lism and peripheral neuropathy are the major concern. The introduction of anticoagulant prophylaxis has reduced the rate of thromboembolism to less than 10%. Immediate thalidomide dose reduction or discontinuation when paresthesia is complicated by pain or motor deficit has decreased the severity of neuropathy. Future studies will define the most effective or the best sequence of combinations which could improve life expectancy.

Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: An analysis of 10 549 patients from the International Myeloma Working Group (Article)

2008-04-15T00:00:00Z

We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P< .001) both after conventional (median, 4.5 years vs 3.3 years; P < .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.

Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy (Article)

2008-04-01T00:00:00Z

BACKGROUND. Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current analysis, they determined 1) the efficacy of PLD plus bortezomib versus bortezomib alone in patients with MM who had failed on prior thalidomide/lenalidomide (immunomodulatory drug [IMiD]) treatment and 2) the efficacy and safety profile of PLD plus bortezomib in IMiD-exposed and IMiD-naive patients. METHODS. This prespecified analysis included 646 patients who were randomized to receive either PLD with bortezomib (n = 324; 194 IMiD-naive patients and 130 IMiD-exposed patients) or bortezomib alone (n = 322; 184 IMiD-naive patients and 138 IMiD-exposed patients). The primary efficacy endpoint was TTP, and secondary endpoints included overall survival, response rate, and safety. RESULTS. The median TTP was significantly longer with PLD plus bortezomib compared with bortezomib alone in IMiD-exposed patients (270 days vs 205 days). No statistical difference was noted with respect to TTP between IMiD-naive (295 days) versus IMiD-exposed (270 days) subgroups who received PLD plus bortezomib. A sustained trend favoring combination therapy was observed in analyses of overall survival. In patients who achieved a response, the response duration was comparable for IMiD-naive patients and IMiD-exposed patients in the combination treatment group and lasted a median of 310 days and 319 days, respectively. The incidence of grade 3/4 adverse events was similar with PLD plus bortezomib regardless of prior IMiD exposure. CONCLUSIONS. A significantly prolonged TTP was observed with combined PLD plus bortezomib combination therapy compared with bortezomib alone despite prior IMiD exposure. For the combination treatment arm in the IMiD-naive and IMiD-exposed subgroups, TTP was comparable. Similarly, the safety profile of the PLD plus bortezomib combination was unaltered by prior IMiD exposure.

Efficacy and safety of bortezomib in patients with renal impairment: Results from the APEX phase 3 study (Article)

2008-04-01T00:00:00Z

Renal impairment is associated with poor prognosis in multiple myeloma (MM). This subgroup analysis of the phase 3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study of bortezomib vs high-dose dexamethasone assessed efficacy and safety in patients with relapsed MM with varying degrees of renal impairment (creatinine clearance (CrCl) <30, 30-50, 51-80 and >80 ml min-1). Time to progression (TTP), overall survival (OS) and safety were compared between subgroups with CrCl >50 ml min-1(severe-to-moderate) and >50 ml min-1(no/mild impairment). Response rates with bortezomib were similar (36-47%) and time to response rapid (0.7-1.6 months) across subgroups. Although the trend was toward shorter TTP/OS in bortezomib patients with severe-to-moderate vs no/mild impairment, differences were not significant. OS was significantly shorter in dexamethasone patients with CrCl >50 vs >50ml min-1(P=0.003), indicating that bortezomib is more effective than dexamethasone in overcoming the detrimental effect of renal impairment. Safety profile of bortezomib was comparable between subgroups. With dexamethasone, grade 3/4 adverse events (AEs), serious AEs and discontinuations for AEs were significantly elevated in patients with CrCl >50 vs >50 ml min-1. These results indicate that bortezomib is active and well tolerated in patients with relapsed MM with varying degrees of renal insufficiency. Efficacy/safety were not substantially affected by severe-to-moderate vs no/mild impairment.

Dose-finding study of imatinib in combination with intravenous cytarabine: Feasibility in newly diagnosed patients with chronic myeloid leukemia (Article)

2008-03-01T00:00:00Z

The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytara- bine (200 mg/m2or 1000 mg/m2days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose- limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which werecaused bystreptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m2) prolonged time to neutro- phil recovery and platelet recovery compared with a standard dose (200 mg/m2). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytara- bine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cy-togenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible. This study was registered at www.kankerbestrijding.nl as no. CKTO- 2001-03.

Anti-müllerian hormone as a marker of ovarian function in women after chemotherapy and radiotherapy for haematological malignancies (Article)

2008-03-01T00:00:00Z

BACKGROUND: In female cancer survivors, the accelerated loss of primordial follicles as a result of gonadal damage may lead to premature ovarian failure (POF). However, the extent of the damage is unpredictable. Anti-Müllerian hormone (AMH) constitutes a sensitive marker of ovarian reserve. Serum AMH levels were measured to assess sub-clinical ovarian damage in patients treated with gonadotoxic therapy. METHODS: In 25 patients with haematological malignancies, serum AMH concentrations were measured prior to and after cancer therapy and were compared with normo-ovulatory controls. RESULTS: In all patients, AMH concentrations were lower than controls prior to treatment. Thirteen patients were treated with multi-drug chemotherapy. Although in most patients treated with chemotherapy menstrual cyclicity was restored, median serum AMH levels were lower than in controls. Twelve patients had stem cell transplantation (SCT) after total body irradiation. They all developed POF and their serum AMH concentrations were undetectable. CONCLUSIONS: Female cancer survivors treated with SCT all developed POF. Hence, in these patients fertility preservation should be considered. In patients treated with chemotherapy, ovarian reserve seems to be compromised as well.

Report of the European Myeloma Network on multiparametric flow cytometry in multiple myeloma and related disorders (Article)

2008-03-01T00:00:00Z

The European Myeloma Network (EMN) organized two flow cytometry workshops. The first aimed to identify specific indications for flow cytometry in patients with monoclonal gammopathies, and consensus technical approaches through a questionnaire-based review of current practice in participating laboratories. The second aimed to resolve outstanding technical issues and develop a consensus approach to analysis of plasma cells. The primary clinical applications identified were: differential diagnosis of neoplastic plasma cell disorders from reactive plasmacytosis; identifying risk of progression in patients with MGUS and detecting minimal residual disease. A range of technical recommendations were identified, including: 1) CD38, CD138 and CD45 should all be included in at least one tube for plasma cell identification and enumeration. The primary gate should be based on CD38 vs. CD138 expression; 2) after treatment, clonality assessment is only likely to be informative when combined with immunophenotype to detect abnormal cells. Flow cytometry is suitable for demonstrating a stringent complete remission; 3) for detection of abnormal plasma cells, a minimal panel should include CD19 and CD56. A preferred panel would also include CD20, CD117, CD28 and CD27; 4) discrepancies between the percentage of plasma cells detected by flow cytometry and morphology are primarily related to sample quality and it is, therefore, important to determine that marrow elements are present in follow-up samples, particularly normal plasma cells in MRD negative cases.

Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma (Article)

2008-02-01T00:00:00Z

The incidence of venous thromboembolism (VTE) is more than 1‰ annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with ≤1 risk factor for VTE. LMWH (equivalent to enoxaparin 40mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.

Extended follow-up of a phase 3 trial in relapsed multiple myeloma: Final time-to-event results of the APEX trial (Article)

2007-11-15T00:00:00Z

Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).

Hepatotoxicity of oral and intravenous voriconazole in relation to cytochrome P450 polymorphisms (Article)

2007-11-01T00:00:00Z

Objectives: Voriconazole, like all other antifungals of the azole group, is potentially hepatotoxic. A large interpatient variability of liver enzyme elevations during oral or intravenous (iv) voriconazole administration is observed. This interpatient variability may be explained by differences in voriconazole metabolism because of cytochrome P450 polymorphisms. We examined the relationship between cytochrome P450 polymorphisms and hepatotoxicity in immunocompromised patients predominantly receiving oral formulations of voriconazole. Methods: In a single institution retrospective study of 86 immunocompromised patients receiving oral (n = 74) or iv (n = 12) voriconazole, we studied the influence of cytochrome P450 polymorphisms (CYP2C19, CYP2C9 and CYP3A5) on the maximum bilirubin and serum liver enzyme levels [alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), serum aspartate aminotransferase and serum alanine aminotransferase] and their respective common toxicity criteria scores (CTC-scores). Results: Median serum bilirubin as well as the level of all other liver enzymes increased during voriconazole treatment. A decline in CTC-score was observed in zero (0%) to six (7%) patients; an increase in CTC-score was demonstrated in 36 (42%) to 54 (63%) patients. No statistically significant differences in maximum value or maximum increase of liver enzymes or CTC-score in relation to cytochrome P450 polymorphisms were observed. Only a trend towards higher maximum CTC-score of GGT for wild-type of CYP2C9 was observed (P = 0.046). Conclusions: No significant relationship between CYP2C9, CYP2C19 or CYP3A5 polymorphisms and serum liver enzyme levels was observed in patients treated with voriconazole.

Predictive value of alkaline phosphatase for response and time to progression in bortezomib-treated multiple myeloma patients (Article)

2007-09-01T00:00:00Z

Myeloma bone disease is characterized by osteolytic destruction associated with suppressed osteoblastic activity. Using data from the APEX (Richardson et al., N Engl J Med 2005;352:2487-2498) study, we have assessed the relationship of changes in alkaline phosphatase (ALP) levels during bortezomib therapy with response and time to progression on this therapy. The percentage of ALP increments in responders (complete and partial response) and nonresponders was analyzed at different thresholds and time points. For all bortezomib-treated patients enrolled in the trial (N = 333), at least a 25% increase in ALP from the baseline at 6 week was the most powerful predictor of treatment response (P < 0.0001) and time to progression (206 vs. 169 days) relative to patients with less than a 25% increase in ALP (P = 0.01). Markers of osteoblastic activation may predict quality and duration of response in multiple myeloma. In addition, our data suggest that bone anabolism could inhibit myeloma growth.

Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: Long-term follow-up of the Dutch Cooperative Group HOVON 24 trial (Article)

2007-07-01T00:00:00Z

Background and Objectives: The Dutch-Belgian HOVON group performed a randomized phase 3 trial to compare single non-myeloablative intensive treatment with double, intensive treatment in previously untreated patients with multiple myeloma (MM). Design and Methods: Three hundred and three patients with stage II/III MM were randomized after VAD induction chemotherapy to receive two cycles of non-myeloablative intermediate-dose melphalan (70 mg/m2) (single treatment) or the same regimen followed by cyclophosphamide 120 mg/kg iv plus total body irradiation (TBI) 9 Gy and autologous stem cell transplantation (double, intensive treatment). In both treatment arms interferon alia was given as maintenance until relapse/progression. Results: A significantly higher proportion of patients achieved a complete remission (CR) on protocol treatment with double, intensive therapy (32% vs 13%, p<0.001). Double treatment produced better outcome in terms of event-free survival (median 22 vs 21 months, 28% vs 14% at 4 years and 15% vs 7% at 6 years after randomization; logrank p=0.013; univariate HR 0.74, 95% CI, 0.58-0.94), progression-free survival (median 27 vs 24 months, 33% vs 16% at 4 years, and 17% vs 9% at 6 years after randomization; logrank p=0.006; HR=0.71, 95% CI 0.56-0.91), but not overall survival (median 50 vs 55 months, 52% vs 56% at 4 years and 39% vs 36% at 6 years after randomization; logrank p=0.51; HR=1.10, 95% CI 0.83-1.46). The achievement of a CR had a favorable prognostic impact on event-free survival (HR=0.60, 95% CI=0.44 -0.82, p=0.001) and progression-free survival (HR=0.62, 95% CI=0.45 - 0.84, p=0.002). Interpretation and Conclusions: Double, intensive treatment resulted in a better CR rate, event-free survival and progression-free survival but not overall survival compared to single non-myeloablative treatment in previously untreated patients with multiple myeloma.

The expression of the Peripheral Cannabinoid receptor on cells of the immune system and Non-Hodgkin's lymphomas (Article)

2007-07-01T00:00:00Z

The peripheral cannabinoid receptor CB2 is expressed highly on normal human B-lymphocytes. C-terminal specific anti-CB2 antibody recognises a non-phosphorylated inactive receptor on naïve and resting B-lymphocytes. Another, N-terminal specific CB2 antibody, primarily recognises B-cells present in the germinal centres of secondary follicles in lymph nodes. We hypothesise that N-terminal specific CB2 antibody recognises activated CB2 receptors. In this study, we showed using these antibodies, that expression of CB2 is generally absent on T-lymphocytes in reactive, non-malignant human lymphoid tissues. Applying single and dual immunohistochemistry, CD23+follicular dendritic cells and a small but significant subpopulation of CD68+macrophages showed positive staining with the N-terminal specific CB2 antibody but not with the C-terminal specific CB2 antibody. This may indicate the presence of an active CB2 receptor on these cells with possible involvement in immunomodulation. In contrast to the low expression on normal T-cells, abundant levels of CB2 protein were present on T-non-Hodgkin's lymphomas (NHL). Moreover, in many B-NHL, high CB2 protein expression was found as well. In contrast to the distinct expression patterns in normal immune tissues using the two different CB2 antibodies, NHL specimens in general stained positively with both. We conclude that CB2 receptor expression pattern may be abnormal in NHL.

Prothrombotic coagulation abnormalities in patients with paraprotein-producing B-cell disorders (Article)

2007-07-01T00:00:00Z

Purpose: An increased incidence of thromboembolic complications has been observed in multiple myeloma (MM), especially when patients are treated with anthracycline-based chemotherapy. In patients with MM, plasma levels of several prothrombotic coagulation factors are increased, and this can contribute to the prothrombotic state of these patients. Recently, an increased thrombosis risk has also been described for other plasma cell disorders (PCDs), such as monoclonal gammopathy of uncertain significance (MGUS) and systemic amyloidosis. The aim of this study was to analyze prothrombotic coagulation disorders in patients with paraprotein-producing B-cell disorders, such as MGUS, systemic amyloidosis, Waldenstrom's macroglobulinemia, and MM. Patients and Methods: An increase in factor VIII and von Willebrand factor was observed in patients with MGUS and systemic amyloidosis that was similar to increases seen in patients with untreated MM. The highest levels were observed in patients with systemic amyloidosis. Results: We observed several coagulation abnormalities in patients with different PCDs. Conclusion: These prothrombotic changes in patients with MM, systemic amyloidosis, and Waldenström's macroglobulinemia might be causally related to the observed incidence of venous thromboembolism in these forms of PCDs.

Safety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma (Article)

2007-06-01T00:00:00Z

Adverse prognostic factors in multiple myeloma include advanced age, number of prior therapies, and higher International Staging System (ISS) disease stage. In the international, randomised, phase-3 Assessment of Proteasome Inhibition for Extending Remissions (APEX) study, bortezomib demonstrated significantly longer time to progression (TTP), higher response rates and improved survival compared with high-dose dexamethasone in patients with relapsed multiple myeloma following one to three prior therapies. In this APEX subgroup analysis, efficacy of bortezomib and dexamethasone was compared in elderly (age ≥65 years) and high-risk (>1 prior line of therapy; ISS stage II/III; refractory to prior therapy) patients. Bortezomib demonstrated substantial clinical activity in these patients. Response rate (34-40% vs. 13-19%), including complete response rate (5-8% vs. 0-1%), was significantly higher with bortezomib versus dexamethasone in all four subgroups. Similarly, median TTP was significantly longer with bortezomib versus dexamethasone, and 1-year survival probability was significantly higher in all subgroups. As in the total APEX population, rates of grade 3/4 adverse events were higher in bortezomib- versus dexamethasone-treated patients aged ≥65 years and with >1 prior line, while rates of serious adverse events were similar; toxicities generally proved manageable. Bortezomib should be considered an appropriate treatment for elderly and high-risk patients with relapsed multiple myeloma.

Thalidomide in newly diagnosed multiple myeloma: Influence of thalidomide treatment on peripheral blood stem cell collection yield (Article)

2007-06-01T00:00:00Z

In a phase III randomized, multicenter study, the German-speaking Myeloma-Multicenter Group (GMMG) and the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) group investigated the influence of thalidomide (Thal) on the outcome of peripheral blood stem cell (PBSC) collection in multiple myeloma (MM) before peripheral autologous blood stem cell transplantation (ABSCT). We analyzed the data of 398 myeloma patients after induction with Thal, doxorubicin and dexamethasone (TAD) in comparison with vincristine, doxorubicin and dexamethasone (VAD) followed by mobilization with cyclophosphamide, doxorubicin, dexamethasone (CAD) and PBSC collection. Within both the study groups, patients treated with TAD showed to collect significantly fewer CD34+cells compared with VAD (GMMG, TAD: median 9.8 × 106/kg; range 2.0-33.6; VAD: median 10.9 × 106/kg range 3.0-36.0; P=0.02) (HOVON, TAD: median 7.4 × 106/kg; range 2.0-33.0; VAD: median 9.4 × 106/kg; range 0.0-48.7; P=0.009). However, engraftment after peripheral autologous stem cell transplantation showed no difference between Thal and VAD groups. We conclude that Thal as a part of induction regimen is associated with better response rates (GMMG-HD3: CR/PR 79%, VAD: CR/PR 58%; HOVON-50: TAD: CR/PR 81%, VAD: CR/PR 61%), but significantly affects the yield of PBSC collection. Nevertheless, the number of total CD34+cells collected was sufficient for double autologous transplantation in 82% of the Thal patients, with at least 2.5 × 106/kg CD34+cells.

CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age (Article)

2007-05-01T00:00:00Z

Clinical resistance to chemotherapy in acute myeloid leukemia (AML) is associated with the expression of the multidrug resistance (MDR) proteins P-glycoprotein, encoded by the MDR1/ABCB1 gene, multidrug resistant-related protein (MRP/ABCC1), the lung resistance-related protein (LRP), or major vault protein (MVP), and the breast cancer resistance protein (BCRP/ABCG2). The clinical value of MDR1, MRP1, LRP/ MVP, and BCRP messenger RNA (mRNA) expression was prospectively studied in 154 newly diagnosed AML patients ≤60 years who were treated in a multicenter, randomized phase 3 trial. Expression of MDR1 and BCRP showed a negative whereas MRP1 and LRP showed a positive correlation with high white blood cell count (respectively, p<0.05, p<0.001,p<0.001 and p<0.001). Higher BCRP mRNA was associated with secondary AML (p<0.05). MDR1 and BCRP mRNA were highly significantly associated (p<0.001), as were MRP1 and LRP mRNA (p<0.001) expression. Univariate regression analyses revealed that CD34 expression, increasing MDR1 mRNA as well as MDR1/BCRP coexpression, were associated with a lower complete response (CR) rate and with worse event-free survival and overall survival. When adjusted for other prognostic actors, only CD34-related MDR1/BCRP coexpression remained significantly associated with a lower CR rate (p=0.03), thereby identifying a clinically resistant subgroup of elderly AML patients.

Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib (Article)

2007-04-15T00:00:00Z

The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents.

Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: A phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) (Article)

2007-04-01T00:00:00Z

Optimal dose and timing of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy for aggressive non-Hodgkin lymphoma (NHL) is still an unresolved issue. We assessed whether dose intensifications with cyclophosphamide and doxorubicin might improve outcome in younger patients with intermediate-risk aggressive NHL. Previously untreated patients were assigned to receive either 8 courses of standard CHOP (n = 239) or 6 courses of intensified (I)-CHOP (n = 238). Although there was a tendency in favor of I-CHOP for overall survival (OS), disease-free survival (DFS), and event-free survival (EFS), the differences were not significant. However, although these analyses were not planned, when the intermediate-risk group was divided into low-intermediate- and high-intermediate-risk patients according to the International Prognostic Index (IPI), low-intermediate-risk patients had improved 6-year OS (67% vs 52%; P = .05), DFS (58% vs 45%; P = .06), and EFS (41% vs 30%; P = .21) when they were treated with I-CHOP compared with standard CHOP. On the other hand, high-intermediate-risk patients seem to have no benefit from I-CHOP. Although clinically relevant side effects occurred more often in the I-CHOP arm, treatmen-trelated mortality was similar. These data suggest that I-CHOP might be preferable to standard CHOP in younger patients with low-intermediate-risk aggressive NHL.

Influence of genetic polymorphisms in CYP3A4, CYP3AS, GSTP1, GSTM1, GSTT1 and MDR1 genes on survival and therapy-related toxicity in multiple myeloma (Article)

2007-02-01T00:00:00Z

We investigated the role of single nucleotide polymorphisms in genes encoding for drug-metabolizing enzymes in 209 newly diagnosed multiple myeloma patients included in a clinical trial comparing single with double intensive therapy. We observed no significant association between polymorphisms in CYP3A4, CYP3A5, MDR1, GSTM1 and GSTT1 and outcome either after treatment with induction chemotherapy or after high-dose therapy.

Abnormalities of chromosome 1p/q are highly associated with chromosome 13/13q deletions and are an adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma (Article)

2007-02-01T00:00:00Z

The prognostic value of chromosomal abnormalities was studied in untreated multiple myeloma patients who were registered into a prospective randomised multicentre phase 3 study for intensified treatment (HOVON24). A total of 453 patients aged less than 66 years with stage II and III A/B disease were registered in the clinical study. Cytogenetic analysis was introduced as a standard diagnostic assay in 1998. It was performed at diagnosis in 160 patients and was successful in 137/160 patients (86%). An abnormal karyotype was observed in 53/137 (39%) of the patients. Abnormalities of chromosome 1p and 1q were found in 19 (36% of patients with an abnormal karyotype) and 21 patients (40%). There was a strong association between chromosome 1p and/or 1q abnormalities and deletion of chromosome 13 or 13q (n = 27, P < 0.001). Patients with karyotypic abnormalities had a significantly shorter overall survival (OS) than patients with normal karyotypes. Complex abnormalities, hypodiploidy, chromosome 1p abnormalities, chromosome 1q abnormalities, and chromosome 13 abnormalities were associated with inferior OS on univariate analysis, as well as after adjustment for other prognostic factors. In conclusion, chromosome 13 abnormalities and chromosome 1p and/or 1q abnormalities were highly associated, and are risk factors for poor outcome after intensive therapy in multiple myeloma.

Management of multiple myeloma with bortezomib: Experts review the data and debate the issues (Article)

2007-02-01T00:00:00Z

Cure for multiple myeloma is rare; the success of treatment is measured by response, and length of remissions and survival. Initial treatment for patients young and fit enough is high-dose chemotherapy with autologous stem cell transplantation. Various chemotherapy regimens are employed as initial therapy in patients who cannot withstand the autologous stem cell transplantation regimen, and for treatment of refractory or relapsed disease. Commonly used agents either alone or in combination have included dexamethasone, vincristine, doxorubicin, melphalan, cyclophosphamide, etoposide, cisplatin and, more recently, thalidomide. Within the past few years, the first-in-class proteasome inhibitor bortezomib has been introduced for the treatment of relapsed multiple myeloma with data demonstrating efficacy and safety. Throughout Europe, a faculty of experts conducted a series of debates with over 450 clinicians to discuss the efficacy of bortezomib vis-à-vis other available therapies. Of primary concern was the place of bortezomib in maximizing efficacy throughout the course of the disease and treatment by increasing response rates and improving duration of response, while maintaining an acceptable level of toxicity. The experts concluded that bortezomib, with its unique mechanism of action and demonstrated clinical efficacy and safety, should be considered as standard, early treatment in patients with relapsed multiple myeloma, especially after first relapse. Copyright

Various distinctive cytogenetic abnormalities in patients with acute myeloid leukaemia aged 60 years and older express adverse prognostic value: Results from a prospective clinical trial (Article)

2007-01-01T00:00:00Z

Diagnostic cytogenetic abnormalities are considered important prognostic factors in patients with acute myeloid leukaemia (AML). However, the prognostic assessments have mainly been derived from patients with AML aged <60 years. Two recent studies of AML patients of 60 years and older proposed prognostic classifications with distinct discrepancies. To further study the prognostic value of cytogenetic abnormalities in this patient population, we have evaluated cytogenetic abnormalities in a series of 293 untreated patients with AML aged 60 years and older, included in a randomised phase 3 trial, also in relation to patient characteristics and clinical outcome. The most frequently observed cytogenetic abnormality was trisomy 8 (+8), in 31 (11%) patients. Abnormalities, such as -5, 5q-, abn(17p) and abn(17q), were almost exclusively present in complex karyotypes. A relatively favourable outcome was only observed in five patients with core-binding factor abnormalities t(8;21) and inv(16)/del(16)/ t(16;16). However, most of the other evaluated cytogenetic abnormalities, such as 5q-, -7, +8, abn(17p), abn(17q), and complex aberrations expressed a more adverse prognosis when compared with patients with AML aged 60 years and older with a normal karyotype. Large studies to confirm the prognosis of individual cytogenetic aberrations are warranted.

Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials (Article)

2007-01-01T00:00:00Z

In multiple myeloma, deletion of chromosome 13 (del(13)) is associated with poor prognosis regardless of treatment. This study analyzed the impact of del(13) status on response and survival following treatment with either bortezomib or high-dose dexamethasone in patients in the SUMMIT and APEX trials. Additionally, matched-pairs subset analyses were conducted of patients with and without del(13), balanced for age and International Staging System parameters. In both SUMMIT and APEX, prognosis appeared to be poorer in bortezomib-treated patients with del(13) compared with patients with no del(13) by metaphase cytogenetics. In the SUMMIT and APEX matched-pairs analysis, response and survival appeared comparable in bortezomib-treated patients with or without del(13) by metaphase cytogenetics. However, patients with del(13) receiving dexamethasone in APEX appeared to have markedly decreased survival compared with those without del(13) by metaphase cytogenetics. These matched-pairs analyses suggest that bortezomib may overcome some of the poor impact of del(13) as an independent prognostic factor. However, sample sizes were very small; these findings require confirmation from further studies.

Sequential analysis of chromosome aberrations in multiple myeloma during disease progression (Article)

2007-01-01T00:00:00Z

Purpose: Several chromosomal aberrations have been associated with molecular pathogenesis and classification of multiple myeloma. It is not known whether the expression of abnormal karyotypes is consistent in patients during disease progression. Herein, we report on sequential analysis of conventional cytogenetics as well as fluorescence in situ hybridization (FISH) data of 79 bone marrow specimens from 38 patients with myeloma who were longitudinally followed. Patients and Methods: We determined and characterized the development of additional chromosomal aberrations during progressive disease. Results: Overall, conventional cytogenetics detected an abnormal karyotype in 42% of the samples, whereas this increased to 69% by FISH. Among the cases with an abnormal conventional karyotype, 52% had a hyperdiploid subtype of myeloma. Progressive disease was correlated with an increased complexity of genetic abnormalities, which in the majority, consisted of structural aberrations acquired in later stages of disease. Using conventional cytogenetics, rearrangements of chromosome 1 were the most common structural abnormality (15%). In the majority, these rearrangements consisted of unbalanced translocations of 1p and 1q; however, no specific locus was predominantly affected. Second in frequency were structural aberrations of chromosomes 8 and 17 (6%). The frequency of del(13q) by FISH was 40% and did not increase in later stages of the disease, suggesting that del(13q) is not a genetic event associated with disease progression. Change of ploidy category during disease progression occurred in a minority of the cases. Conclusion: This study supports the notion that cytogenetic abnormalities in multiple myeloma are not random. Particular chromosomal alterations are associated with disease progression, whereas others show a stable pattern during the course of the disease.

Acute dystonic reaction to metoclopramide in patients carrying homozygous cytochrome P450 2D6 genetic polymorphisms (Article)

2006-01-01T00:00:00Z

BACKGROUND: Extrapyramidal syndromes (EPS) are clinically relevant side effects of metoclopramide which are often not anticipated. PATIENTS AND METHODS: Two patients who received metoclopramide developed an acute dystonic reaction. Symptoms disappeared after biperiden or trihexyphenidyl were given. Molecular analysis of the CYP2D6 gene was performed using a PCR-based method. RESULTS: Both patients were homozygous for inactive CYP2D6 alleles (CYP2D6*4/*4 and CYP2D6*4/*5), which are associated with slow drug metabolism. CONCLUSION: Metoclopramide-induced acute dystonic reactions may occur in patients carrying a CYP2D6 genetic polymorphism.

Genetic variations in the glucocorticoid receptor gene are not related to glucocorticoid resistance in childhood acute lymphoblastic leukemia. (Article)

2005-08-15T00:00:00Z

Glucocorticoid sensitivity is an important prognostic factor in pediatric acute lymphoblastic leukemia (ALL). For its antileukemic effect, glucocorticoid binds the intracellular glucocorticoid receptor (GR) subsequently regulating transcription of downstream genes. We analyzed whether genetic variations within the GR gene are related to differences in the cellular response to glucocorticoids. METHODS: In leukemic samples of 57 children, the GR gene was screened for nucleotide variations using a PCR/single-strand conformational polymorphism sequencing strategy. Data were linked to in vivo and in vitro glucocorticoid resistance. RESULTS: No somatic mutations were detected in the GR gene coding region, but six polymorphisms (i.e., ER22/23EK, N363S, BclI, intron mutation 16 bp upstream of exon 5, H588H, and N766N) were identified. In 67% of ALL cases, at least one minor allele of these polymorphisms was detected. Although only borderline significant, the incidence for the N363S polymorphism minor allele was higher (12% versus 6%, P = 0.06) and for the ER22/23EK minor allele lower (4% versus 7.6%, P = 0.1) than in a healthy, comparable population. The different genotypes of the polymorphisms were not related to prednisone resistance. In conclusion, polymorphisms but not somatic mutations in the GR gene coding region occur in leukemic blasts of children with ALL. Our data suggest that these genetic variations are not a major contributor for differences in cellular response to glucocorticoids in childhood ALL. The higher incidence of the N363S minor allele and the lower incidence of the ER22/23EK minor allele in our ALL population as compared with a normal population warrants further research.

The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis (Article)

2005-01-01T00:00:00Z

To determine whether MDR1 reversal by the addition of the P-glycoprotein (P-gp) inhibitor PSC-833 to standard induction chemotherapy would improve event-free survival (EFS), 419 untreated patients with acute myeloid leukemia (AML) aged 60 years and older were randomized to receive 2 induction cycles of daunorubicin and cytarabine with or without PSC-833. Patients in complete remission were then given 1 consolidation cycle without PSC-833. Neither complete response (CR) rate (54% versus 48%; P = .22), 5-year EFS (7% versus 8%; P = .53), disease-free survival (DFS; 13% versus 17%; P = .06) nor overall survival (OS; 10% in both arms; P = .52) were significantly improved in the PSC-833 arm. An integrated P-gp score (IPS) was determined based on P-gp function and P-gp expression in AML cells obtained prior to treatment. A higher IPS was associated with a significantly lower CR rate and worse EFS and OS. There was no significant interaction between IPS and treatment arm with respect to CR rate and survival, indicating also a lack of benefit of PSC-833 in P-gp-positive patients. The role of strategies aimed at inhibitory P-gp and other drug-resistance mechanisms continues to be defined in the treatment of patients with AML.

Efflux kinetics and intracellular distribution of daunorubicin are not affected by major vault protein/lung resistance-related protein (vault) expression. (Article)

2004-07-15T00:00:00Z

Vaults may contribute to multidrug resistance by transporting drugs away from their subcellular targets. To study the involvement of vaults in the extrusion of anthracyclines from the nucleus, we investigated the handling of daunorubicin by drug-sensitive and drug-resistant non-small lung cancer cells, including a green fluorescent protein (GFP)-tagged major vault protein (MVP)-overexpressing transfectant (SW1573/MVP-GFP). Cells were exposed to 1 microm daunorubicin for 60 min, after which the cells were allowed to efflux the accumulated drug. No significant differences in daunorubicin efflux kinetics were observed between the sensitive SW1573 and SW1573/MVP-GFP transfectant, whereas the drug-resistant SW1573/2R120 cells clearly demonstrated an increased efflux rate. It was noted that the redistribution of daunorubicin from the nucleus into distinct vesicular structures in the cytoplasm was not accompanied by changes in the intracellular localization of vaults. Similar experiments were performed using mouse embryonic fibroblasts derived from wild-type and MVP knockout mice, which were previously shown to be devoid of vault particles. Both cell lines showed comparable drug efflux rates, and the intracellular distribution of daunorubicin in time was identical. Reintroduction of a human MVP tagged with GFP in the MVP(-/-) cells results in the formation of vault particles but did not give rise an altered daunorubicin handling compared with MVP(-/-) cells expressing GFP. Our results indicate that vaults are not directly involved in the sequestration of anthracyclines in vesicles nor in their efflux from the nucleus.

High EVI1 expression predicts poor survival in acute myeloid leukemia: a study of 319 de novo AML patients (Article)

2003-01-01T00:00:00Z

The proto-oncogene EVI1 encodes a DNA binding protein and is located on chromosome 3q26. The gene is aberrantly expressed in acute myeloid leukemia (AML) patients carrying 3q26 abnormalities. Two mRNAs are transcribed from this locus: EVI1 and a fusion of EVI1 with MDS1 (MDS1-EVI1), a gene located 5' of EVI1. The purpose of this study was to investigate which of the 2 gene products is involved in transformation in human AML. To discriminate between EVI1 and MDS1-EVI1 transcripts, distinct real-time quantitative polymerase chain reaction (PCR) assays were developed. Patients with 3q26 abnormalities often showed high EVI1 and MDS1-EVI1 expression. In a cohort of 319 AML patients, 4 subgroups could be distinguished: EVI1(+) and MDS1-EVI1(-) (6 patients; group I), EVI1(+) and MDS1-EVI1(+) (26 patients; group II), EVI1(-) and MDS1-EVI1(+) (12 patients; group III), and EVI1(-) and MDS1-EVI1(-) (275 patients; group IV). The only 4 patients with a 3q26 aberration belonged to groups I and II. Interestingly, high EVI1 and not MDS1-EVI1 expression was associated with unfavorable karyotypes (eg, -7/7q-) or complex karyotypes. Moreover, a significant correlation was observed between EVI1 expression and 11q23 aberrations (mixed lineage leukemia [MLL] gene involvement). Patients from groups I and II had significantly shorter overall and event-free survival than patients in groups III and IV. Our data demonstrate that high EVI1 expression is an independent poor prognostic marker within the intermediate- risk karyotypic group.

Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study (Article)

2003-01-01T00:00:00Z

We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (VAD) to receive intensified chemotherapy, that is, melphalan 140 mg/m(2) administered intravenously in 2 doses of 70 mg/m(2) (intermediate-dose melphalan [IDM]) without stem cell rescue (n = 129) or the same regimen followed by myeloablative therapy consisting of cyclophosphamide, total body irradiation, and autologous stem cell reinfusion (n = 132). Interferon-alpha-2a was given as maintenance. Of the eligible patients, 79% received both cycles of IDM and 79% of allocated patients actually received myeloablative treatment. The response rate (complete remission [CR] plus partial remission [PR]) was 88% in the intensified chemotherapy group versus 95% in the myeloablative treatment group. CR was significantly higher after myeloablative therapy (13% versus 29%; P =.002). With a median follow-up of 33 months (range, 8-65 months), the event-free survival (EFS) was not different between the treatments (median 21 months versus 22 months; P =.28). Time to progression (TTP) was significantly longer after myeloablative treatment (25 months versus 31 months; P =.04). The overall survival (OS) was not different (50 months versus 47 months; P =.41). Intensified chemotherapy followed by myeloablative therapy as first-line treatment for multiple myeloma resulted in a higher CR and a longer TTP when compared with intensified chemotherapy alone. However, it did not result in a better EFS and OS.

The formation of vault-tubes: a dynamic interaction between vaults and vault PARP (Article)

2003-01-01T00:00:00Z

Vaults are barrel-shaped cytoplasmic ribonucleoprotein particles that are composed of a major vault protein (MVP), two minor vault proteins [telomerase-associated protein 1 (TEP1), vault poly(ADP-ribose) polymerase (VPARP)] and small untranslated RNA molecules. Not all expressed TEP1 and VPARP in cells is bound to vaults. TEP1 is known to associate with the telomerase complex, whereas VPARP is also present in the nuclear matrix and in cytoplasmic clusters (VPARP-rods). We examined the subcellular localization and the dynamics of the vault complex in a non-small cell lung cancer cell line expressing MVP tagged with green fluorescent protein. Using quantitative fluorescence recovery after photobleaching (FRAP) it was shown that vaults move temperature independently by diffusion. However, incubation at room temperature (21 degrees C) resulted in the formation of distinct tube-like structures in the cytoplasm. Raising the temperature could reverse this process. When the vault-tubes were formed, there were fewer or no VPARP-rods present in the cytoplasm, suggesting an incorporation of the VPARP into the vault-tubes. MVP molecules have to interact with each other via their coiled-coil domain in order to form vault-tubes. Furthermore, the stability of microtubules influenced the efficiency of vault-tube formation at 21 degrees C. The dynamics and structure of the tubes were examined using confocal microscopy. Our data indicate a direct and dynamic relationship between vaults and VPARP, providing further clues to unravel the function of vaults.

Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia (Article)

2003-01-01T00:00:00Z

BACKGROUND: Sensitization of leukemic cells with hematopoietic growth factors may enhance the cytotoxicity of chemotherapy in acute myeloid leukemia (AML). METHODS: In a multicenter randomized trial, we assigned patients (age range, 18 to 60 years) with newly diagnosed AML to receive cytarabine plus idarubicin (cycle 1) and cytarabine plus amsacrin (cycle 2) with granulocyte colony-stimulating factor (G-CSF) (321 patients) or without G-CSF (319). G-CSF was given concurrently with chemotherapy only. Idarubicin and amsacrin were given at the end of a cycle to allow the cell-cycle-dependent cytotoxicity of cytarabine in the context of G-CSF to have a greater effect. The effect of G-CSF on disease-free survival was assessed in all patients and in cytogenetically distinct prognostic subgroups. RESULTS: After induction chemotherapy, the rates of response were not significantly different in the two groups. After a median follow-up of 55 months, patients in complete remission after induction chemotherapy plus G-CSF had a higher rate of disease-free survival than patients who did not receive G-CSF (42 percent vs. 33 percent at four years, P=0.02), owing to a reduced probability of relapse (relative risk, 0.77; 95 percent confidence interval, 0.61 to 0.99; P=0.04). G-CSF did not significantly improve overall survival (P=0.16). Although G-CSF did not improve the outcome in the subgroup with an unfavorable prognosis, the 72 percent of patients with standard-risk AML benefited from G-CSF therapy (overall survival at four years, 45 percent, as compared with 35 percent in the group that did not receive G-CSF [relative risk of death, 0.75; 95 percent confidence interval, 0.59 to 0.95; P=0.02]; disease-free survival, 45 percent vs. 33 percent [relative risk, 0.70]; 95 percent confidence interval, 0.55 to 0.90; P=0.006). CONCLUSIONS: Sensitization of leukemic cells with growth factors is a clinically applicable means of enhancing the efficacy of chemotherapy in patients with AML.

Disruption of the murine major vault protein (MVP/LRP) gene does not induce hypersensitivity to cytostatics (Article)

2002-01-01T00:00:00Z

Vaults are ribonucleoprotein particles with a distinct structure and a high degree of conservation between species. Although no function has been assigned to the complex yet, there is some evidence for a role of vaults in multidrug resistance. To confirm a direct relation between vaults and multidrug resistance, and to investigate other possible functions of vaults, we have generated a major vault protein (MVP/lung resistance-related protein) knockout mouse model. The MVP(-/-) mice are viable, healthy, and show no obvious abnormalities. We investigated the sensitivity of MVP(-/-) embryonic stem cells and bone marrow cells derived from the MVP-deficient mice to various cytostatic agents with different mechanisms of action. Neither the MVP(-/-) embryonic stem cells nor the MVP(-/-) bone marrow cells showed an increased sensitivity to any of the drugs examined, as compared with wild-type cells. Furthermore, the activities of the ABC-transporters P-glycoprotein, multidrug resistance-associated protein and breast cancer resistance protein were unaltered on MVP deletion in these cells. In addition, MVP wild-type and deficient mice were treated with the anthracycline doxorubicin. Both groups of mice responded similarly to the doxorubicin treatment. Our results suggest that MVP/vaults are not directly involved in the resistance to cytostatic agents.

Multiple human vault RNAs. Expression and association with the vault complex. (Article)

2001-10-05T00:00:00Z

Human vaults are intracellular ribonucleoprotein particles believed to be involved in multidrug resistance. The complex consists of a major vault protein (MVP), two minor vault proteins (VPARP and TEP1), and several small untranslated RNA molecules. Three human vault RNA genes (HVG1-3) have been described, and a fourth was found in a homology search (HVG4). In the literature only the association of hvg1 with vaults was shown in vivo. However, in a yeast three-hybrid screen the association of hvg1, hvg2, and hvg4 with TEP1 was demonstrated. In this study we investigated the expression and vault association of different vault RNAs in a variety of cell lines, including pairs of drug-sensitive and drug-resistant cells. HVG1-3 are expressed in all cell lines examined, however, none of the cell lines expressed HVG4. This probably is a consequence of the absence of essential external polymerase III promoter elements. The bulk of the vault RNA associated with vaults was hvg1. Interestingly, an increased amount of hvg3 was bound to vaults isolated from multidrug-resistant cell lines. Our findings suggest that vaults bind the RNA molecules with different affinities in different situations. The ratio in which the vault RNAs are associated with vaults might be of functional importance.

Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells (Article)

2001-01-01T00:00:00Z

Glucocorticoids play an important role in the treatment of a number of hematological malignancies, such as multiple myeloma. The effects of glucocorticoids are mediated through the glucocorticoid receptor alpha, the abundance of which can be modulated by alternative splicing of the glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have been described: glucocorticoid receptor beta, which reportedly has a dominant negative effect on the actions of the glucocorticoid receptor alpha, and glucocorticoid receptor P, of which the effects are unknown. In this study, we have investigated the expression levels of these two splice variants at the mRNA level in multiple myeloma cells and in a number of other hematological tumors. Although the glucocorticoid receptor beta mRNA was, if at all, expressed at very low levels, considerable amounts (up to 50% of the total glucocorticoid receptor mRNA) glucocorticoid receptor P mRNA was present in most hematological malignancies. In transient transfection studies in several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor alpha. These results suggest that the relative levels of the glucocorticoid receptor alpha and the glucocorticoid receptor P may play a role in the occurrence of glucocorticoid resistance in tumor cells during the treatment of hematological malignancies with glucocorticoids.

MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia (Article)

2001-01-01T00:00:00Z

The expression of P-glycoprotein (P-gp), encoded by the MDR1 gene, is an independent adverse prognostic factor for response and survival in de novo acute myeloid leukemia (AML). Little is known about MDR1 expression during the development of disease. The present study investigated whether MDR1 gene- related clonal selection occurs in the development from diagnosis to relapsed AML, using a genetic polymorphism of the MDR1 gene at position 2677. Expression and function of P-gp were studied using monoclonal antibodies MRK16 and UIC2 and the Rhodamine 123 retention assay with or without PSC 833. No difference was found in the levels of P-gp function and expression between diagnosis and relapse in purified paired blast samples from 30 patients with AML. Thirteen patients were homozygous for the genetic polymorphism of MDR1 (n = 7 for guanine, n = 6 for thymidine), whereas 17 patients were heterozygous (GT). In the heterozygous patients, no selective loss of one allele was observed at relapse. Homozygosity for the MDR1 gene (GG or TT) was associated with shorter relapse-free intervals (P =.002) and poor survival rates (P =.02), compared with heterozygous patients. No difference was found in P-gp expression or function in patients with AML with either of the allelic variants of the MDR1 gene. It was concluded that P-gp function or expression is not upregulated at relapse/refractory disease and expression of one of the allelic variants is not associated with altered P-gp expression or function in AML, consistent with the fact that MDR1 gene-related clonal selection does not occur when AML evolves to recurrent disease. (Blood. 2001;97:3605-3611)

Consensus strategy to quantitate malignant cells in myeloma patients is validated in a multicenter study. Belgium-Dutch Hematology-Oncology Group (Article)

2000-01-01T00:00:00Z

Recently the Belgium-Dutch Hematology-Oncology group initiated a multicenter study to evaluate whether myeloma patients treated with intensive chemotherapy benefit from additional peripheral stem cell transplantation. To determine treatment response accurately, we decided to quantitate malignant cells. To test a consensus quantitation strategy, 5 centers independently determined the immunoglobulin heavy chain sequences of patient tumor cells and developed allele-specific oligonucleotides (ASO) and ASO-polymerase chain reaction (PCR). We compared the reproducibility of real-time quantitation with quantitation using limiting dilutions. We distributed DNA samples with a 4-log range of tumor cell concentrations and found average quantitation values deviating 74% and 42% from the input values with real-time PCR (1 center) and limiting dilutions (4 centers), respectively. Within single centers we found an average variation coefficient of 0.74, with limiting dilutions not significantly different from the average 0.82 center-to-center variation coefficient. Within a single center, real-time quantitation proved more reproducible (average variation coefficient, 0.36). Quantification was confirmed in 3 patients during treatment in the protocol. This report shows that real-time PCR or limiting dilution assays can be used for quantitation in a single multicenter trial. We present a consensus strategy that allows an accurate comparison of quantitation data generated in independent centers.

Tussen laboratorium en kliniek (Inaugural Lecture)

1999-04-09T00:00:00Z

Complete remission of t(11;17) positive acute promyelocytic leukemia induced by all-trans retinoic acid and granulocyte colony-stimulating factor (Article)

1999-01-01T00:00:00Z

The combined use of retinoic acid and chemotherapy has led to an important improvement of cure rates in acute promyelocytic leukemia. Retinoic acid forces terminal maturation of the malignant cells and this application represents the first generally accepted differentiation-based therapy in leukemia. Unfortunately, similar approaches have failed in other types of hematological malignancies suggesting that the applicability is limited to this specific subgroup of patients. This has been endorsed by the notorious lack of response in acute promyelocytic leukemia bearing the variant t(11;17) translocation. Based on the reported synergistic effects of retinoic acid and the hematopoietic growth factor granulocyte colony-stimulating factor (G-CSF), we studied maturation of t(11;17) positive leukemia cells using several combinations of retinoic acid and growth factors. In cultures with retinoic acid or G-CSF the leukemic cells did not differentiate into mature granulocytes, but striking granulocytic differentiation occurred with the combination of both agents. At relapse, the patient was treated with retinoic acid and G-CSF before reinduction chemotherapy. With retinoic acid and G-CSF treatment alone, complete granulocytic maturation of the leukemic cells occurred in vivo, followed by a complete cytogenetical and hematological remission. Bone marrow and blood became negative in fluorescense in situ hybridization analysis and semi-quantitative polymerase chain reaction showed a profound reduction of promyelocytic leukemia zinc finger-retinoic acid receptor-alpha fusion transcripts. This shows that t(11;17) positive leukemia cells are not intrinsically resistant to retinoic acid, provided that the proper costimulus is administered. These observations may encourage the investigation of combinations of all-trans retinoic acid and hematopoietic growth factors in other types of leukemia.