Burnett, A.K.

Therapeutic advances in acute myeloid leukemia (Article)

2011-02-10T00:00:00Z

The choice of treatment approach and outcome in acute myeloid leukemia (AML) depends on the age of the patient. In younger patients, arbitrarily defined as being younger than 60 years, 70% to 80% enter complete disease remission with several anthracycline-based chemotherapy combinations. Consolidation with high-dose cytarabine or stem-cell transplantation in high-risk patients will restrict overall relapse to approximately 50%. A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha, EVI1). These are increasingly being used to direct postinduction therapy, but they are also molecular targets for a new generation of small molecule inhibitors that are in early development; however, randomized data have yet to emerge. In older patients who comprise the majority, which will increase with demographic change, the initial clinical decision to be made is whether the patient should receive an intensive or nonintensive approach. If the same anthracycline/cytarabine-based approach is deployed, the remission rate will be around 50%, but the risk of subsequent relapse is approximately 85% at 3 years. This difference from younger patients is explained partly by the ability of patients to tolerate effective therapy, and also the aggregation of several poor risk factors compared with the young. There remains a substantial proportion of patients older than 60 years who do not receive intensive chemotherapy. Their survival is approximately 4 months, but there is considerable interest in developing new treatments for this patient group, including novel nucleoside analogs and several other agents.

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.

Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet (Article)

2010-01-21T00:00:00Z

In 2003, an international working group last reported on recommendations for diagnosis, response assessment, and treatment outcomes in acute myeloid leukemia (AML). Since that time, considerable progress has been made in elucidating the molecular pathogenesis of the disease that has resulted in the identification of new diagnostic and prognostic markers. Furthermore, therapies are now being developed that target diseaseassociated molecular defects. Recent developments prompted an international expert panel to provide updated evidenceand expert opinion-based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials. A new standardized reporting system for correlation of cytogenetic and molecular genetic data with clinical data is proposed.

FLT3 inhibition as a targeted therapy for acute myeloid leukemia (Article)

2009-11-01T00:00:00Z

The management of acute myeloid leukemia (AML) presents significant challenges, and there remains a need for new therapies with greater efficacy and better tolerability than existing treatments. An improved understanding of the genetic and molecular changes underlying AML can help both to guide treatment strategies and to predict clinical outcomes, thereby enabling more precise decision-making regarding the optimal treatment strategy for individual patients. Recent findings: The tyrosine kinase receptor FLT3 plays an important role in the survival and proliferation of blasts, and approximately 25% of patients with AML have mutations in the FLT3 gene. This protein is therefore an obvious therapeutic target in AML Amongst recently developed tyrosine kinase inhibitors of FLT3, lestaurtinib and midostaurin are two orally bioavailable agents that have shown encouraging activity, both preclinical and in relapsed AML, and are now in phase III clinical trials. These agents are also being tested in combination with conventional chemotherapy. Summary Oral FLT3 inhibitors offer a hope of improved treatment outcomes for patients with relapsed and newly diagnosed AML.

Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet (Article)

2009-02-26T00:00:00Z

The introduction of all-trans retinoic acid (ATRA) and, more recently, arsenic trioxide (ATO) into the therapy of acute promyelocytic leukemia (APL) has revolutionized the management and outcome of this disease. Several treatment strategies using these agents, usually in combination with chemotherapy, but also without or with minimal use of cytotoxic agents, have provided excellent therapeutic results. Cure of APL patients, however, is also dependent on peculiar aspects related to the management and supportive measures that are crucial to counteract life-threatening complications associated with the disease biology and molecularly targeted treatment. The European LeukemiaNet recently appointed an international panel of experts to develop evidence- and expert opinion-based guidelines on the diagnosis and management of APL. Together with providing current indications on genetic diagnosis, modern risk-adapted front-line therapy and salvage treatment, the review contains specific recommendations for the identification and management of most important complications such as the bleeding disorder, APL differentiation syndrome, QT prolongation and other ATRA-and ATO-related toxicities, as well as for molecular assessment of response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women.

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.

The emerging role of targeted therapy for hematologic malignancies: Update on bortezomib and tipifarnib (Article)

2007-04-16T00:00:00Z

As therapy for hematologic malignancy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients. Bortezomib and tipifarnib are two new, targeted treatments for hematologic malignancies. Bortezomib, a proteasome inhibitor, has shown impressive efficacy in patients with relapsed multiple myeloma and as initial treatment, including before autologous stem cell transplantation. It has been studied as monotherapy and in combination with standard treatments such as dexamethasone, and with newer agents such as the immunomodulators thalidomide and lenalidomide; response is encouraging, even in patients who have relapsed after previously receiving components of a regimen as single agents. Bortezomib is generally well tolerated, including in combination with novel and conventional agents. Tipifarnib is a specific inhibitor of farnesyltransferase. Clinical trials in patients with high-risk acute leukemias and myelodysplastic syndromes have demonstrated good efficacy with tipifarnib. Continued investigation with these new, targeted treatments will further define their use as treatment options in patients with hematologic cancer.

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.

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.