Treatment results of AML in elderly patients are unsatisfactory. We hypothesized that addition of tosedostat, an aminopeptidase inhibitor, to intensive chemotherapy may improve outcome in this ...population. After establishing a safe dose in a run-in phase of the study in 22 patients, 231 eligible patients with AML above 65 years of age (median 70, range 66-81) were randomly assigned in this open label randomized Phase II study to receive standard chemotherapy (3+7) with or without tosedostat at the selected daily dose of 120 mg (
= 116), days 1-21. In the second cycle, patients received cytarabine 1000 mg/m
twice daily on days 1-6 with or without tosedostat. CR/CRi rates in the 2 arms were not significantly different (69% (95% C.I. 60-77%) vs 64% (55-73%), respectively). At 24 months, event-free survival (EFS) was 20% for the standard arm versus 12% for the tosedostat arm (Cox-p = 0.01) and overall survival (OS) 33% vs 18% respectively (
= 0.006). Infectious complications accounted for an increased early death rate in the tosedostat arm. Atrial fibrillation was more common in the tosedostat arm as well. The results of the present study show that the addition of tosedostat to standard chemotherapy does negatively affect the therapeutic outcome of elderly AML patients.
The JAK2 V617F mutation, the thrombopoietin receptor MPL W515K/L mutation and calreticulin (CALR) mutations are mutually exclusive in essential thrombocythemia and support a novel molecular ...categorization of essential thrombocythemia. CALR mutations account for approximately 30% of cases of essential thrombocythemia. In a retrospective study, we examined the frequency of MPL and CALR mutations in JAK2 V617F-negative cases of essential thrombocythemia (n=103). In addition, we compared the clinical phenotype and outcome of CALR mutant cases of essential thrombocythemia with a cohort of JAK2 V617F-positive essential thrombocythemia (n=57). CALR-positive cases represented 63.7% of double-negative cases of essential thrombocythemia, and most carried CALR type 1 or type 2 indels. However, we also identified one patient who was positive for both the JAK2 V617F and the CALR mutations. This study revealed that CALR mutant essential thrombocythemia is associated with younger age, higher platelet counts, lower erythrocyte counts, leukocyte counts, hemoglobin, and hematocrit, and increased risk of progression to myelofibrosis in comparison with JAK2 V617F-positive essential thrombocythemia. Analysis of the CALR mutant group according to indel type showed that CALR type 1 deletion is strongly associated with male gender. CALR mutant patients had a better overall survival than JAK2 V617F-positive patients, in particular patients of age 60 years or younger. In conclusion, this study in a Belgian cohort of patients supports and extends the growing body of evidence that CALR mutant cases of essential thrombocythemia are phenotypically distinct from JAK2 V617F-positive cases, with regards to clinical and hematologic presentation as well as overall survival.
Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option in both adult and pediatric patients with malignant and non-malignant hematological diseases. ...Chimerism analysis, which determines the donor or recipient origin of hematopoietic cells in HSCT recipients, is an essential aspect of post-HSCT follow-up.Objectives: To review the current literature and develop Belgian consensus guidelines for the use of chimerism analysis in the standard of care after allogeneic HSCT.Methods: Non-systematic review of the literature in consultancy with the members of the BHS transplantation committee.Results: Clinical application with regards to prediction of graft failure or relapse as well as cell source are reviewed. A consensus guideline on the use of chimerism analysis after HSCT is presented.Conclusion: Monitoring of the dynamics or kinetics of a patient's chimerism status by serial analysis at fixed time points, as well as on suspicion of relapse or graft failure, is needed to monitor engraftment levels, as well as disease control and possible relapse.
This retrospective multicenter study in patients with chronic myeloid leukemia in chronic phase was undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily ...practice. Forty-one patients, with 47 imatinib plasma measurements, were analyzed during treatment with imatinib given at a fixed 400mg daily dose. A significant inverse relationship of imatinib concentration with the patients' weight was observed (Pearson's test: p=0.02, R2=0.1). More interestingly, patients with poor response (switched to another tyrosine kinase inhibitor because of imatinib failure, or because of disease progression after an initial response) displayed a significantly lower mean imatinib concentration as compared to patients maintained on imatinib (822ng/mL vs 1099ng/mL; Student's t-test, p=0.04). Failure or disease progression occurred more often in patients in the lowest quartile of imatinib concentrations compared to patients in the highest quartile (p=0.02, logrank test). No correlation could be established with other biological or clinical parameter, including complete cytogenic response and major molecular response. In conclusion: in patients treated with imatinib at a fixed daily dose of 400mg, imatinib plasma concentrations decreased with increasing body weight and were lower in patients switched to another tyrosine kinase inhibitor due to imatinib failure. Systematic determination of imatinib plasma trough levels should be encouraged in such patients.
•In patients treated with a fixed daily dose of imatinib, imatinib plasma concentrations are lower in overweight patients•Lower imatinib concentrations are associated with treatment failure•Imatinib plasma concentration assessment during the chronic phase of chronic myelocytic leukemia should be encouraged
Bleeding and thrombotic events are major clinical complications of ET, together with progression to myelofibrosis and leukemic transformation (AML). The JAK2 V617F mutation, the thrombopoietin ...receptor mutation MPL W515K/L and the most recently discovered calreticulin (CALR) mutations are mutually exclusive in ET, account for up to 80-90 % of ET cases and support a novel molecular categorization of ET. In a retrospective study, we have examined the clinical phenotype and outcome of a Belgian cohort of 165 ET patients in relation to their mutational status. 38% of the patients were CALR mutated, 22% and 12% of whom carried Type 1 (p.L367fs*46) and Type 2 (p.K385fs*47) indels respectively. 35% were JAK2 V617F positive, 7% were MPL W515K/L positive, one patient was positive for both CALR and JAK2 V617F mutations, and 20% were triple negative (Fig. 1). We compared the hematological and clinical features between CALR mutant patients and JAK2 V617F positive patients. This revealed that CALR mutant ET is associated with younger age than JAK2 V617F positive ET (median age 56 y (range 23-84) versus 65 y (range 36-94), p<0.001), male gender (58% versus 39%, p=0.03), higher platelet count (988 ± 367*109/L versus 870 ± 291*109/L, p=0.04 (mean ± SD)), lower leukocyte count (9.1 ± 3.2*109/L versus 11.6 ± 5.8*109/L, p<0.001), lower erythrocyte count (4.36 ± 0.9*1012/L versus 4.98 ± 0.65*1012/L, p<0.001), hemoglobin (13.2 ± 1.8 g/dL versus 14.3 ±1.6 g/dL, p=0.001) and hematocrit (40 ± 6.2 % versus 44 ± 4.6 %, p<0.001). Analysis of the CALR mutant group according to the indel type showed that CALR Type 1 deletion is strongly associated with male gender (62%). Contrary to previously published findings, we did not find significant differences between CALR type I and II mutations with regard to age and platelet count.CALR mutant patients had a better overall survival than JAK2 V617F positive patients (mean survival 28 y versus 16 y, p=0.01). However, the better overall survival for CALR mutant ET was restricted to patients less than 60 years old (mean survival 29.2 y versus 18.5 y, p=0.02) while in the age group above 60 years, the overall survival was not significantly different (mean survival 18.3 y versus 13 y, p=0.32) (Fig. 2). In our cohort, no difference in myelofibrosis-free survival or leukemia-free survival was found between the molecular subtypes, although the risk of developing myelofibrosis was unexpectedly higher in the CALR mutant group (18% versus 4%, p=0.01). In contrast to other studies, we found no difference in the frequency of arteriovenous complications. In conclusion, this study on a Belgian cohort supports the notion that CALR mutant ET is phenotypically distinct from JAK2 V617F positive ET, with regard to the clinical and hematological presentation as well as the overall survival. In this cohort, the better overall survival was most marked in ET patients less than 60 y of age. Our study adds to the growing body of evidence that CALR mutant ET is a disease entity distinct from JAK2 V617F positive ET.
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