Venous thromboembolism prevention during asparaginase-based therapy for acute lymphoblastic leukemia.

BACKGROUND: Venous thromboembolism (vte) is a recognized complication in patients treated with asparaginase-containing chemotherapy regimens; the optimal preventive strategy is unclear. We assessed the safety and efficacy of prophylaxis using low-dose low molecular weight heparin in adult patients with acute lymphoblastic leukemia in complete remission treated with an asparaginase-based post-remission chemotherapy regimen. METHODS: As part of the intensification phase of the Dana-Farber Cancer Institute 91-01 regimen, asparaginase was administered weekly to 41 consecutive patients for 21-30 weeks; these patients also received prophylaxis with enoxaparin 40 mg daily (60 mg for patients ≥80 kg). Outcomes were assessed against outcomes in a comparable cohort of 99 patients who received the same chemotherapy regimen without anticoagulation prophylaxis. RESULTS: The overall rate of symptomatic venous thrombosis was not significantly different in the prophylaxis and non-prophylaxis cohorts (18.92% and 21.74% respectively). Among patients receiving prophylaxis, vte occurred in higher proportion in those who weighed at least 80 kg (42.86% vs. 4.35%, p = 0.0070). No major bleeding complications occurred in the prophylaxis group (minor bleeding: 8.1%). CONCLUSIONS: Prophylaxis with low-dose enoxaparin during the intensification phase was safe, but was not associated with a lower overall proportion of vte.

The prognostic impact of FLT3-ITD and NPM1 mutations in patients with relapsed acute myeloid leukemia and intermediate-risk cytogenetics.

Internal tandem duplication of the fms-like tyrosine kinase-3 gene (FLT3-ITD) and nucleophosmin-1 (NPM1) mutations have prognostic importance in acute myeloid leukemia (AML) patients with intermediate-risk karyotype at diagnosis, but less is known about their utility to predict outcomes at relapse. We retrospectively analysed outcomes of 70 patients with relapsed, intermediate-risk karyotype AML who received a uniform reinduction regimen, with respect to FLT3-ITD and NPM1 mutation status and first complete remission (CR1) duration. CR1 duration, but not molecular status, was significantly correlated with CR2 rate. On univariate analysis, patients with mutated FLT3-ITD (FLT3+) had significantly worse overall survival (OS) compared with those with neither an NPM1 nor FLT3-ITD mutation (NPM1-/FLT3-). On multivariate analysis, shorter CR1 duration was significantly correlated with inferior OS at relapse (P<0.0001), while FLT3 and NPM1 mutation status and age were not significantly correlated with OS. Patients who subsequently underwent allogeneic stem cell transplant (alloSCT) had a superior OS regardless of CR1 duration, but outcomes were better in patients with CR1 duration>12 months. In intermediate-risk karyotype AML patients receiving reinduction, CR1 duration remains the most important predictor of OS at relapse; FLT3-ITD and NPM1 status are not independent predictors of survival.

A phase I/II study of imatinib plus reinduction therapy for c-kit-positive relapsed/refractory acute myeloid leukemia: inhibition of Akt activation correlates with complete response.

This phase I/II study evaluated imatinib as a c-kit inhibitor combined with mitoxantrone, etoposide and cytarabine therapy for patients with primary refractory or relapsed c-kit+ acute myeloid leukemia (AML). Imatinib was escalated through three dose levels in successive six patient cohorts. The combination was well tolerated up to 400 mg/day imatinib. Of 21 patients treated at this dose, 13 (62%) achieved complete response (CR), 7 (33%) were non-responders and one died during induction. The CR rate was 80% in patients with standard-risk karyotype versus 33% in patients with adverse karyotype. The CR rate for primary non-responders was 6/14 (43%) versus 7/7 (100%) for relapsed patients. AML blasts from peripheral blood were assayed for phosphorylated Akt (pAkt) and phosphorylated ERK (pERK) by flow cytometry before to and after imatinib dosing. Of eight patients achieving CR with reinduction, seven demonstrated marked (≥60%) pAkt inhibition with imatinib therapy. In contrast, all the six non-responders to reinduction demonstrated <60% pAkt inhibition (P=0.005). There was no correlation between pERK inhibition and response to therapy. These results indicate that lack of pAkt inhibition in vivo is associated with resistance to reinduction therapy using this regimen. Further studies using agents that are able to inhibit Akt more effectively are warranted.

A phase I study of tipifarnib combined with conventional induction and consolidation therapy for previously untreated patients with acute myeloid leukemia aged 60 years and over.

Patients aged 60 years and over with previously untreated acute myeloid leukemia were enrolled in a Phase I study combining tipifarnib with standard induction therapy. The regimen consisted of cytarabine 100 mg/m(2)/day continuous intravenous (i.v.) infusion on days 1-7, daunorubicin 60 mg/m(2)/day i.v. push x 3 on days 6-8 and tipifarnib twice daily on days 6-15. Tipifarnib was escalated over four dose levels (200, 300, 400 and 600 mg). Patients achieving complete response (CR) were eligible to receive one consolidation using the same regimen. The following dose-limiting toxicities (DLTs) were identified during induction: dose level I: 2/6 (hyperbilirubinemia, respiratory arrest), level II: 0/3, level III: 0/3 and level IV: 4/10 (one each of diarrhea, neutropenic enterocolitis, arrhythmia and delayed hematologic recovery post-consolidation). There were no DLTs due to delayed hematologic recovery post-induction. Of 22 evaluable patients, there were 10 CR, 2 morphologic leukemia-free state (MLFS), 2 partial remission (PR) and 8 non-responders. Of seven patients with adverse risk cytogenetics, there were four CR/MLFS and one PR. In summary, this regimen was well tolerated and the maximum tolerated dose was not reached, although somewhat more severe gastrointestinal toxicity was seen at dose level IV. Tipifarnib 600 mg b.i.d. is considered the recommended dose for further study using this regimen.