Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials.

BACKGROUND: Several tyrosine kinase inhibitors (TKIs) are available for treatment of patients with chronic myeloid leukaemia in chronic phase (CML-CP). We analysed long-term molecular and cytogenetic response and survival outcomes for four TKI modalities used as frontline therapy for CML-CP. METHODS: In a retrospective cohort analysis, we included data from patients with CML-CP treated in prospective clinical trials with frontline TKI modalities at a single institution between July 31, 2000, and Sept 10, 2013. The main aim of the study was to determine whether achievement of complete cytogenetic response or major molecular response had similar prognostic implications irrespective of the frontline TKI modality used. We analysed each TKI modality for response assessment and analysed survival endpoints (event-free, failure-free, transformation-free, and overall survival) with the Kaplan-Meier method. Univariate and multivariate analyses were done with Cox proportional hazard regression. FINDINGS: Our analysis included 482 patients who were treated with imatinib 400 mg daily (n=68), imatinib 800 mg daily (n=200), dasatinib 50 mg twice daily or 100 mg daily (n=106), or nilotinib 400 mg twice daily (n=108). More patients receiving imatinib 800 mg or second-generation TKIs (ie, dasatinib or nilotinib) achieved complete cytogenetic response (58 [87%] of 67 for imatinib 400 mg vs 180 [90%] of 199 for imatinib 800 mg, vs 100 [96%] of 104 for dasatinib vs 99 [93%] of 107 for nilotinib), major molecular response (51 [76%] vs 171 [86%] vs 93 [90%] vs 97 [91%]), and 4·5 log or higher reduction in BCR-ABL transcripts (MR(4·5) response 38 [57%] vs 148 [74%] vs 76 [71%] vs 76 [71%]). This finding was consistent over time (3-60 months). 5-year event free survival significantly differed between the imatinib 400 mg group and the other TKI groups (imatinib 800 mg p=0·029, dasatinib p=0·003, nilotinib p=0·031). There was no significant difference in 5-year failure-free survival (p=0·32, p=0·075, p=0·332), transformation-free survival (p=0·053, p=0·038, p=0·493), or overall survival (p=0·563, p=0·162, p=0·981). Multivariate analysis showed that therapy with imatinib 800 mg (HR 0·51, 95% CI 0·29-0·88, p=0·016), dasatinib (0·28, 0·12-0·66, p=0·004), or nilotinib (0·42, 0·20-0·89, p=0·024) predicted for better event-free survival compared with imatinib 400 mg, but that failure-free, transformation-free, and overall survival were similar irrespective of the TKI used. 28 (41%) patients receiving imatinib 400 mg, 85 (43%) receiving imatinib 800 mg, 23 (21%) receiving dasatinib, and 27 (25%) receiving nilotinib discontinued treatment for any reason. INTERPRETATION: Treatment with imatinib 800 mg or the second-generation TKIs dasatinib or nilotinib resulted in superior and deeper responses than did standard-dose imatinib, which were maintained after 5 years of follow-up. Results with imatinib 800 mg were similar to those with second-generation TKIs, although more patients discontinued therapy. FUNDING: MD Anderson Cancer Center, National Cancer Institute.

Acute myeloid leukemia with MYC rearrangement and JAK2 V617F mutation.

Little is known about MYC dysregulation in myeloid malignancies, and the authors were unable to find published studies that evaluated MYC protein expression in primary cases of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Herein, we describe the clinical, morphologic, immunophenotypic, cytogenetic, and molecular genetic findings in two MDS/AML cases that contained both MYC rearrangement and the JAK2 V617F mutation. We also demonstrate MYC protein expression by immunohistochemistry in both patients.

Tyrosine kinase inhibitors as initial therapy for patients with chronic myeloid leukemia in accelerated phase.

BACKGROUND: Accelerated phase CML most frequently represents a progression state in CML. However, some patients present with AP features at the time of diagnosis. There is limited information on the outcome of these patients who received TKIs as initial therapy. PATIENTS AND METHODS: We analyzed the outcome of 51 consecutive patients with CML who presented with features of AP at the time of diagnosis, including blasts ≥ 15% (n = 6), basophils ≥ 20% (n = 22), platelets < 100 × 10(9)/L (n = 3), cytogenetic clonal evolution (n = 17), or more than 1 feature (n = 3). Patients received initial therapy with imatinib (n = 30), dasatinib (n = 5), or nilotinib (n = 16). RESULTS: The rate of complete cytogenetic response for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR) (Breakpoint Cluster Region (BCR)-Abelson (ABL)/ABL ≤ 0.1%, International Scale [IS]) was achieved in 69% of patients including complete molecular response (BCR-ABL/ABL ≤ 0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with 2GTKIs, 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKIs. CONCLUSION: TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis.

Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation.

Patients received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ~1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890.