• Azacytidine and sorafenib are effective in patients with relapsed and refractory FLT3-mutated AML.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. (Blood. 2013;121(23): 4655-4662)
Summary
Background
Several tyrosine kinase inhibitors (TKI) are available for treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). We analyzed long term response and compared outcomes of patients treated with 4 TKI modalities used as frontline therapy for CML-CP.
Methods
This is a retrospective cohort analysis of 482 patients with chronic phase CML treated in prospective clinical trials with frontline TKI modalities at a single institution. Patients 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 a day (n=108). Primary end point of the study was to determine whether achieving complete cytogenetic response (CCyR) or major molecular response (MMR) has comparable prognostic implications regardless of the type of frontline TKI modality. Intention to treat analyses were performed for each TKI modality for response assessment and survival endpoints were analyzed using the Kaplan-Meier method and differences calculated by the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazard regression.
Findings
Overall, higher proportions of patients receiving imatinib 800 and 2nd generation TKI achieved complete cytogenetic response (CCyR), major molecular response (MMR) and ≥4.5 log reduction in BCR-ABL transcripts (MR4.5) at all time-points (3–60 months). Disease transformation occurred in 35/482 patients (7%), events occurred in 76/482 (16%) and 53/482 patients (11%) died. Overall, 5 year outcomes were event-free survival (EFS) 84%, failure-free survival (FFS) 70%, transformation-free survival (TFS) 92%, and overall survival (OS) 93%. Compared to other 3 treatment modalities, patients treated with imatinib 400 had significantly inferior EFS, FFS and TFS. Multivariate analysis demonstrated that therapy with imatinib 800, dasatinib or nilotinib predicted for EFS while FFS, TFS and OS were similar irrespective of the TKI used.
Interpretation
Treatment with imatinib 800, dasatinib or nilotinib demonstrates superior rates of responses, which are maintained even at longer follow up (5 years). Patient outcomes are improved after treatment with imatinib 800 and 2nd generation TKI’s as compared to imatinib 400. Results with imatinib 800 are similar to 2nd generation TKI with higher rate of discontinuation.
Background
Accelerated phase CML (CML-AP) 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 when receiving tyrosine kinase inhibitors (TKI) as initial therapy.
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 <100×109/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 (CCyR) for patients treated with imatinib was 80%, and with dasatinib or nilotinib was 90%. Major molecular response (MMR, BCR-ABL/ABL ≤0.1%, by International Scale [IS]) was achieved in 69% including complete molecular responses (MR4.5, BCR-ABL/ABL ≤0.0032% IS) in 49%. MMR rates for patients treated with imatinib were 63%, and with second generation TKI (2GTKIs) 76%. Overall survival at 36 months was 87% with imatinib and 95% with 2GTKI’s.
Conclusion
TKIs should be considered standard initial therapy for patients with AP at the time of diagnosis.
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