To compare a reduced-intensity conditioning regimen (RIC) with a myeloablative conditioning regimen (MAC) before allogeneic transplantation in patients with myelodysplastic syndrome (MDS) within a randomized trial.
Patients and MethodsWithin the European Society of Blood and Marrow Transplantation, we conducted a prospective, multicenter, open-label, randomized phase III trial that compared a busulfan-based RIC with MAC in patients with MDS or secondary acute myeloid leukemia. A total of 129 patients were enrolled from 18 centers. Patients were randomly assigned in a 1:1 ratio and were stratified according to donor, age, and blast count.
ResultsEngraftment was comparable between both groups. The CI of acute graft-versus-host disease II to IV was 32.3% after RIC and 37.5% after MAC (P = .35). The CI of chronic graft-versus-host disease was 61.6% after RIC and 64.7% after MAC (P = .76). The CI of nonrelapse mortality after 1 year was 17% (95% CI, 8% to 26%) after RIC and 25% (95% CI, 15% to 36%) after MAC (P = .29). The CI of relapse at 2 years was 17% (95% CI, 8% to 26%) after RIC and 15% (95% CI, 6% to 24%) after MAC (P = .6), which resulted in a 2-year relapse-free survival and overall survival of 62% (95% CI, 50% to 74%) and 76% (95% CI, 66% to 87%), respectively, after RIC, and 58% (95% CI, 46% to 71%) and 63% (95% CI, 51% to 75%), respectively, after MAC (P = .58 and P = .08, respectively).
ConclusionThis prospective, randomized trial of the European Society of Blood and Marrow Transplantation provides evidence that RIC resulted in at least a 2-year relapse-free survival and overall survival similar to MAC in patients with MDS or secondary acute myeloid leukemia.
This retrospective study shows that final outcomes after myeloablative conditioning using IV Bu/Cy were not statistically different from those after Cy/TBI.
Purpose
The clinical relevance of targeting RAS/RAF/MEK/ERK pathway, activated in 70-80% of acute myeloid leukemia (AML) patients, is unknown.
Experimental Design
Selumetinib is an oral small molecule inhibitor of MEK1/2 kinase. Forty-seven patients with relapsed/refractory AML or ≥60 years old with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial and minor). Leukemia cells were analyzed for ERK and mTOR phosphorylation.
Results
Common drug-related toxicities were grade I-II diarrhea, fatigue, nausea, vomiting and skin rash. In the FLT3 wild type cohort, 6/36 (17%) patients had a response [1 partial response, 3 minor responses, 2 unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single nucleotide polymorphism (SNP) rs3733542 in exon 18 of KIT gene was detected in significantly higher number of patients with response/stable disease compared with non-responders (60% vs 23%; p=0.027).
Conclusion
Selumetinib is associated with modest single agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials.
The addition of arsenic trioxide (ATO) to frontline therapy of acute promyelocytic leukemia (APL) has been shown to result in significant improvements in disease-free survival (DFS). FLT3 mutations are frequently observed in APL, but its prognostic significance remains unclear. We analyzed 245 newly diagnosed adult patients with APL treated on intergroup trial C9710 and evaluated previously defined biological and prognostic factors and their relationship to FLT3 mutations and to additional karyotypic abnormalities. FLT3 mutations were found in 48% of patients, including 31% with an internal tandem duplication (FLT3-ITD), 14% with a point mutation (FLT3-D835) and 2% with both mutations. The FLT3-ITD mutant level was uniformly low, <0.5. Neither FLT3 mutation had an impact on remission rate, induction death rate, DFS or overall survival (OS). The addition of ATO consolidation improved outcomes regardless of FLT3 mutation type or level, initial white blood cell count, PML–RARA isoform type or transcript level. The presence of a complex karyotype was strongly associated with an inferior OS independently of post-remission treatment. In conclusion, the addition of ATO to frontline therapy overcomes the impact of previously described adverse prognostic factors including FLT3 mutations. However, complex karyotype is strongly associated with an inferior OS despite ATO therapy.
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