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Improving consolidation therapy in acute myeloid leukemia - a tough nut to crack
Richard F. Schlenk,1,2 Sonia Jaramillo2 and Carsten Müller-Tidow2
1NCT-Trial Center, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg, and 2Department of Hematology, Oncology, and Rheumatology at Heidelberg University Hospital, University of Heidelberg, Germany
E-mail: richard.schlenk@nct-heidelberg.de doi:10.3324/haematol.2018.200485
After intensive induction therapy, 60% to 80% of younger (≤60 years) and 40% to 60% of older (>60 years) patients with acute myeloid leukemia (AML) achieve a complete remission.1 However, despite intensive consolidation therapy including intensive chemotherapy, autologous or allogeneic hematopoietic cell transplantation approximately half of younger and 80% to 90% of older patients relapse and the majority of relapsed patients suc- cumb to their disease.2 Based on these figures, it is expected that prevention of relapse by better consolidation therapy would immediately translate into better overall survival. This interrelationship appears to be simple but it is now 24 years ago that this could be demonstrated in a randomized clinical trial that showed a dose-response effect for cytarabine, with improved relapse-free and overall survival among the patients receiving high-dose cytarabine,3 which remains a cornerstone of consolidation chemotherapy in AML.1,4,5
In this issue of Haematologica, Burnett and colleagues report on a randomized comparison evaluating the addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in AML.6 Everolimus was given for a maximum of 84 days between chemothera- py courses in the experimental arm of the study. Despite the pre-clinical in vitro and in vivo rationale for everolimus, fur- ther supported by promising clinical data from phase I/II tri- als, the independent Data Monitoring Committee (DMC) advised study termination after randomization of 339 patients (2:1 ratio) due to excessive mortality in the everolimus arm. Toxicity of everolimus was primarily gas- trointestinal (mucositis and diarrhea) and biochemical evi- dence of liver toxicity. The primary reason for increased mortality was infection-related deaths within the first 6 months of treatment mainly due to the immunosuppressive effects of everolimus, which reflects what has been seen with the use of this drug in solid tumors.7
This is a remarkable study and we would like to highlight two aspects: (i) the important role of the DMC in taking care of patients’ safety, (ii) the issue of whether we have the right strategies to improve results in consolidation therapy.
Overall, the DMC played a very active role in the study by first recommending dose-reduction for the starting dose from 10 mg to 5 mg after randomization of 146 patients, based on the observation of increased side effects and reduced compli- ance; the DMC then recommended stopping the trial prema- turely after randomization of 339 of the intended 600 patients. These DMC decisions were based, at those time points during the study, on incomplete datasets and were associated with some uncertainty and thus the decisions were not easy to take.8 In hindsight, with more trial data available, these decisions were clearly justified and prevented exposure of additional patients to an increased risk of death. This trial is, therefore, a good example of successful DMC work with useful recommendations at the right time points
during a study. This underlines the importance of anticipating risks already in the planning phase of a clinical trial, incorpo- rating the identified risks into the statistical design and struc- ture of a study with predefined interim analyses, selecting appropriate DMC members with engagement at the interim analyses as well as unscheduled analyses if necessary and, finally, of having an experienced and alert study team.
The second interesting aspect of the study which we like to focus on is whether we are using the right strategy to improve consolidation therapy in AML. Based on favorable results with mammalian target of rapamycin inhibitors in preclinical models and clinical phase I/II studies in patients with active disease (newly diagnosed or relapsed AML), everolimus was added in the UK NCRI AML17 trial to con- solidation therapy for patients who were in first complete remission. One assumption behind this approach is that effective biological mechanisms of action are similar during induction treatment and during consolidation therapy with residual leukemic cells hidden in bone marrow niches. It became apparent that this was not the case: in contrast to the encouraging results of everolimus in patients with active dis- ease, the use of this inhibitor as an add-on to standard con- solidation chemotherapy was associated with increased tox- icity and a significant excess of deaths in remission. Even more disappointing was the fact that there was no evidence that everolimus is effective in preventing relapses. Interestingly, this mirrors data from clinical trials evaluating midostaurin and gemtuzumab ozogamicin (GO).
Based on the pivotal large international multicenter ran- domized double-blinded phase III trial (CALGB 10603, RAT- IFY, clinicaltrials.gov: NCT00651261) in young adults (18-59 years) with FLT3-mutated AML, the US Food & Drug Administration (FDA) and the European Medicines Agency (EMA) recently approved midostaurin as an adjunct to con- ventional chemotherapy, including induction and post-remis- sion therapy, without an upper age limit.9 A debate is ongoing how midostaurin affects overall survival and about the role of midostaurin in consolidation and maintenance therapy. A recent exploratory analysis of the trial revealed that midostaurin most effectively prevented relapse in patients who underwent allogeneic hematopoietic cell transplantation in first complete remission. These patients had a trend to bet- ter survival (P=0.07) and a significantly lower cumulative incidence of relapse (P=0.02).10 In contrast, patients in first complete remission who received high-dose cytarabine con- solidation therapy had a comparable cumulative incidence of relapse rate whether they received midostaurin or not. Thus again, there is no clear evidence that midostaurin given as add-on therapy to high-dose cytarabine prevents relapse. In fact, the addition of midostaurin to first induction therapy seems to have the greatest impact on the observed beneficial effect on event-free and overall survival.9
Based on the results of the ALFA-0701 (NCT00927498)
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