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State of the science: High-priority transplant trials for AML, MDS
In my June 10 column in HemOnc Today, I introduced a series of articles about contemporary clinical challenges and research priorities in the field of hematopoietic stem cell transplantation.
I began by reviewing the recent 2014 Blood and Marrow Transplant Clinical Trials Network (BMT CTN) State of the Science Symposium (SOSS), at which time several topic-specific committees presented potential research initiatives that were discussed and prioritized for subsequent development.
From this process, 12 study concepts from 10 topic-specific committees emerged.
William Wood
In this and in future columns, I’d like to spend some time reviewing several of the priority study concepts that were put forward at the 2014 BMT CTN SOSS, in part so that I can try to provide some background and context for the nontransplant clinician regarding current practices and needs in the field of HSCT.
I’ll try to stay to a common format throughout these columns. First, I’ll present a vignette or two that illustrates a common clinical scenario in practice that is relevant to one of the priority areas identified at the 2014 BMT CTN SOSS. I’ll briefly discuss what is known in the area and will then introduce the specific priority that emerged from the BMT CTN SOSS. I’ll then offer some concluding thoughts, including why this might be relevant to the nontransplant provider.
With that, I’ll get started on the first set of topics that were discussed, related to acute myeloid leukemia and myelodysplastic syndrome (MDS).
Clinical scenarios
Scenario 1: A 52-year-old woman presents with leukocytosis, anemia and thrombocytopenia. Bone marrow aspirate and biopsy demonstrate 60% blasts, and a diagnosis of AML is given.
Routine cytogenetic analysis is normal, but molecular testing confirms the presence of an internal tandem duplication mutation in the FLT3 receptor (FLT3-ITD) without other abnormalities. She is treated with standard induction chemotherapy, including daunorubicin at a dose of 90 mg/m2, and enters remission.
HLA typing was performed, but you do not know about potential donors. You are considering options for post-remission therapy and wonder if allogeneic stem cell transplantation is justified given the high risk for relapse — even after transplant — of FLT3-ITD–positive AML.
Scenario 2: A 67-year-old man has had mild pancytopenia for the past 2 years, detected and followed by his primary care physician. He was referred to your practice after requiring a blood transfusion for anemia.
You have confirmed a diagnosis of MDS, with less than 5% blasts in the bone marrow but with an abnormality of chromosome 7 on cytogenetic analysis. You have assigned a prognostic score of intermediate risk-2 by the International Prognostic Scoring System (IPSS) and high risk by the revised IPSS.
Your patient receives two cycles of azacytidine, and he no longer requires red cell transfusions. You are considering referral for consideration of allogeneic stem cell transplantation, but you wonder about the benefit of transplant in this patient.
Current guidelines
The National Marrow Donor Program/Be The Match and the American Society for Blood and Marrow Transplantation jointly developed the following transplant referral guidelines in 2013:
- Transplant referral is recommended for patients with AML in first complete remission. The exception is favorable-risk AML, defined as t(16;16); inv 16; t(8;21); t(15;17); or normal cytogenetics with NPM1 or biallelic CEBPA mutation without FLT3-ITD.
- Transplant referral for MDS is recommended for any patient with an intermediate or high IPSS score, as well as for any patient with MDS with poor prognostic features, including adverse cytogenetics or transfusion dependence.
Risk for relapse
Relapse after allogeneic stem cell transplantation remains a major concern in the field and may limit the enthusiasm of providers for referring patients with high-risk disease.
Because of the upfront morbidity and mortality risks following transplant, an expectation of benefit from the procedure is critical.
A recent article by Middeke and colleagues, published in Blood, examined AML patients with 17p abnormalities. They determined early post-transplant relapse was the greatest contributor to mortality, with a cumulative incidence estimate of 49%.
Some OS estimates after hematopoietic stem cell transplant in CR1 for high-risk AML are around 20%, including AML with FLT3-ITD mutations and AML with monosomal karyotype.
Despite these findings, however, there are now abundant data that confirm the feasibility of allogeneic transplantation for individuals with high-risk diseases, such as FLT3-ITD–positive AML and older individuals with MDS, and there are very few long-term survivors of these diseases who are managed with non-transplant strategies.
A recent decision analysis by Koreth and colleagues has provided additional evidence to support transplant vs. non-transplant strategies for older individuals with intermediate-risk and higher MDS.
National Comprehensive Cancer Network guidelines also recommend allogeneic transplantation as a suitable option for patients with high-risk AML or MDS. Thus, despite the risk for relapse, we recommend strongly that these patients are referred early for potential allogeneic transplant.
High-priority strategies
In recognition of the continuing challenge of relapse after allogeneic transplantation for high-risk diseases, the BMT CTN SOSS committee focusing on leukemia proposed the following concepts that were subsequently designated as high priorities:
- Strategy 1: A randomized, double blind, phase 3 study of FLT3 inhibition compared with placebo as maintenance therapy in patients with FLT3-ITD–positive AML who are in remission after an allogeneic HSCT.
- Strategy 2: A randomized, phase 3 study of low-dose azacytidine maintenance compared with no maintenance in patients with AML and MDS at high risk for relapse after HSCT.
Both of the above strategies are envisioned as large, 300- to 500-patient studies designed to determine the potential benefit of post-transplant relapse-prevention strategies. If successful, these studies would further improve the benefit-to-risk ratio for transplant vs. non-transplant strategies for these high-risk diseases, directly leading to long-term survival in patients without other curative options.
There are now several FLT3 inhibitors available to target the FLT3 mutation in patients with AML.
Although these drugs have been studied in the primary management of FLT3-ITD AML with varying results, there are reasons to think that FLT3 inhibitors may be particularly effective in the early post-transplant maintenance setting, and preliminary data from early-phase studies lend support to this hypothesis.
At the 2014 BMT Tandem meetings, Chen and colleagues presented data from a trial of maintenance sorafenib (Nexavar, Bayer HealthCare) after allogeneic HSCT for patients with FLT3-ITD AML. There were no cases of disease relapse after transplant among the 15 patients in remission before transplantation, with a median follow-up of 10.9 months. Thus, a large phase 3 study represents an important and exciting opportunity to evaluate a novel relapse-prevention strategy after allogeneic transplantation for this high-risk group.
From the standpoint of other high-risk AML and MDS, we already have data that suggest feasibility and low toxicity for low-dose azacytidine maintenance after allogeneic HSCT for leukemia.
The Alliance for Clinical Trials in Oncology recently completed a 64-patient phase 2 study of 5-azacitidine maintenance after reduced-intensity transplantation, and a single-center phase 3 study designed to evaluate this strategy is ongoing at The University of Texas MD Anderson Cancer Center.
Oral hypomethylating agents are now available and could be used in this setting. A large multisite, phase 3 study of this strategy appears warranted, and demonstration of its efficacy could significantly improve the benefit of transplantation in a prevalent population that represents many of the patients who are seen in practice.
Conclusion
Relapse is an important problem after allogeneic transplantation for patients with high-risk myeloid diseases. Despite this, transplantation often represents the only curative approach for this population, and referrals to transplant centers early in the course of disease are strongly recommended.
Risk–benefit considerations, obviously, are quite important, but as transplant specialists, this is an important part of our practice. We are eager to work with referring providers to determine an individually tailored plan that makes the most sense for each patient we evaluate, regardless of whether that plan includes transplant.
Importantly, the BMT CTN SOSS committee has identified two high-priority studies that will help us to evaluate novel or emerging relapse prevention strategies after transplant — one for patients with FLT3-ITD AML, and another for patients with other high-risk AML or MDS.
We strongly encourage referrals for patients with these conditions so that we can help to answer important questions associated with post-transplant relapse. Working together with patients and with our referring provider community, our goal is to rapidly achieve improvement in long-term survival for patients with high-risk myeloid diseases.
As always, I welcome further conversation or questions about these topics. Readers are encouraged to email me or to visit Healio.com/HemOnc so we can continue this dialogue.
References:
Be The Match. Transplant Referral Timing Guidelines. 2013. Available at: https://bethematchclinical.org/transplant-indications-and-outcomes/referral-timing-guidelines. Accessed June 6, 2014.
Chen Y-B. Phase 1 trial of maintenance sorafenib after allogeneic HSCT for patients with FLT3-ITD AML. Presented at: BMT Tandem Meetings; Feb. 26-March 2, 2014; Grapevine, Texas.
Cornelissen JJ. J Clin Oncol. 2012;30:2140-2146.
Jabbour E. Cancer. 2009;1899-1905.
Koreth J. J Clin Oncol. 2013;31:2662-2670.
Middeke JM. Blood. 2014;123:2960-2967.
Sengsayadeth SM. Bone Marrow Transplant. 2012;47:1535-1537.
Swords R. Leukemia. 2012;26:2176-2185.
For more information:
William Wood, MD, is an assistant professor of medicine in the division of hematology/oncology at the University of North Carolina in Chapel Hill. He also is a HemOnc Today Editorial Board member. He can be reached at UNC Health Care System, Division of Hematology and Oncology, 101 Manning Drive, Chapel Hill, NC 27514; email: wawood@med.unc.edu. You also may follow him on Twitter (@WoodBD).
Disclosure: Wood reports no relevant financial disclosures.