Is Less More in Therapy for High-Risk MDS in the Elderly?

A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients w/ Intermediate-2 & High Risk Myelodysplastic Syndrome (BMT CTN #1102)

NCT02016781

Medical College of Wisconsin

Nonrandomized, multicenter, prospective, comparative biologic assignment

approximately 400 patients

36 study sites in North America

This is a multicenter, prospective trial that compares three-year overall survival and outcomes of older patients with higher-risk myelodysplastic syndromes (MDS) treated with either reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC alloHCT), or nontransplant therapy or best supportive care. Eligible patients will be 50 to 75 years old individuals who have (or who have previously had) intermediate-2 or high-risk de novo MDS. Patients are deemed suitable candidates for a RIC alloHCT at the time of enrollment based on performance status, medical history, physical examination, available laboratory tests, and intent to proceed with RIC alloHCT if a matched sibling or matched unrelated donor is identified, with no requirement as to the timing of the transplantation. Patients and physicians must be willing to comply with treatment assignment and have neither intent to proceed with an alternative donor alloHCT not specified in the protocol nor intent to use myeloablative-conditioning regimens.

To reduce enrollment bias and to optimize the control arm, patients who have had tissue typing initiated for an unrelated donor will not be eligible. Patients who have started a sibling donor search or who have found a matched sibling donor are eligible. Importantly, patients may have received prior therapies for the treatment of MDS, including DNA hypomethylating agent–based therapy and cytotoxic chemotherapy.

All subjects are initially assigned to the nontransplant therapy arm and will be reassigned to the transplantation arm should a suitable donor (HLA-matched related donor or 8/8 HLA well-matched unrelated donor) be identified within 90 days of informed consent. The selection of the RIC alloHCT regimen and nontransplant therapy/best supportive care will be at the discretion of the treating physician. Patients will be evaluated for survival, progression to acute leukemia, and quality of life. Additionally, this study will assess the cost-effectiveness of these two alternative treatment approaches. An important predefined subgroup analysis is to determine the impact of pre-HCT hypomethylating agent–based therapy on study outcomes.

MDS predominantly affects older individuals. Currently, the only potentially curative therapy for MDS is alloHCT. This approach is considered beneficial in a subset of patients with higher-risk MDS (intermediate-2 and high-risk). However, because of the substantial risk of morbidity and nonrelapse mortality associated with myeloablative allo-HCT, many patients, especially older patients with comorbidities and poor performance status, are deemed candidates for nontransplant therapy. Alternatively, they are never even referred to a transplantation center for consideration as they are thought to be unlikely to benefit from a myeloablative HSCT. The introduction of reduced-intensity conditioning regimens has expanded the age for alloHCT, though data are limited on its use in MDS. There is a lack of definitive prospective data evaluating the relative risks and benefits of alloHCT compared with nontransplant therapies such as hypomethylating agents, which have been shown to prolong progression-free survival and overall survival in patients with higher-risk MDS. BMT CTN #1102 addresses this knowledge gap.

The relative risks and benefits of alloHCT in older patients with higher-risk MDS remain a source of considerable uncertainty. The investigators reasonably expect that most enrolled patients assigned to the nontransplant therapy arm of this study will be treated with hypomethylating agent–based therapies, which have an established therapeutic efficacy in higher-risk MDS and are widely used in clinical practice. By addressing a fundamental question as to whether RIC alloHCT offers a survival advantage compared with this nontransplant therapy among older higher-risk MDS patients who are thought to be transplantation candidates, BMT CTN 1102 has the potential to change practice.