Post-transplant maintenance therapy for MDS and AML: a bridge too far or the beginning of a new era?

The pioneering efforts of laboratory teams led by Don Metcalf and Ashley Dunn in the purification and cloning of granulocyte-macrophage colony-stimulating factor (GM-CSF) [1,2], lay the foundation for clinical research to determine its therapeutic role in patients with impaired hematopoiesis. GM-CSF was also shown to recruit acute myeloid leukemia (AML) blasts into Sphase, propagating studies to determine if cytokine ‘priming’ could enhance activity of drugs such as cytarabine, with anti-leukemic activity dominant in dividing cells [3]. Clinical results were conflicting, with one study showing no benefit for GM-CSF commenced prior to chemotherapy [4], in contrast to another randomized trial, which found that GM-CSF, when commenced concomitantly with induction, shortened time to neutrophil recovery (median 29 to 24 days) and improved 2-year disease-free survival (21% to 48%) [5]. Allogeneic hematopoietic stem cell transplantation (HSCT) has been a cornerstone of post-remission therapy in AML, leveraging donor cell immunity to reduce relapse risk in patients with higher risk disease. Although reduced-intensity and nonmyeloablative (NMA) conditioning approaches are less toxic in older patients, this comes at the cost of increased posttransplant relapse risk. Based on the established role of azacitidine in patients with higher risk myelodysplastic syndrome (MDS) and elderly AML [6,7], many investigators have explored the role of post-transplant hypomethylating agent-based maintenance therapy, aimed at mitigating relapse risk, particularly within the first 12months after donor stem cell infusion. These studies (summarized in Table 1), have established a tolerable dose of azacitidine up to 40mg/m2 5 days per 28-day cycle, commencing as early as 30 days post-HSCT. Many of these studies have been hampered by slow recruitment and reluctance of investigators to commence maintenance therapy in the first few months after transplantation, related in part, to concerns regarding the myelosuppressive effects of azacitidine on engrafted donor cells. The current study by Webster and colleagues [Ref] was a prospective single institution phase II study that examined the feasibility of combining azacitidine with GM-CSF as a post-transplant maintenance strategy in patients with poor risk AML/MDS [8]. The John Hopkins team originally planned to enroll 25 patients in each arm (myeloablative vs. NMA conditioning), with the ambitious goal of demonstrating an increase in median relapse-free survival (RFS) from 1.5 to 3.1 years in the myeloablative conditioned group and 1.3 to 3.1 years in the NMA group. Eligibility included poor-risk AML or MDS, either therapy-related or de novo AML with age 60 years-old, trilineage dysplasia, second complete remission (CR2þ), FLT3-ITD mutation, measurable residual disease (MRD) at the time of HSCT or poor-risk cytogenetics. Patients were permitted to commence azacitidine 60–185 days after HSCT, with azacitidine commenced at a dose of 37.5mg/m2 days 1–5 each 28-day cycle and escalated every 2 cycles, to a maximum dose of 75mg/m2 for a planned total of 12 cycles. GM-CSF was administered on days 1–10 of each cycle. The choice of GM-CSF was influenced by prior work from the authors showing that GM-CSF can promote AML differentiation and suppress clonal proliferation [9]. A meta-analysis of outcomes after autologous or allogeneic SCT, however, suggests a greater tendency for G-CSF to reduce duration of fever and parenteral antibiotic use, whereas GM-CSF led to an increase in these adverse outcomes compared to control populations [10]. Reassuringly, in the current study by Webster and colleagues, the azacitidine/GM-CSF combination resulted in a low incidence of treatment-related grade 3/4 anemia, neutropenia or