Maintenance therapy after allogeneic transplant for acute myeloid leukemia: great expectations

Abstract

Allogeneic transplantation rightly considered the most effective treatment for acute leukemia also has many limitations, not least a high rate of recurrence. Many studies have been conducted to decrease relapse after transplant by modulating the induction regimens, optimizing the conditioning regimens and graft sources to target a graft vs. leukemia (GVL) effect, or utilizing maintenance therapy. Improvements in induction therapy result in higher rates of minimal residual disease (MRD) negativity and as a result better cure rates with the transplant. This can be achieved by targeted therapies (i.e. FLT3 inhibitors), intensified therapies in younger/fit patients, or newer approaches for specific populations, such as CPX-351 [1,2]. Modulating conditioning intensity is challenging as intensification can result in increased non-relapse mortality (NRM) and reducing intensity may cause increased relapse rates, especially for those with residual disease pre-transplant [3,4]. Donor sources may be important and cord blood grafts, in particular, are associated with decreased rates of disease recurrence, particularly in patients with the high-risk disease [5]. Donor KIR type may also decrease relapse rates but is limited by the complexity of KIR-based donor selection and cord blood transplantation and no centers have investigated this prospectively [6]. Maintenance therapy is another way in which to improve outcomes after transplant. With autologous transplants, the administration of rituximab for posttransplant maintenance for follicular lymphoma or mantle cell lymphoma or lenalidomide for multiple myeloma has resulted in clear benefits. It has also been attempted in allogeneic transplantation but until recently, without much success. Prophylactic infusion of donor cells, in a randomized study, caused more graft vs. host (GVHD) and increased NRM [7]. A retrospective matched-pair analysis suggested possible benefits restricted to those with high-risk leukemia [8]. Hypomethylating agents administered after transplant increase HLA expression and probably also have direct antileukemic effects. Tolerance post-transplant can be poor and in an initial randomized study, no survival benefit was shown [9]. Lenalidomide, given after allogeneic transplantation for myeloma can increase GVHD in an unacceptable fashion [10]. But the landscape is changing fast, thanks to advances in leukemia biology, targeted drug development, and minimal residual disease detection. FLT3 inhibitors in particular are now widely used for posttransplant maintenance. Three randomized studies have shown improved outcomes by administration of post-transplant tyrosine kinase inhibitors (TKI) and a fourth trial has been completed with results awaited (Table 1). Here Shimoni et al. confirm the feasibility of post-transplant TKI administration in a real-world setting [11]. Their data add to the literature, but also illustrate some of the challenges and limitations. One of the major issues relates to toxicity. Stem cell transplantation results in a massive pill burden in the first six months after transplant accompanied by frequent and severe gastrointestinal disturbances including anorexia, nausea, and diarrhea—even in the absence of GVHD. TKI adds considerably to this burden and compliance becomes an issue—as. A result, seven of 41 patients (17%) stopped the medications. Others may have reduced their dose or been less than fully compliant. Were they the ones who relapsed? What is the optimal dose? What is the optimal duration? Which one is the best TKI in terms of toxicity/benefit trade-offs? These are all questions that will require further study.