Acute Myeloid Leukemia
Maintenance Therapy Post Allogeneic Stem Cell Transplantation in AML
This week’s highlighted AML article can be viewed below. Allogeneic stem cell transplantation is a potentially curative treatment for AML, but relapses do occur. Researchers and clinicians are eager to develop new strategies that might help more patients with AML to live longer lives.
Although patients with acute myeloid leukemia (AML) may be cured with allogeneic stem cell transplantation, too many individuals ultimately relapse. Efforts to increase the cure fraction in AML include the investigation of potential maintenance therapies in the post-transplant setting.
For a long time, allogeneic stem cell transplantation was seen as the end of treatment for patients with AML. After the transplant, immunosuppression would be tapered, and then, ideally, after some time, the patient would get far enough out to be considered cured. The sobering reality is that, even after transplant, too many patients with AML will relapse. Further, certain AML subgroups are much more likely to relapse than others; for example, the majority of those with TP53 mutations, unfortunately, will relapse post transplant.
When we think about the broad subject of post-transplant maintenance therapy, there are many considerations and arguments that can be made for each side of the issue. If you had a very well-tolerated therapy that lowered relapse rates, this might be a more favorable scenario and one in which the use of maintenance therapy could be entertained; however, maintenance therapies may also add toxicities and present other challenges.
There may be some advantages to tailoring decisions about maintenance therapy to a patient’s mutation type. For example, in the prospective SORMAIN study, patients with FLT3-ITD–positive AML in complete hematologic remission were randomized to sorafenib or to placebo after transplant. Researchers concluded that sorafenib maintenance therapy improved relapse-free survival in these patients. Studies with more highly selective and potent FLT3 inhibitors are ongoing.
One of the challenges is that it is not yet possible to identify and treat only those patients who absolutely require maintenance therapy. Take, for instance, a 50% cure rate with transplant alone. If you then treat the whole population with maintenance therapy, you would be “overtreating” the other half by giving maintenance therapy to patients who, in the end, would not actually need it.
Another strategy that has been employed is hypomethylating agent maintenance therapy. Both azacitidine and decitabine have toxicity profiles that can be more challenging after transplant, and we must be aware of risks such as low blood counts and flares of graft-vs-host disease. I think that the use of azacitidine or decitabine as maintenance therapy has generally been limited to patients with the highest-risk features. And I think that decisions regarding implementing therapy should also involve the consideration of disease characteristics at diagnosis and before transplant (ie, detectable residual disease and persisting mutations such as TP53). Individuals with a high variant allele fraction before transplant are among the highest-risk patients. And so, for those patients, putting them on some type of maintenance therapy makes a lot of sense, because their outcomes can be so poor without it.
While post-transplant maintenance therapy is not currently a global standard of care, I do believe that there is a growing recognition that there are some patients with high-risk disease whose treatment cannot end with allogeneic stem cell transplantation.
Burchert A, Bug G, Fritz LV, et al. Sorafenib maintenance after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN). J Clin Oncol. 2020;38(26):2993-3002. doi:10.1200/JCO.19.03345
El Chaer F, Borate U, Duléry R, et al. Azacitidine maintenance after allogeneic hematopoietic cell transplantation for MDS and AML. Blood Adv. 2021;5(6):1757-1759. doi:10.1182/bloodadvances.2020003839
Jacoby MA, Duncavage EJ, Chang GS, et al. Subclones dominate at MDS progression following allogeneic hematopoietic cell transplant. JCI Insight. 2018;3(5):e98962. doi:10.1172/jci.insight.98962
Keruakous AR, Holter-Chakrabarty J, Schmidt SA, Khawandanah MO, Selby G, Yuen C. Azacitidine maintenance therapy post-allogeneic stem cell transplantation in poor-risk acute myeloid leukemia. Hematol Oncol Stem Cell Ther. 2021;S1658-3876(21)00030-3. doi:10.1016/j.hemonc.2021.03.001
Köhler N, Ruess DA, Kesselring R, Zeiser R. The role of immune checkpoint molecules for relapse after allogeneic hematopoietic cell transplantation. Front Immunol. 2021;12:634435. doi:10.3389/fimmu.2021.634435
Oran B, de Lima M, Garcia-Manero G, et al. A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients [published correction appears in Blood Adv. 2021;5(6):1755-1756]. Blood Adv. 2020;4(21):5580-5588. doi:10.1182/bloodadvances.2020002544