The amount of measurable residual disease (MRD) both before and after a SCT is another factor that can indicate likelihood of post-transplant relapse. MRD can be assessed by looking at bone marrow specimens under a microscope, using flow cytometry, and through molecular tests, which are the most sensitive.
“Molecular tests for MRD are one of the areas where we’re making the most progress,” Dr Webster explained. “There are many patients that have tiny amounts of leukemia, below the level that can be detected by looking at cells through a microscope. If you have an MRD test that is quantitative and you can see MRD rising on successive bone marrow biopsies following transplant, you know that patient might benefit from relapse prevention therapy.”
Relapse Prevention Through Targeted Therapy and Hypomethylating Agents
There are few standard approaches for prevention of post-transplant AML relapse. For patients with FLT3 mutation-positive AML (which accounts for 30% of all AML cases), FLT3 inhibitors such as sorafenib have been used to prevent relapse after SCT, although sorafenib is not approved by the US Food and Drug Administration (FDA) for this purpose. There is currently only retrospective evidence for the efficacy of sorafenib in AML relapse prevention.
A recent phase 3 trial in patients with relapsed or refractory FLT3-mutated AML compared the FLT3 inhibitor gilteritinib with salvage chemotherapy. Treatment with gilteritinib yielded improvements in overall and event-free survival; a higher proportion of patients receiving gilteritinib achieved complete remission as well.
Another type of therapy that is routinely used after transplant in AML is the hypomethylating agent azacitidine. This therapy can be given to any patient with AML, regardless of genetic mutations. Dr Webster noted that both sorafenib and azacitidine are associated with significant toxicities, which can be particularly concerning at a time when patients are under risk for complications from the transplantation.
“This is the reason we need strong evidence from a prospective, randomized trial showing that survival is improved for patients who received maintenance therapy compared with those who did not,” said Dr Webster.
Immunotherapy for Prevention of Relapse
There is a longstanding research interest in employing immunologic approaches to augment the GVL effect after transplantation and prevent relapse or reinduce remission after relapse.1 In post-transplant AML, advances have been made with 3 immunotherapy strategies: donor-lymphocyte infusion, immune checkpoint inhibitors, and other monoclonal antibodies such as antibody-drug conjugates.
There is evidence from small clinical trials showing that immune checkpoint inhibitors can help patients who have experienced relapse achieve remission again. However, unleashing the immune system can also increase risk for graft-versus-host disease (GVHD).
“The problem with these immunotherapy approaches is that the rate of complications is as high as the rate of success for relapsed patients. The question is: Are we going to be able to make it safe enough to use immune checkpoint inhibitors in the maintenance setting?” said Dr Webster.
Some studies have explored donor lymphocyte infusion for prevention of relapse, but this approach is also associated with significant complications and is quite resource-intensive. The antibody-drug conjugate gemtuzumab ozogamicin is approved by the FDA in AML, but its potential as a maintenance therapy after transplant is hampered by the risk for serious complications, including fatal liver toxicity.
Ongoing Challenges and Future Directions
Given the significant risk for complications, currently available prophylactic therapies should ideally be offered only to patients who are at high risk for relapse. The ability to reliably identify such patients remains a challenge and a focus of ongoing research.
“Another area where we’re really making progress is understanding why patients relapse after a transplant. We’re learning more and more that there are immunologic mechanisms that are driving risk [for] relapse after a transplant. The better we understand them, the better we’ll be able to reverse those mechanisms of relapse,” concluded Dr Webster.
- Sterling C, Webster J. Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia [published online February 5, 2020]. Am J Hematol. doi:10.1002/ajh.25750
- Tang X, Alatrash G, Ning J, et al. Increasing chimerism after allogeneic stem cell transplantation is associated with longer survival time. Biol Blood Marrow Transplant. 2014;20(8):1139-1144.