Hematopoietic stem cell transplantation (HCT) is one of the most important treatment options for acute leukemias. However, posttransplant cancer recurrence remains a continuing issue. And while there are reasons to think that hypomethylating agents (HMAS) could be helpful as maintenance tools to prevent cancer recurrence after HCT in leukemia, a hematologist/oncologist told colleagues that the treatment isn’t yet ready for prime time.
“I don’t think you can prefer hypomethylating agents over anything right now. Unfortunately, there’s no data that we can hang our hat on that says they are of benefit in the posttransplant setting,” said Frederick Appelbaum, MD, executive vice president and deputy director of the Fred Hutchinson Cancer Research Center, Seattle, in a presentation at the virtual Acute Leukemia Forum of Hemedicus.
However, there’s still plenty of room for improvement for patients following HCT, he said, pointing to the findings of a 2020 study. The report, which he cowrote, found that 200-day mortality after HCT fell by a third from 2003-2007 to 2013-20017, but also noted that “relapse of cancer remains the largest obstacle to better survival outcomes.”
Dr. Appelbaum described the findings this way: “Without a doubt, the major limitation to transplants for hematologic malignancies today is disease recurrence,” he said. “In fact, if you look at patients after day 100, over 60% of the reason for failure is tumor regrowth. Thus, people are very anxious to look at any method that we can to prevent posttransplant relapse, including the use of hypomethylating agents.”
In regard to strategy, “we don’t have to get rid of every last leukemic cell. Just delaying recurrence might be enough,” he said. “If you can keep the patient from relapsing for the first 3 months, and then take the brakes off the immune suppression and allow immunity to regrow, that may be enough to allow increased numbers of patients to be cured of their disease.”
A potential role
Why might HMAS be a possible option after transplant? They do appear to play a role after chemotherapy, he said, pointing to four 2019 studies: One that examined decitabine and three that examined azacytidine: Here, here, and here.
“These four studies provide convincing evidence that hypomethylating-agent therapy after conventional chemotherapy may either prevent or delay relapse when given as maintenance,” Dr. Appelbaum said.
If HMAS work after standard chemotherapy, why might they fail to work after transplantation? “For one, by the time the disease has been able to go through chemotherapy and transplant, you’re left with highly resistant cells,” he said. “Therefore, hypomethylating agents may not be enough to get rid of the disease. Secondly, any of you who have tried to give a maintenance therapy after transplantation know how difficult it can be with CMV [cytomegalovirus] reactivation, count suppression with ganciclovir, graft-versus-host disease [GVHD] causing nausea and vomiting, diarrhea and renal dysfunction caused by calcineurin inhibitors. These are daily events during the first 3 months after transplantation, making drug administration difficult.”
In addition, he said, “even if you can give the drug, the clinical and disease variability may make it very difficult to detect an effect.”
In another study, researchers “did make a valiant attempt to study azacitidine in the posttransplant setting by randomizing 181 patients to either azacitidine or observation,” Dr. Appelbaum said. “Unfortunately, as they reported in 2018, they could not detect a difference in either disease-free or overall survival.”
The researchers reported that nearly 75% of patients in the azacitidine arm failed to complete the planned 12 cycles of treatment, he said. “The reasons for stopping the drug were pretty profound. Half of the patients stopped because they relapsed. Others had stopped because of grades three or four toxicity, death, or severe GVHD or significant infections. It is very difficult to give the drug.”
In the future, “if we truly want to optimize the benefit of using hypomethylating agents after transplantation, it’s going to be very important for us to understand how they work,” he said. “Understanding that would then help us to select which drug we should use, what the dosing and schedule might be, and also to select patients that might benefit from it. Unfortunately, right now, it’s pretty much of a black box. We don’t really understand the effects of hypomethylating agents in the posttransplant period.”
Still, he added, “without question, the results that we have seen with the use of hypomethylating agents after conventional chemotherapy – prolonging disease-free and, probably, overall survival – are going to provide a very, very strong stimulus to study hypomethylating agents after transplantation as well.”
Dr. Appelbaum reports no disclosures.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.