1. Fuerst, Mark L.

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Minimal residual disease (MRD)-positive acute myeloid leukemia (AML) patients who have received initial therapy should not proceed directly to allogeneic stem cell transplantation (alloSCT). That's the definitive statement by a leukemia expert during a debate at the 2021 Great Debates & Updates in Hematologic Malignancies meeting.


"Is the patient MRD-positive in AML after initial therapy? Fuggedaboutit or do something different than transplant," said Richard M. Stone, MD, Chief of Staff at Dana-Farber Cancer Institute, as well as Director of Translational Research in the Leukemia Division, Department of Medical Oncology, and Professor of Medicine at Harvard Medical School in Boston.


Stone noted the key potential uses of MRD monitoring in CR1 AML patients that would change therapy. He quoted famous British transplant specialist Anthony Goldstone: "Modify choice of consolidation therapy (alloSCT vs. chemotherapy) within a given diagnosis-based risk group based on post-induction MRD findings. If MRD is negative, you don't need transplant; if MRD is positive, transplant won't work."

Richard M. Stone, MD... - Click to enlarge in new windowRichard M. Stone, MD. Richard M. Stone, MD

If biology is adverse, transplant, Stone noted. If biology is good, use chemotherapy. "The goal is to get to a complete response (CR) with a deep level of disease burden reduction." Clinicians still use pre-treatment factors in making the decision to transplant or not. "Does MRD-negative status trump adverse biology? Does MRD-positive status trump favorable biology?" asked Stone.


When it comes to measuring MRD, "we are not sure what technique to use and we are not sure when to use it. We are sure that within any given technique at a given time point the prognosis is better if detectability is not present or present at a lower level than if present at a higher level. For example, pre-transplant MRD is worrisome," said Stone.


Deep remission is required to reduce the risk of relapse. "If you find MRD, can outcome be influenced by alloSCT? As we say in Boston, positive MRD is wicked bad pre-transplant," said Stone. AlloSCT does not seem to attenuate the relapse risk attributed to pre-transplant MRD. "MRD negativity in CR2 is good. It trumps the degree of remission," he said.


Intensification of BMT conditioning does not reduce the risk of relapse in the MRD-positive setting, so perhaps an intensification approach is good. "MRD-positive remission equals active disease. You need to transplant. Transplanting a patient with MRD positivity is a fool's errand," said Stone.


If clinicians are worried because MRD is positive by flow cytometry, NPM1 by polymerase chain reaction (PCR) or fusion transcript by PCR is positive after 2 chemotherapy cycles, they have two options, said Stone. "Take a benzodiazepine and transplant the patient or grab a coffee and erase the MRD. Why erase the MRD? Transplants are costly and toxic. Don't put someone through it unless there's a good chance of success. Deeper remissions are better remissions, according to midostaurin and CPX-351 trials. Getting to an MRD state is good, no matter how you get there."


Studies show overall survival after alloSCT in CR1 puts patients in better shape, probably due to MRD negativity. This shows the potential benefit MRD conversion prior to alloSCT. "Do something about MRD negativity. Don't just go to transplant," he said.


Many drug suitors are available to convert patients to negative MRD. These include anti-CD33 agents, such as gemtuzumab and other anti-CD33 antibody drug conjugates (ADCs); anti-CD123 agents, including ADCs, bispecific T-cell engagers, and dual-affinity retargeting agents; radiolabeled antibodies; and SL-401 (tagraxofusp), a genetically engineered diphtheria toxin fused with interleukin-3. Immunological possibilities also include dendritic cell vaccine.


Low-dose chemotherapies include, for example, azacitidine and venetoclax. The RELAZA2 trial showed that azacitidine can convert some MRD-positive patients to negative, but it is unknown whether it will change the long-term outcome, he said. The FDA has approved oral azacitidine for the continued treatment of adult patients with AML who achieved first CR or CR with incomplete blood count recovery following intensive induction chemotherapy who are not able to complete intensive curative therapy, but it is unknown whether it works by reducing MRD.


Future studies will test whether new therapies can erase MRD. These include an upcoming US Intergroup Trial. After initial therapy, if the AML patient is MRD-positive, the patient is randomized to standard therapy or experimental therapies to see whether the MRD can be erased and do better than sending patients to alloSCT.


Stone concluded by quoting the often-quoted New York Yankee baseball player Yogi Berra to help understand MRD in AML: "You can observe a lot by just watching." "I never said most of the things I said." "When you come to a fork in the road, take it." He also quoted the Talmud: "A hungry dog will even eat dung."


Mark L. Fuerst is a contributing writer.


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