The next generation of approaches to prevent acute myeloid leukemia (AML) relapse following allogeneic hematopoietic cell transplantation (HCT) are already in clinical trials and clinical practice. Novel targets, next-gen transplantation techniques, combination HCT and CAR T-cell therapy, and minimal residual disease (MRD) monitoring are already here.

“The major cause of death after HCT is relapse of the underlying malignancy,” said Robert Zeiser, MD, full professor of medicine and director of the Division of Tumor Immunology at the Department of Hematology, Oncology, and Stem-Cell Transplantation at the Medical Center-University of Freiburg in Freiburg, Germany. “The question is why and what do we do about it?”

Zeiser opened the scientific session Concurrent: Eliminating Post-HCT Relapse in AML: From Biology to Implementation with a look at novel biologic factors that contribute to post-transplant relapse

Naïve T cells are reprogrammed after transplantation, Zeiser said. Some become memory T cells, others effector T cells, driven by glycolysis.

Work in patients suggested that glycolysis is more prevalent in patients following relapse, a finding supported by cell culture analyses. The altered T-cell metabolism shows lower proliferative capacity and lower anti-tumor activity in both human cell culture and in mouse models.

Analysis of cell culture and supernatant and patient sera samples showed an increase in lactic acid metabolites, lowering the intracellular pH in the tumor microenvironment. Returning the intracellular pH to normal levels using sodium bicarbonate altered the T-cell phenotype and improved their metabolic fitness with greater proliferation, cytokine production, and graft versus leukemia (GVL) tumor control.

Another approach targets the Tim-3 ligand, which induces T-cell death or exhaustion. An anti-Tim-3 antibody enhances GVL effect in mice by altering T-cell metabolism. Genetic deletion of donor Tim-3 also enhances GVL effects. A clinical trial with sabatolimab, an anti-Tim-3 monoclonal antibody, is under way.

Novel approaches to allogeneic HCT are also in play. Targeted cellular immunotherapy works in AML, but relapse is common.

“It’s hard to find the correct antigen (to target) and leukemia is heterogeneous within individual patients and between patients,” said Vanessa Kennedy, MD, assistant professor of blood and marrow transplantation and cellular therapy, Stanford University School of Medicine. “Shared myeloid target antigens give you on-target, off-tumor toxicities and cytopenias. Autologous immune cells become exhausted. And cytokine secretion promotes AML growth.”

Allogeneic HCT also works, but not as well as it might. Problems include inadequate cytoreduction and MRD, donor mismatch, immune escape and HLA loss, consolidation and maintenance, and clonal evolution.

Biology suggests that combining immunotherapy and allogeneic HCT could play to the strengths of both approaches, Kennedy noted. Early reports on combination therapy show good results.

It is also possible to use CAR T-cell therapy for pre-transplant conditioning. Early work with an allogeneic CD7 CAR T-cell therapy in AML and T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) had multiple advantages, Kennedy said, with no pharmacologic conditioning or pharmacologic graft-versus-host disease (GVHD) prophylaxis, better long-term cytotoxicity, and improved long-term GVL potential.

One-year survival was 68% and one-year disease-free survival was 54%. Patients had lower rates of GVHD, lower rates of relapse, and no increase in infections.

Donor cells can be shielded by deleting or editing antigen(s) of interest, Kennedy continued. Patients receive the shielded hematopoietic stem/progenitor cells (HSPCs), followed by targeted immunotherapy, antibody-drug conjugate, or CAR T-cell therapy. A proof-of-concept trial using CD33 suggested the strategy can be applied broadly.

MRD has become a key concept in maintenance therapy after HCT, but the practicalities of MRD testing and interpretation can be challenging. Challenges start with the question of just how sensitive, and useful, MRD testing is in the real world.

“Monitoring (after HCT) comes down to MRD,” explained Yi-Bin Chen, MD, professor and Allen B. Rogers, Jr. and Cara J. Rogers Endowed Chair of Medicine at Harvard Medical School and director of the Hematopoietic Cell Transplant & Cell Therapy Program at Massachusetts General Hospital. “That depends on having an MRD test that you can actually use.”

Standard testing can better be called recurrent disease testing, not MRD testing, Chen continued, with sensitivity around 10^-1. Sensitivity improves with fluorescence in situ hybridization (FISH) chimerism, the most commonly used method, to 10^-2. Polymerase chain reaction (PCR) takes sensitivity down to 10^-4, while PCR and next-generation sequencing (NGS) drops it to 10^-6.

There is little consensus around using MRD testing. It can be a signal that more therapy is needed for some clinicians and simply a prognostic marker for others.

Payment can be problematic. Blood-based MRD is as sensitive as FISH, as well as being easier on clinician and patient. But few payers cover this most practical of all current assays because it is new.

Maintenance therapy options are expanding. Current agents include FLT3 tyrosine kinase inhibitors, hypomethylating agents (HMAs), IDH1 and IDH2 inhibitors, and menin inhibitors. Other targeted agents are on the horizon, as are HMA combination and cellular therapy.

“When I get with a patient, I have a threshold on toxicity that I will accept to prevent relapse and so does the patient,” Chen said. “The marriage of transplants and novel agents will help us all.”

This and other sessions at the 2025 Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT® and CIBMTR® will be available for on-demand viewing for registered attendees following the live presentation.