When more isn’t more for AML patients undergoing hematopoietic stem cell transplant

From the Walter and Storb Labs, Translational Sciences and Therapeutics Division

Bone marrow transplantation (BMT) was a pioneering treatment of the Hutch when it opened its doors in the 1970s, facilitating a revolutionary advancement in the treatment of leukemias and lymphomas (cancers of the blood). Patients would receive radiation or chemotherapies to kill off tumor cells prior to receiving genetically matched bone marrow transplants to resupply their ablated diseased tissue and healthy immune cells. However, BMT was primarily limited to younger patients with few comorbidities since cancer treatment regimens had high levels of toxicity and posed serious risks for older and more vulnerable patients. This was a significant hurdle to overcome, since many of these diseases primarily affected older individuals. Then, in the late 1970s, a seminal discovery was made by Dr. Rainer Storb, a Professor in the Therapeutics and Translational Sciences Division and Head of the Transplantation Biology Program at Fred Hutch. Dr. Storb identified the graft-vs-tumor effect, recognizing that part of BMT efficacy was due to immune cells from the donor bone marrow are capable of killing off patients’ remaining tumor cells. This new understanding helped spur a litany of advances in the world of cancer research, including the field of immune-oncology, CAR-T cell therapies, and the inclusion of wider demographics of patients.

After discovering the graft-vs-tumor effect, Dr. Storb developed a nonmyeloablative (NMA) conditioning treatment in the late 1990’s, sometimes referred to as a ‘mini-transplant’, which finally allowed for use of BMT in individuals previously excluded from consideration due to age or comorbidities. These regimens use just enough radiation or chemotherapy to allow engraftment of the donor bone marrow, and then rely on the graft-vs-tumor effect to destroy patients’ tumor cells, which it seems to be very efficient at doing in most cases. Dr. Storb reflected on the first ever mini-transplant patient, saying that within 6 months he had no more detectable tumor cells, and “that convinced people there might be something to it.” After NMA regimens were developed, reduced intensity conditioning (RIC) followed, which bridged NMA and the more intensive myeloablative (conventional) treatments, with the rationale that increasing the intensity in vulnerable patients, when possible, may result in higher treatment efficacy.

Figure show risk for adverse events of patients undergoing HCT after RIC or NMA conditioning. Risk of a) relapse, b) relapse-free survival, c) overall survival and d) non-relapse mortality show non-significant differences in outcome based on conditioning regimen.
Figure show risk for adverse events of patients undergoing HCT after RIC or NMA conditioning. Risk of a) relapse, b) relapse-free survival, c) overall survival and d) non-relapse mortality show non-significant differences in outcome based on conditioning regimen. Image taken from original article.

Not all of this will be a history lesson, of course, but recognizing the decades of context underlying the study recently published by Dr. Roland Walter and Dr. Rainer Storb in Bone Marrow Transplantation, emphasizes the importance of their findings. NMA and RIC conditioning regimens are now both widely used, but whether there is any benefit or drawback in comparison to one another, has not been well defined. That was the main question that Dr. Walter and Dr. Storb set out to answer, using a retrospective cohort of patients from Fred Hutch receiving either of these treatment options. They analyzed data from over 300 patients who received hematopoietic stem cell transplantation (HCT; the modern form of BMT) for Acute Myeloid Leukemia (AML) in their first or second remission.

They used these data to assess whether a variety of outcomes were associated with either treatment. One such outcome is graft-vs-host disease (GVHD), a common and significant risk to HCT patients wherein donor immune cells attack healthy host tissue, in addition to or instead of tumor cells, and can cause significant disease or even death. They found no difference in incidence of acute or chronic GVHD for either group, but the latter was observed earlier in NMA HCT patients. A particularly important finding of theirs was that there was no statistically significant difference in relapse, overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM) between either treatment group. Despite this, they noted that relapse risk was slightly higher and NRM risks, RFS, and OS at the 3-year mark were slightly lower in NMA group. Similarly, at the 100-day mark, NRM was slightly, but not significantly, higher in the RIC group. Dr. Walter and Dr. Storb explained that this difference is likely consistent with a belief that increased conditioning regimen treatments may have some benefits for reducing relapse but comes with toxicity and risk for treatment-related mortality, which may ‘cancel’ out such benefits in the long term. Furthermore, by using univariate and multivariate approaches, they found no significant association between treatment regimen and the outcomes of relapse, OS, RFS, and NRM.

The research team is hopeful that their findings will encourage physicians to consider NMA conditioning regimens as a first choice for patients who are ineligible for conventional myeloablative HCT, as it is less intensive, may pose less treatment-related risk to the patient, and allows for a fully outpatient experience. Dr. Storb noted for the first NMA regimen patient, that he became disease free “without ever seeing the hospital from the inside”. He believes that this type of approach could lower expenses for patients as well as improve their overall mental well-being. Dr. Walter also emphasized that the increased conditioning intensity used in RIC, compared to NMA, didn’t appear to make any difference and it may spare patients the toxicity from those treatments and “find other ways to get more bang for your buck.” Noting that relapse rates have not improved for AML patients in many decades, despite treatment-related mortalities decreasing, both Dr. Storb and Dr. Walter were confident that the way forward would be to find ways to intensify the graft-vs-tumor effect, not the treatment regimen. Luckily, such undertakings are already underway with AML-specific drugs, targeted radiation, and other immuno-therapeutic approaches, which will hopefully act to improve patient outcomes in the near future. Overall, this work emphasizes the importance of the considerations when deciding treatment plans, and that for these patients, as Dr. Storb noted, “less is probably better.”

This spotlight research was funded by the National Cancer Institute.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Drs. Roland Walter, Brenda M Sandmaier, Megan Othus, Masumi U Oshima and Rainer Storb contributed to this study.

Walter RB, Sandmaier BM, Othus M, Orvain C, Rodríguez-Arbolí E, Oshima MU, Schoch G, Davis C, Joachim Deeg H, Storb R. Comparison of reduced intensity and nonmyeloablative conditioning for adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation in first or second remission. 2023. Bone Marrow Transplant.