Expanding ACCESS: Transplant Strategy Boosts Survival in Blood Cancers, Offers Potential Savings

For years, when patients with blood cancers needed a stem cell transplant, finding a donor came down to the odds breaking their way.

And for too many Black and Hispanic patients, they did not.

A hematopoietic stem cell transplant (HSCT) can restore the body’s ability to produce healthy blood cells following chemotherapy or radiation, which wipes out diseased bone marrow. Armed with new immune cells, a patient can resume the battle against any remaining cancer.¹

But HSCT can read the patient’s body as the enemy, resulting in graft-vs-host disease (GVHD). This happens when certain proteins between the donor and the patient are out of alignment; as genetic differences between donors and patients increase, so does the risk of GVHD.²

The problem? Bone marrow registries include mostly White donors, making it harder for Hispanic and Black patients to find a match.³ Antonio Jimenez Jimenez, MD, associate professor of medicine in the Division of Transplantation and Cellular Therapy at Sylvester Comprehensive Cancer Center at the University of Miami in Florida, spelled it out in an interview with The American Journal of Managed Care (AJMC): “The likelihood for a [White] patient to find a fully matched donor is close to 80%, but that number drops to less than 50% for a Hispanic patient and less than 30% for an African American patient.”

Can a patient receive a transplant from a donor who is not a full match? They can, Jimenez Jimenez said, but that has meant trade-offs.

“While the use of a partially matched or mismatched donor is an option and sometimes truly the only option for these patients, historically, we have paid a price when we use mismatched donors,” he said. “Because when traditional GVHD prophylaxis was used, this resulted in significant mortality with each degree of mismatch.”

By degree of mismatch, Jimenez Jimenez refers to the number of key human leukocyte antigen (HLA) markers that the patient and donor share, expressed as 0/8 to 8/8, with the latter being a full match; 7/8 is considered an acceptable alternative, with steps taken to prevent GVHD.⁴ The fewer common HLA markers between donor and patient, the higher the degree of mismatch.

Jimenez Jimenez is the senior author of a study, the phase 2 ACCESS trial (NCT04904588), that aims to reset the odds for minority patients, both for common blood cancers and for other conditions such as sickle cell disease (SCD) that can be treated with transplant. Over the past year, highly promising results from ACCESS have been published, including in the Journal of Clinical Oncology (JCO),⁵ and in December, Jimenez Jimenez presented updated data at the American Society of Hematology.⁶

ACCESS pursues a concept that sounds almost too good to be true: The multicenter, prospective study, sponsored by the National Marrow Donor Program (NMDP), combines prophylaxis strategy that is already widely practiced with a drug that was approved more than 65 years ago, the chemotherapy cyclophosphamide.⁷

Jeffery Auletta, MD, senior vice president and chief scientific director of the Center for International Blood and Marrow Transplant Research at NMDP, explained the origins of the study in the interview with AJMC. ACCESS, he said, borrowed a strategy from an earlier phase 2 trial called 15-MMUD for “mismatched unrelated donor.”⁸ That study was among several experimenting with alternatives to traditional GVHD prophylaxis, which for decades combined a calcineurin inhibitor—either tacrolimus or cyclosporine—with an antimetabolite, most commonly methotrexate or mycophenolate mofetil (MMF).

The 15-MMUD study (NCT02793544) added posttransplant cyclophosphamide (PTCy) to tacrolimus and MMF for GVHD prophylaxis, with the transplant being an allograft of bone marrow. The results, presented in 2021, showed a 79% overall survival (OS) at 12 months.⁸

But would this approach be practical for most patients?

“Bone marrow tends to have less chronic graft-vs-host disease, and so that’s why it was chosen [for the 15-MMUD study],” Auletta explained. “But it is not the most common allograft source, which is peripheral blood…. That was the reason for the ACCESS trial. We’re using peripheral blood from mismatched unrelated donors, which is faster, safer, and easier to acquire.”

Using peripheral blood stem cells (PBSCs) offers practical advantages, Auletta said. Bone marrow requires a donor to undergo a surgical procedure in an operating room; PBSCs are mobilized into the bloodstream using cytokines and collected through apheresis.

Unique Study Design and Groundbreaking Findings

ACCESS enrolled 268 adults at 21 US centers between September 2021 and August 2023. Although patients with more types of blood cancer were eligible, most had acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome. All patients received PBSC grafts from unrelated donors mismatched at 1 to 4 HLA markers, ranging from 7/8 down to 4/8. These included 183 patients with 7/8 matches and 85 with matches of less than 7/8.^5,6

Patients received a uniform GVHD prophylaxis regimen of PTCy on days 3 and 4 post transplant, combined with tacrolimus and MMF. The participants then underwent either myeloablative conditioning or reduced-intensity/nonmyeloablative conditioning.

At 1 year, OS was 86% in the group with matches of less than 7/8 and 79% in the 7/8 group. Other data showed relapse rates were 23% and 17% in the 2 groups, and nonrelapse mortality was 8% and 14%, respectively.⁶ In addition:

• GVHD-free, relapse-free survival was 55% for the group with fewer than 7/8 matches and 51% for 7/8 recipients. Rates of acute and chronic GVHD and primary graft failure were low and comparable between groups.
• Patients in the group with fewer than 7/8 matches were racially and ethnically diverse, with 61% identifying as other than non-Hispanic White.

“There was no difference based on degree of mismatch,” Jimenez Jimenez said. “Nonrelapse mortality was less than 10%. Relapse rates were lower than what we typically see in this particular setting. And while the study is not designed to compare to fully matched or any other graft source, it was historically comparable to what we see even in fully matched settings.”

For Auletta, the population-level math was a revelation. “For a Black patient, the 29% chance of finding a matched unrelated donor increases to 80% if you go down to 7/8,” he said. “If you go to 6/8, that goes almost to about 95% to 99%. So just in 2 levels of mismatch, we go from 30%—or a 1 in 3 chance—all the way up to nearly 3 of 3 chances for a Black patient. That’s the aha moment with this. It is the impact: the ability to provide a donor, irrespective of ancestry.”

The ACCESS trial did not happen in a vacuum; several recent trials have explored potential uses for cyclophosphamide post transplant. The same month the JCO article appeared, for example, an Australian research group reported findings in the New England Journal of Medicine⁹from a 3-year randomized phase 3 trial involving patients undergoing SCT from matched, related donors. Although the studies involved vastly different donor types, the results from both showed highly favorable results for cyclophosphamide.

“In line with previous reports that posttransplantation cyclophosphamide can prevent GVHD without increasing the risk of relapse, the incidence of relapse without a previous GVHD event did not appear to be increased with posttransplantation cyclophosphamide–cyclosporin,” the Australian authors reported. “Moreover, the post hoc analysis of relapse-free survival was suggestive of a favorable outcome with experimental prophylaxis.”⁹

New Hope for Diverse Patient Groups

Jimenez Jimenez emphasized how the study breaks new ground. “What was unique about the trial was that the prior PTCy studies largely focused on patients receiving haploidentical or less extreme mismatch settings,” he said. “ACCESS is the first prospective trial to evaluate PTCy in peripheral blood and unrelated donors with mismatch levels as low as 4/8. Importantly, over half of enrolled participants identified as belonging to a racial or ethnic group historically underrepresented in hematopoietic cell transplant clinical trials.”

This is key, Auletta said, because the nation’s population is changing. “The genetic diversity of America is only increasing,” he said. “When we look at US census data, with regard to 2010 vs 2020, we see the diversity index increasing quite substantially.”¹⁰

It only makes sense, he said, “that we are obviously responding to that, in terms of trying to overcome the HLA barrier through the use of mismatched, unrelated donor transplant.”

Improving Accessibility Brings Downstream Advantages

Beyond clinical outcomes, the ACCESS trial brings significant implications for managed care. As an established chemotherapy agent, cyclophosphamide is not a novel biologic or gene therapy product; the regimen of 50 mg/kg per day used in PTCy is given intravenously for GVHD prophylaxis, although there are oral formulations of cyclophosphamide available for other indications.¹¹ In the interview, Auletta and Jimenez Jimenez said PTCy can be implemented at any center already performing transplants without requiring specialized infrastructure or proprietary technology.

Auletta drew the contrast with other cellular therapies. “If you were to look and rank the expense of cell therapy, hematopoietic stem cell transplant is the cheapest,” he said. “When we compare gene therapy to hematopoietic stem cell transplant, there is a logarithmic expense incurred with the gene therapy. When we think about the world, people outside of the United States, and low- to middle-income countries and the ability to provide a disease cure, most likely, it’s going to come from a hematopoietic stem cell transplant.”

The platform’s familiarity is itself a form of access, Jimenez Jimenez said in the interview. “We use a platform that has been used before, which means it was easy for centers to implement,” he said. “It’s not some sort of niche technology or strategy that is very difficult to implement, which I think has very important implications—not only for accruing quickly in trials but also very important global implications.”

Accessibility matters especially for patients with low income, who face compounding barriers, first with finding a matched donor and then with downstream costs of severe GVHD if traditional prophylaxis fails. Reducing the incidence of high-grade acute and chronic GVHD through PTCy-based prophylaxis shortens and simplifies the posttransplant course, Auletta and Jimenez Jimenez said, with potential reductions in hospitalization costs and improvements in quality of life.

Improving the Platform for Other Uses

One challenge that investigators are working to address is that of adverse events, as approximately 70% of patients experienced clinically significant infections due to PTCy’s immunosuppressive effects and prolonged myelosuppression.^5,6 Auletta is leading the ongoing OPTIMIZE trial (NCT06001385) to learn whether a reduced PTCy dose can preserve GVHD protection while decreasing infection burden and accelerating immune reconstitution.¹² He noted that early data from OPTIMIZE show more expeditious neutrophil recovery, a potentially meaningful improvement in the posttransplant experience. Auletta also discussed the potential of ACCELERATE (NCT06859424), which is investigating different drug combinations for optimal PTCy-based prophylaxis.

Once outcomes in the malignant setting are fully optimized, Auletta looks forward to using the platform in nonmalignant diseases such as SCD, where HSCT offers a potential cure at a fraction of the cost of gene therapy but where donors are no less hard to find.

He said that NMDP is also working to address non-HLA barriers through its ACCESS Initiative with the American Society for Transplantation and Cellular Therapy, which is addressing social determinants of health, travel time to transplant centers, caregiver requirements, and other factors that limit who can realistically pursue transplantation.

Jimenez Jimenez sees ACCESS as both a clinical success and a moral imperative.

“We’re seeing outcomes that rival those of fully matched donors, even in patients who previously had little chance of finding a match,” he said. “That’s transformative for our field and for our patients. With a platform that is proven, affordable, and globally scalable, the question is no longer whether mismatched unrelated donor transplantation can work but how quickly the field can make it available to everyone who needs it.”

References

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2. Petersdorf EW. Which factors influence the development of GVHD in HLA-matched or mismatched transplants? Best Pract Res Clin Haematol. 2017;30(4):333-335. doi:10.1016/j.beha.2017.09.003
3. Bone marrow statistics. Institute for Justice. Accessed March 26, 2026. https://ij.org/bonemarrowstatistics/
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6. Al Malki MM, Bo-Subait S, Logan B, et al. Mismatching of unrelated donors beyond a single HLA-locus does not adversely impact outcomes at one year following transplantation: results from the NMDP sponsored ACCESS study. Blood. 2025;146(suppl 1):936. doi:10.1182/blood-2025-936
7. Cyclophosphamide (Cytoxan) was approved by the FDA. LifeScienceHistory.com. Accessed March 26, 2026. https://lifesciencehistory.com/cyclophosphamide-cytoxan-was-approved-by-the-fda/
8. Al Malki MM, Devine SM, Shaw BE, et al. ACCESS: a multi-center, phase II trial of HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplantation cyclophosphamide for patients with hematologic malignancies. Blood. 2022;140(suppl 1):7591-7593. doi:10.1182/blood-2022-162581
9. Curtis DJ, Patil SS, Reynolds J, et al; Australasian Leukaemia and Lymphoma Group. Graft-versus-host disease prophylaxis with cyclophosphamide and cyclosporin. N Engl J Med. 2025;393(3):243-254. doi:10.1056/NEJMoa2503189
10. Jensen E, Jones N, Rabe M, et al. The chance that two people chosen at random are of different race or ethnicity groups has increased since 2010. US Census Bureau. August 12, 2021. Accessed March 26, 2026. https://www.census.gov/library/stories/2021/08/2020-united-states-population-more-racially-ethnically-diverse-than-2010.html
11. DeMeyer ES. Post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis. Cancer Nursing Today. October 17, 2023. Accessed March 26, 2026. https://www.cancernursingtoday.com/post/post-transplant-cyclophosphamide-ptcy-for-gvhd-prophylaxis
12. Auletta JJ, Devine SM, Stefanski SE, et al. OPTIMIZE: a phase II study of reduced dose post transplantation cyclophosphamide as GVHD prophylaxis in adult patients with hematologic malignancies receiving HLA-mismatched unrelated donor peripheral blood stem cell transplantation. Blood. 2024;144(suppl 1):3514.1. doi:10.1182/blood-2024-198252