Radiation-Free Stem Cell Transplant Regimen Shows Promise for Elderly Cancer Patients

For thousands of older patients with blood cancers, a stem cell transplant can offer the only realistic chance of a cure, yet the treatment itself has often been considered too dangerous to attempt. A new study from Grenoble-Alpes University Hospital in France now provides fresh evidence that a chemotherapy-only conditioning regimen, adapted from a widely used protocol that normally relies on total body irradiation, can deliver respectable long-term outcomes in elderly and medically frail patients receiving transplants from half-matched family donors or mismatched unrelated donors.

Conditioning is the intensive preparatory phase that precedes an allogeneic stem cell transplant, in which a patient receives blood-forming cells from a donor. Its purpose is twofold: to wipe out the patient’s diseased bone marrow and malignant cells, and to suppress the immune system enough that the donor cells can engraft rather than being rejected. For decades, many conditioning protocols incorporated total body irradiation, or TBI, because radiation is an effective tool for eradicating malignant cells throughout the body. But irradiating the entire body comes at a cost, particularly for older patients, who face higher risks of organ damage, secondary cancers, and prolonged recovery. Reduced-intensity conditioning regimens were developed precisely to soften this blow, using lower doses of treatment to make transplantation feasible for patients who could never tolerate a myeloablative approach.

One of the most successful reduced-intensity strategies in current use is the Baltimore regimen, which pairs fludarabine with low-dose total body irradiation and high-dose post-transplant cyclophosphamide to prevent graft-versus-host disease. The post-transplant cyclophosphamide component is the crucial innovation: by administering high doses of cyclophosphamide in the days immediately after the donor cells are infused, clinicians can selectively eliminate the rapidly proliferating donor T cells that would otherwise attack the recipient’s tissues, while sparing the slower-dividing stem cells that must rebuild the patient’s blood and immune systems. This approach has transformed haploidentical transplantation, allowing nearly any patient with a healthy relative to serve as a donor.

The problem, as the Grenoble team points out, is that not every transplant center has reliable access to total body irradiation. Radiation oncology capacity varies widely across countries and institutions, and in some settings the logistical burden of coordinating TBI sessions for transplant patients is prohibitive. To address this gap, the researchers evaluated a modified, radiation-free version of the Baltimore regimen, designated FE2B2, which replaces the irradiation component with a combination of fludarabine, cyclophosphamide, and busulfan. Fludarabine is a purine analog that potently suppresses lymphocytes; cyclophosphamide adds further immunosuppression and cytotoxic activity; and busulfan, an alkylating agent, takes over the marrow-ablative role that low-dose radiation would otherwise play. The regimen retains the signature post-transplant high-dose cyclophosphamide for graft-versus-host disease prophylaxis.

To test whether this modified protocol could stand in for the original, the investigators conducted a non-interventional, monocentric, retrospective cohort study at their tertiary care center. They included adult patients over the age of eighteen who had received an HLA haploidentical or mismatched unrelated donor peripheral blood stem cell graft with the non-TBI modified Baltimore conditioning between March 2016 and April 2022. The primary endpoints were overall survival at two and five years after transplantation. Secondary endpoints covered the full spectrum of transplant outcomes: donor engraftment, progression-free survival, non-relapse mortality, graft-versus-host disease-free and relapse-free survival, and the incidence of acute and chronic graft-versus-host disease at the same time points.

The cohort comprised sixty-five patients, and their profile reflects exactly the population for whom such a regimen is designed. The median age of the recipients was sixty-six years, an age at which conventional ablative conditioning would be considered unacceptably toxic by many centers. One-third of the patients carried a hematopoietic cell transplantation-specific comorbidity index score of three or higher, signaling substantial pre-existing health burdens. Forty-three percent of the transplants came from haploidentical family donors, meaning donors who share only half of the patient’s human leukocyte antigens, while fifty-seven percent came from mismatched unrelated donors. Both donor types carry elevated immunologic risk compared with fully matched donors, making the results particularly relevant to patients who lack a well-matched donor option. The median follow-up reached sixty-one months, long enough to capture genuinely durable outcomes.

The engraftment data were unambiguous. Neutrophil engraftment, the first milestone of transplant success indicating that donor cells have taken hold and are producing infection-fighting white blood cells, was achieved in every single patient. Platelet engraftment, which restores clotting capacity and is typically slower and less reliable, occurred in ninety-seven percent of patients. These figures suggest that the busulfan-based, radiation-free conditioning creates a receptive marrow environment as effectively as the irradiation-based original. Graft-versus-host disease rates were also in line with expectations for this transplant setting: the cumulative incidence of grade II-IV acute graft-versus-host disease was forty-five percent, grade III-IV acute disease was fourteen percent, chronic graft-versus-host disease reached twenty percent at both two and five years, and moderate to severe chronic disease affected twelve percent of patients.

Non-relapse mortality, the measure of deaths caused by the transplant procedure itself rather than by returning cancer, was twenty-two percent at two years and twenty-five percent at five years. The authors note that four patients died within the first twenty days after transplant, three from hemorrhagic complications and one from cardiogenic shock secondary to pericarditis, underlining that early toxicity remains a genuine hazard in this fragile population even under a reduced-intensity approach. Survival outcomes were correspondingly moderate: two-year and five-year overall survival stood at forty-eight percent and thirty-seven percent respectively, progression-free survival at forty-three percent and thirty-two percent, and graft-versus-host disease-free, relapse-free survival, a stringent composite endpoint requiring patients to remain free of both relapse and significant graft-versus-host disease, at twenty-nine percent and nineteen percent.

The authors conclude that in their cohort of elderly and frail patients with high-risk disease, the FE2B2 regimen demonstrated acceptable toxicity, with long-term outcomes that align with published data for the classical Baltimore conditioning that includes total body irradiation. In practical terms, this means that centers without access to radiation facilities can offer a defensible alternative without apparently compromising the fundamental transplant outcomes that matter most to patients. Given that roughly half of patients diagnosed with hematologic malignancies are over sixty and that donor availability increasingly favors haploidentical options, a validated radiation-free pathway could meaningfully expand the number of older patients who are offered curative-intent transplantation rather than palliative treatment alone.

The study’s limitations are those inherent to its design. As a retrospective, single-center analysis of sixty-five patients, it cannot deliver the statistical power of a randomized trial, and center-specific supportive care practices may influence outcomes such as early hemorrhagic deaths. A longer median follow-up beyond five years would also sharpen estimates of late relapse and chronic graft-versus-host disease. Nevertheless, the findings add to a growing body of evidence that transplant eligibility need not be dictated by age or by the technological resources of a given hospital. For elderly and unfit patients with high-risk blood cancers and only half-matched or mismatched donors available, the modified Baltimore regimen offers a chemically engineered route to engraftment that requires no radiation at all, bringing a once-exclusive therapy closer to universal availability.

Subject of Research: A non-TBI chemotherapy conditioning regimen for allogeneic stem cell transplantation in elderly or unfit patients with haploidentical or mismatched unrelated donors.

Article Title: A Baltimore-modified non-TBI conditioning for allogeneic stem cell transplantation in elderly or unfit patients with haploidentical or mismatched donors

Article References: Volpari, V., Bulabois, C.-E., Thiebaut-Bertrand, A., Regny, C., Park, S., Carre, M., & Meunier, M. (2026). A Baltimore-modified non-TBI conditioning for allogeneic stem cell transplantation in elderly or unfit patients with haploidentical or mismatched donors. Annals of Hematology. https://doi.org/10.1007/s00277-026-07260-1

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07260-1

Keywords: allogeneic stem cell transplantation, reduced-intensity conditioning, Baltimore regimen, total body irradiation, haploidentical donor, mismatched unrelated donor, post-transplant cyclophosphamide, graft-versus-host disease, non-relapse mortality, elderly patients, busulfan, hematologic malignancies