Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a curative option for a range of hematologic malignancies suitable for elderly or medically frail patients. Nonmyeloablative (NMA) conditioning with fludarabine, cyclophosphamide, and low-dose total body irradiation (Flu/Cy/2Gy TBI) limits non-relapse mortality (NRM) while preserving graft-versus-leukemia (GVL) effects. Post-transplant cyclophosphamide (PTCy) in combination with mycophenolate mofetil (MMF) and Sirolimus can be effective GVHD prophylaxis.

Methods: Between 2022 and 2025, 133 patients underwent allo-HSCT with Flu/Cy/2Gy TBI conditioning with PTCy-based GVHD prophylaxis; all used peripheral blood stem cell grafts. Fludarabine was given on D-6 to D-2, Cyclophosphamide 50mg/kg was given days -6, with TBI given as 2Gy on day -1 as a single dose. PTCy at 50mg/kg was given on days +3 and +4, followed by Sirolimus plus MMF starting day +5. Endpoints were non-relapse mortality (NRM) at 1 year, relapse-free survival (RFS) at 2 years, overall survival (OS) at 2 years, incidence of acute (aGVHD) at 180 days, and chronic GVHD (cGVHD) at 2 years and GVHD-relapse-free-survival (GRFS) at 2 years.

Results: The median age was 67.8 years (range 30–77), which was similar across diseases, with the majority being male (58%). Indications for HSCT were mostly acute myeloid leukemia (AML) (n=57, 43%) and myelodysplastic syndromes (MDS) (n=35, 26%), followed by chronic lymphoid malignancies, including chronic lymphocytic leukemia and lymphomas (CLL/L) (n=13, 9.7%), acute lymphoblastic leukemia (ALL) (n=8, 6%), and myeloproliferative neoplasms, including chronic myelomonocytic leukemia (MPN) (n=19, 14%). The majority of donors were unrelated (96%), with most matched (73%) or mismatched unrelated donors (20%). The median hematopoietic comorbidity index (HCT-CI) across diseases was 2 (lowest in patients with AML at 1, CLL/L at 2, MPN and ALL at 2.5, and highest in MDS at 3); however, this was not statistically significant between groups.

When it came to survival, OS was 75% with a median OS of 371 days, and relapse-related mortality (RRM) was 21% with a median time to relapse of 180 days. The total NRM was 3.7% with a median time to NRM of 51 days. The incidence of aGVHD grade II-IV (17%) and grade III-IV aGVHD (8.2%) moderate-to-severe cGVHD (13%) was low. The 2yr-GRFS was 45%.

Residual disease at transplant was significantly more common in patients with MPN (79%), compared to CLL/L (38%, p=0.02). The presence of measurable residual disease (MRD) was similar in AML (18%) in comparison to ALL (12.5%).

Patients with AML were more likely to receive post-transplant maintenance chemotherapy compared to those with MDS (36% vs. 17%, p=0.009), with no difference between maintenance in MPNs or CLL/L or ALL.

When compared to AML, ALL had worse RFS (25% vs. 68%, p=0.017), with a median survival of 359 days vs. 388 (p=0.001). There was a trend toward worse RFS when compared to MDS, MPN, and CLL/L (25% vs. 58%, p=0.07). There was no difference in OS, NRM when ALL was compared to AML, MDS, MPN, or CLL/L.

In patients with CLL/L, there was an increased incidence of Grade 2-4 acute GVHD (46% vs. 14%, p=0.004) compared to AML, MDS, MPN, and ALL. There was no difference in the incidence of grade III-IV aGVHD between groups. For patients with CLL/L, the incidence of cGVHD (69% vs. 23%, p=0.0003) was higher in comparison to AML, MDS, MPN, and ALL.

Discussion: Sirolimus-based GVHD prophylaxis following NMA Flu/Cy/2Gy TBI conditioning results in favorable survival outcomes and low rates of transplant-related mortality. Despite the low non-relapse mortality, relapse rates remain high, suggesting a need for disease-specific post-transplant strategies to reduce relapse and transplant-related toxicities.

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2025
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