Haploidentical hematopoietic stem cell transplantation using low-dose alemtuzumab is effective for standard-risk hematological malignancies Free

[Background] We have been performing allogeneic hematopoietic stem cell transplantation from haploidentical related donor using anti-CD52 antibody, alemtuzumab, at a total dose of 1.2 mg/kg or 0.96 mg/kg (Am J Hematol 2013;88:294-300) and 0.5 mg/kg (Eur J Haematol 2019;102: 256-264) in pre-transplant regimens, combined with cyclosporine (CSA) at the target concentration of 500 ng/ml with rapid tapering and methotrexate (MTX) at a dose of 10-7-7-7 mg/m² as graft-versus-host disease (GVHD) prophylaxis. However, high relapse rate (RR) in non-remission (non-CR) patients was observed, and the optimal strategy of haploidentical HSCT with low-dose alemtuzumab remained undermined.

[Methods] Since 2015, haploidentical HSCT using low-dose alemtuzumab was performed with different GVHD prophylaxis according to the disease risk. High-risk disease included acute leukemia and blastic crisis of chronic myeloid leukemia (CML-BC) in non-CR at HSCT and any relapsed hematological malignancies after allogeneic HSCT. Others were classified as standard-risk disease. Total body irradiation (TBI) of 12 Gy and cyclophosphamide (CY) or fludarabine (FLU), intravenous busulfan (ivBU) and melphalan (MEL) were mainly used as myeloablative regimen, and FLU, MEL, and TBI of 4 Gy was the mainly used reduced-intensity regimen. Alemtuzumab was added to each regimen at a total dose of 0.48 or 0.5 mg/kg. In patients with high-risk disease, GVHD prophylaxis changed consisting of lower dose of MTX at 5-5-5-0 mg/m² and CSA at the target concentration of 500 ng/ml followed by reducing to 300 ng/ml within 2 weeks after engraftment and rapid tapering thereafter if patients had not developed severe GVHD. In patients with standard-risk disease, GVHD prophylaxis did not change till 2020, and the same GVHD prophylaxis as high-risk disease was adopted afterwards. We retrospectively analyzed clinical courses of patients who underwent haploidentical HSCT using low-dose alemtuzumab between 2015 and 2024. This study was approved by the Institutional Review Board of Jichi Medical University Saitama Medical Center, and was carried out according to the principles of the Declaration of Helsinki.

[Results] In total, 75 patients were included in this study. Their median age was 48 years (range 17 – 69 years). The underlying diseases were acute leukemia in 54, CML-BC in 4, other myeloproliferative neoplasm in 1, myelodysplastic syndrome in 7, and mature lymphoid malignancy in 9. Thirty-four patients were classified as having high-risk disease at HSCT, and 22 of 34 patients had relapsed disease after allogeneic HSCT. On the other hand, 34 patients were classified as having standard-risk disease at HSCT, including 2 patients after engraftment failure. With a median follow-up times for survivors of 905 days (range 75 – 3428 days), Overall survival (OS) rates, disease-free survival (DFS) rate, relapse rate (RR), and non-relapse mortality (NRM) at 1 year were 72.1% and 22.2%, 52.8% and 13.1%, 25.0% and 54.3%, and 15.5% and 32.4%, and those at 3 years were 50.9% and 7.4%, 48.4% and 7.1%, 28.3% and 54.3%, and 23.2% and 38.6%, in patients with standard- and high-risk disease, respectively. The superiority of OS (P < 0.001)and DFS (P < 0.001), and lower RR (P = 0.007) were observed in patients with standard-risk disease. In patients with standard-risk disease, 12 and 22 patients received HSCT till 2020 and since 2021, respectively. A median neutrophil engraftment day changed from at day 17 to 14. The cumulative incidences of Grade II – IV acute GVHD and chronic GVHD have a tendency to decrease from 50.0% to 18.2% (P = 0.077), and from 33.3% to 9.5% (P = 0.073), respectively, despite the MTX reduction. OS, DFS, RR, and NRM at 1 year were 58.3% and 80.4%, 41.7% and 70.2%, 33.3% and 20.1%, and 25.0% and 9.8%, and those at 3 years were 33.3% and 60.6%, 33.3% and 56.7%, 41.7% and 20.1%, and 25.0% and 23.3% in patients till 2020 and since 2021, respectively. OS was better in patients since 2021 with borderline significance (P = 0.080).[Conclusions] The efficacy of haploidentical HSCT using low-dose alemtuzumab for patients with high-risk disease is low, especially due to the high RR. On the other hand, outcomes of patients with standard-risk disease are promising, and combination with low-dose MTX may improve OS. Further studies are warranted to establish the optimal role of haploidentical HSCT using low-dose alemtuzumab, especially for patients with standard-risk patients.