Adapted Anthracycline-Free Sequential Reduced Intensity Conditioning Regimen for Hematopoietic Stem Cell Transplantation: Initial Safety and Efficacy Outcomes.

Abstract

Background

Myeloablative-conditioning (MAC) regimens have their own limitations of toxicity, demanding supportive-care requirements in resource-constrained settings as well as poor tolerance in elderly. We designed a novel conditioning-regimen, developed on the principles of sequential-reduced-intensity-conditioning (RIC).

Method

The modified FLAG-based sequential-RIC comprised of lower (non-myeloablative) doses of busulfan, cyclophosphamide (only in haploidentical settings) after initial cytoreductive-phase of FLAG-based regimen (Figure 1). Graft-versus-host-disease(GVHD) prophylaxis included: ATLG, cyclosporin, mycophenolate-mofetil and methotrexate.

Additional adaptations were: 1) Lower-dose ATLG (10mg/kg) and fludarabine (120mg/m²) to reduce viral/fungal infections. 2) Rituximab-100mg on Day+4, as EBV-prophylaxis. 3) Low-dose methylprednisolone from Day4-Day30 as additional GVHD-prophylaxis in haploidentical-settings. 4) Idarubicin replaced by etoposide and venetoclax. 5) Premptive donor-lymphocyte-infusion(DLI) on rising/persistent MRD.

Results

Total 28 patients were enrolled between July 2023 to July 2024. Majority were males (75%) and were AML (71.4%) with median age of 31(16-66) years. Ten(35.7%), 7(25%) and 11(39.3%) patients were transplanted in CR1, CR2 and active disease respectively. While 16(57.1%) patients had matched-related-donors (MRD), 12(42.9%) had haploidentical-donors. Sources of graft were either sibling (89.3%) or father (10.7%). After peripheral-blood-stemcell (PBSC) mobilization, median yield of CD34-cells was 21.1(3-42.8)million/kg and CD3 was 415.6(141-1078.5) million/kg. Median CD34-cell dose was 9.5(3-18.8) million/kg and CD3 cell dose 170(36-630) million/kg.

Neutrophil engraftment occurred at median 12.5 (8-20) days and platelet engraftment occurred at 16 (11-37) days. While febrile neutropenia was universal, 22 (78.6%) patients had culture-positive bacterial sepsis. Other toxicity outcomes are given in Table1. Acute and chronic graft-versus-host-disease (GVHD) occurred in 6 and 5 cases respectively. Duration of median follow-up was 117 (11-410) days. Disease-free-survival at 3 months and 6 months were 91.2% (95%CI: 68.9-97.7) and 76.9% (95%CI: 48.1-91.1), while non-relapse mortality(NRM) at 6 months was 11.1% (95%CI: 8.5-30.1) (Figure 2). Pre-transplant remission status (p=0.78) and type of donor (p=0.27) did not affect survival.

Conclusions

In this preliminary report, we find that the adapted sequential-RIC regimen appears safe, with promising short-term efficacy, albeit high infection rates. Long term follow-up is ongoing.