Myeloablative Conditioning Followed by T-Cell Replete Haploidentical Related Donor Peripheral Blood Stem Cell Transplant Using Post-Transplant Cyclophosphamide Immune Tolerance Approach for High Risk Haematological Malignancies: An Indian Perspective.

Haplo-identical peripheral blood stem cell transplant(PBSCT) has become the preferred alternative donor transplant program in most centers in India owing to its logistic and cost advantages. Myeloablative conditioning proposes to reduce the relapse rate at the marginal cost of an increase in transplant related morbidity and mortality. This study is a retrospective analysis of 43 patients suffering from high risk hematological malignancies (AML-27, ALL-4, NHL-2, CML-6, Blastic Plasmacytoid Dendritic cell Leukemia-1, Plasmablastic Lymphoma-1, high risk MDS-2) who underwent haploidentical transplant using a uniform approach in 3 different centres in India. They received Myeloablative conditioning with one of 2 regimens: Fludarabine 120 mg/sq.m + Busulfan 12.8 mg/kg [ ± low dose TBI 200 cGy] (n = 36), or Fludarabine 90 mg/sq.m + Myeloablative TBI (12-14.2 Gy) (n = 7). All patients received Un-manipulated (T-cell replete) PBSCT. GVHD prophylaxis consisted of post-transplant Cyclophosphamide (PTCy:50 mg/kg/d on D+3, D+4) along with Tacrolimus + Mycophenolate Mofetil (D+5 onwards). Among 43 patients [29 males, Median age: 27yrs (6-60yrs)], 19 (44%) had active disease, 12 (28%) were in CR1, 11(25%) were in CR2 or CR3, and 1 (3%) patient had CML in chronic phase with T315I mutation. 16 patients had sex mismatched transplant. 35/38 patients screened pre-transplant by Faecal MDRO (multi-drug resistant organism) surveillance culture, were positive for at least one MDRO [14(37%) were carbapenem resistant]. The median CD 34 cell dose was 6.2 x 10^6 cells/kg. Neutrophils engrafted in 37 (86%) patients by D+15 and platelets engrafted in 35 patients (81%) by D+17. 2 patients died pre-engraftment. Mucositis developed in all patients, 88% GradeIII/IV. In the peri-transplant period, 23 patients had positive blood cultures and 18 were Gram negative bacilli. Acute GVHD was seen in 15 (34.8%) patients [Gr III/IV in 5], Chronic GVHD developed in 13 (30%), Veno-Occlusive Disease in 1, and viral infections/reactivations in 33(76.7%). The 100day mortality was 39.5%. At a median follow up of 31.1 months, the relapse rate, non-relapse mortality and estimated 5year overall survival are 16.2%, 39.5% and 33.5%, respectively. Out of the 24 deaths until last follow up, causes included graft failure/rejection (n = 8), aGVHD(n = 5), infection (n = 5), and relapsed disease(n = 6). 7/24 deaths were attributable to Septicemia by MDRO organisms. In conclusion, Myeloablative conditioning followed by haploidentical transplant by a PTCy approach in high risk disease is feasible and is associated with good engraftment rates, acceptable acute GVHD and modest overall survival rates. The high transplant related morbidity and mortality reflects real challenges in the management of MDRO and viral infections, and draws attention to the logistics and cost of salvage therapies in GVHD and graft failure.