Outcome of Allogeneic Hematopoietic Stem Cell Transplant in Patients with Beta Thalassemia Major: Experience from Resource Constrained Centers
Authors: Ur Rahman Khalil , Ahmed Parvez , Sarwar Shahzad , Nasir Shahzad , Zahur Umar , Nadeem Muhammad , Tazeen Saba , Naseeb Summaira , Ahmed Uzair , Ali Dr Asghar , Peter Hina , Afzal Muhammad , Chaudhry Qamar Un Nisa , Mahmood Syed Karman , Abbasi Sumyyia , Fatima Mehroz 
Published: December 2024

Objective: To assess outcome of hematopoietic stem cell transplant in terms of successful engraftment, overall and disease free survival, and transplant related complications.
Study design: Retrospective observational study
Research setting: Patients of BTM who underwent fully HLA matched allogeneic HSCT at Quaide Azam international hospital (QIH) Islamabad, PATHWEL center of hematology and bone marrow transplant (PATHWEL) Rawalpindi and Gambat institute of medical sciences (GIMS) Sindh; Pakistan between January 2019 to June 2024 were included.
Materials and Methods: Patient's medical records were reviewed for data on patient and donor demographics, risk class, conditioning regimens, graft versus host disease (GVHD) prophylaxis, stem cell dose and source, days to neutrophils and platelets engraftment and transplant related complications. Data was analyzed using SPSS software version 25.0. OS and DFS was calculated using Kaplan-Meier method and factors affecting survival analyzed by Cox proportional hazards model.
Results: A total of 77 patients of BTM underwent HSCT during the study period out of which 43 (55.8%) were male and 34 (44.2%) females. Median age at the time of transplant was 8 years (range 2 to 16 years). Forty patients (52%) were in the good risk category (Pesaro class 1 and class 2) while 37 (48%) had high risk disease (Pesaro class 3). Cytomegalovirus (CMV) IgG was positive in 74 (96%) of patients and 75 (97%) of donors. In 69 patients (89% of cases) donors were matched siblings, 6 had parents, one maternal aunt and one 1st cousin as fully HLA matched donors. Fifty-eight patients (75%) were given conditioning protocol consisting of “Fludarabine 120 mg/m2, Busulfan IV 12.8mg/kg, Cyclophosphamide 160 mg/kg with either Anti-thymocyte globulin (ATG) 5 to 15 mg/kg or Thymoglobulin (TG) 2.5 to 5 mg/kg. Thirteen (16.8%) received modified versions of this protocol while 6 (7.7%) patients were given Busulfan 12.8 mg/kg and Cyclophosphamide 200 mg/kg with ATG or TG as above. Calcineurin inhibitors (CNI) (Cyclosporin or Tacrolimus) along with short course Methotrexate (10 mg/m2 on day +1, 8 mg/m2 on day +3 and +6) were given for GVHD prophylaxis. In cases with higher risk of GVHD or intolerance to calcineurin inhibitors, Mycophenolate Mofetil was either added to or substituted for CNIs. In 68 patients (88%) bone marrow harvest (BMH) was used as a stem cell source, peripheral blood stem cells (PBSC) alone in 3 (4%) and BMH plus PBSC in 6 (8%) cases. Median total nucleated cells (TNC) dose was 6.37 x 108 cells/kg (range 1.59 to 27.6) in patients receiving BMH, while median dose of mononuclear cells (MNC) was 8.30 x 108 cells/kg (range 3.50 to 11.8) in those given PBSC or combination of BMH plus PBSC. Median CD34+ cell dose was 7.30 x 106/kg (range 1.49 to 40.20) in all the patients population. Sixty-nine patients (89.6%) had successful engraftment, 3 (3.8%) had primary graft failure while 5 (6.4%) patients died before engraftment. Median time to neutrophils and platelets engraftment was 13 days (range 10 to 33) and 17 days (range 8 to 43) post-transplant, respectively. After a median follow up of 18 months (range 1 to 67), Overall survival (OS) and disease-free survival (DFS) was 88.3% and 83% respectively with mean survival of 752 days. Acute GVHD was seen in 29 cases (37.6%), with 20 (26%) grade I-II GVHD, and 9 (11.6%) grade III -IV GVHD. Mucositis grade I-II was seen in 43 (55.8%) and grade III-IV in 9 (11.6%) cases. Other complications included neutropenic fever in 67 (87%) cases, cyclosporine induced hypertension in 46 (59% cases) and CMV reactivation in 18 (23%). Cause of death was grade IV refractory gut GVHD in 3 (3.8%), sepsis in 3 (3.8%) and primary graft failure in 3 (3.8%) patients.
Conclusion: Hematopoietic stem cell transplant is a viable curative option despite all the challenges in developing countries. With better infection control, more refined conditioning protocols and GVHD prophylaxis plus pretransplant intensive iron chelation and patient education, better results can be achieved.