Treatment Trends and Outcomes of Allogeneic Haematopoeitic Cell Transplantation (HCT) in Acute Lymphoblastic Leukaemia (ALL) in Resource Restricted Setting; A Pakistan Blood and Marrow Transplant Group (PBMT) Study
Authors: Bokhari Syed Waqas Imam , Khan Mehreen Ali , Ghani Danyal , Ali Natasha , Jamal Aisha , Saad Muhammad , Zaidi Uzma , Ahmad Usman , Ahsan Bushra , Khurram Sana , Khan Farrukh Ali , Bukhari Syed Nasir Abbas , Nadeem Muhammad , Kumari Lavita , Ghafoor Tariq , Mir Muhammad Ayaz , Shabbir-Moosajee Munira , Iftikhar Raheel , Satti Tariq Mahmood 
Published: December 2024

Background: ALL is highly curative in paediatric setting but also proving to have good outcomes in adolescent and young adults (AYA) particularly if treated with paediatric inspired protocols and novel agents such as Blinatumomab and Inotuzumab. Availability of these novel agents is limited due to high-cost in resource limited countries and allogeneic HCT still provides a potential curative treatment.

Method: This multi-centre retrospective study was conducted on behalf of ALL working party of PBMT group across 6 transplant centres to assess the treatments utilised, access to and outcomes of allogeneic HCT for ALL from April 2004 to April 2024. Anonymised data collected by participating centres was shared with PBMT office. Data analysis was done utilising Microsoft excel and SPSS version 24.

Results: A total of 211 allogeneic HCT were performed for ALL from April 2004 to April 2024. 181 out of 211 (86%) transplants were done in past 10 years. Out of total, 149 were males and 62 females. There were 162 patients with B-ALL and 49 with T-ALL. There were 43 patients &lt;18 years of age, 146 between 18-40 years and 22 patients &gt;40 years of age. Only 3 patients were &gt;50 years of age. Cytogenetics were normal in 66 patients, 53 were Philadelphia chromosome positive (PH+), 9 complex, 3 with MLL gene abnormalities and unknown/not done in 80 patients. HyperCVAD was given to 49 patients, BFM-based paediatric inspired protocols in 45, UKALL 2003 or UKALL 2011 in 41 and other regimens (such as FLAG or CalGB) in 9 patients. Commonest salvage re-induction for relapsed cases included FLAG and HyperCVAD. Only 38 out of 53 PH+ patients (71%) received tyrosine kinase inhibitor prior to transplant. The reported indications for transplantation was relapse in 67, delayed measurable residual disease negativity in 37, PH positivity in 53 and high risk features (Age, high WCC, MLL gene abnormalities) in 17 patients. 60% were gender matched transplants, 23 with minor and 33 with major and 4 with bidirectional ABO mismatch. Of total, 165 were matched sibling whereas 46 were haplo-identical related and 2 single antigen mis-matched related transplants. CMV was positive in 207 and negative in 4 donors. Total body irradiation (TBI) based conditioning was used in 67 patients whereas 144 patients received non-TBI chemotherapy-based conditioning. Stem cell source was peripheral blood (PB) in 158, bone marrow (BM) in 46 and both BM and PB in 7 cases. GVHD prophylaxis was with Cyclosporine +/- Methotrexate in 162 (76%) and Tacrolimus or Cyclosporin/Mycophenolate/ATG or Post-transplant Cyclophosphamide in 46 (22%) patients. Days to neutrophil engraftment were 7-31 (median 13) and to platelet engraftment were 8-74 (median 15) with graft failure in 5 patients. Acute GVHD all grades were seen in 73 patients (35%), grade 2-4 in 55 (26%). Chronic GVHD all grades were seen in 56 patients (27%). Other complications included Veno-occlusive disease in 3, CMV disease in 5, thrombotic microangiopathy in 6, haemorrhagic cystitis in 6 and engraftment syndrome in 2 patients. Positive bacterial cultures were reported in 38 patients and 2 patients had invasive fungal infection. 106 out of 211 patients (50%) are alive. Out of the 105 patients who died, 62 (29%) had non-relapse transplant related mortality whereas remaining 44 (21%) had relapse mortality. 5-year Disease free survival (DFS) and overall survival (OS) of the entire cohort was 39% and 40% respectively. Univariate and multivariate analysis for age, T-ALL versus B-ALL, PH+ versus -ve, CR1 versus CR2, matched sibling versus Haploidentical transplants and TBI versus non-TBI based conditioning, did not reveal any significant difference in OS or DFS.

Conclusions: Access to allogeneic HCT in Pakistan for ALL has been quite limited. In the past 10 years, they have been increasing although most are still being done in relapse CR2 or PH+ disease and rarely being done for adults &gt;50 years. There is dearth of availability of the TBI conditioning. All were related transplants and lately more centres have started performing Haplo-identical transplants. 50% of transplanted ALL patients are alive with good long-term survival of 40%. Lack of availability of prohibitively expensive novel agents makes allogeneic HCT an effective therapy for ALL in resource limited countries.