Hematopoietic Stem Cell Transplant for Hematological Malignancies: Experience from a Tertiary Care Center in Northern India and Review of Indian Data

Introduction

Hematopoietic stem cell transplantation (HSCT) is the preferred treatment for high-risk and relapsed/refractory (RR) hematological malignancies. Acute myeloid leukemia (AML) and multiple myeloma (MM) are the most common hematological malignancies requiring HSCT. There is scarcity of data on the feasibility and the outcome of autologous and allogeneic stem cell transplant from the developing countries. We report here the real-world data on the outcome of HSCT done at our transplant center.

Materials and Methods

Five hundred and sixteen patients who underwent HSCT at BLK Super Speciality Hospital, New Delhi, India, from August 2010 to November 2019, were evaluated retrospectively using hospital information system and medical records. Informed consent was taken from all patients, and the study was approved by hospital ethical committee and institutional review board. The transplants were conducted in high-efficiency particulate air-filtered rooms. All patients received conditioning regimens as per transplant protocols and transplant physician's discretion depending upon the type of disease and patient's performance status.

Conditioning intensity was defined as per the Consensus Center for International Blood and Marrow Transplant Research criteria.1 Myeloablative conditioning (MAC) regimens were defined by busulfan (Bu) dose > 6.4 mg/kg intravenously, whereas reduced intensity conditioning (RIC) regimens were defined by Bu dose ≤ 6.4 mg/kg intravenously and melphalan (Mel) ≤ 150 mg/m² intravenously. The various RIC conditioning regimens used were fludarabine (Flu)/Mel (Flu 30 mg/m² intravenously for 5 days and Mel 140 mg/m² intravenously for 1 day), Flu/Bu (Flu 30 mg/m² intravenously for 5 days and Bu 3.2 mg/kg/day intravenously for 2 days), Flu/Ara-C/idarubicin/Mel (Flu 30 mg/m² intravenously for 5 days, cytarabine 2 g/m² intravenously for 5 days, idarubicin 8 mg/m² intravenously for 3 days, and Mel 140 mg/m² intravenously for 1 day), and Flu/cyclophosphamide (Cy) (Flu 30 mg/m² intravenously for 5 days and Cy 60 mg/kg intravenously for 2 days). MAC regimen included Bu/Cy (Bu 3.2 mg/kg/day intravenously for 4 days and Cy 60 mg/kg intravenously for 2 days), Cy/total body irradiation (TBI) (Cy 50 mg/kg intravenously for 3 days and TBI 200 cGy twice daily for 3 days), and Flu/Bu4 (Flu 40 mg/m² intravenously for 4 days and Bu 3.2 mg/m² intravenously once daily for 4 days).

The non-myeloablative haploidentical donor (HID) transplant protocol consisted of Flu/Cy/TBI (Cy 14.5 mg/kg/day intravenously for 2 days, Flu 30 mg/m²/day intravenously on days 5 days, and TBI 200 cGy on day –1), whereas the myeloablative HID transplant protocol consisted of Flu/Bu/Cy (Flu 25 mg/m² intravenously for 5 days, Bu 110 mg/m² intravenously for 4 days, and Cy 14.5 mg/kg for 2 days). Donor-specific antibodies were done using single bead assay for all patients undergoing HID transplants.

For autologous HSCT, MM patients received Mel 200 mg/m² (11 patients received Mel 140 mg/m²) and lymphoma patients received BEAM (BCNU 300 mg/m² on day –6; etoposide 200 mg/m² on days –5 to –2 [total dose 800 mg/m²], cytarabine 200 mg/m² twice daily on days –5 to –2 [total dose 1600 mg/m²], and Mel 140 mg/m² on day –1) as conditioning regimens before transplant. Stem cells were infused on day 0. For myeloma patients peripheral blood hematopoietic stem cells (PBSCs) were noncryopreserved and for lymphoma patients PBSCs were cryopreserved.

PBSC harvest was done in blood bank and bone marrow harvest was done in the operation theater under general anesthesia. Posttransplant graft versus host disease (GVHD) prophylaxis included methotrexate, cyclosporine, or posttransplant cyclophosphamide (50 mg/kg on day +3 and day +4 posttransplant), tacrolimus, and mycophenolate mofetil as per protocol. All patients received antimicrobial prophylaxis including fluconazole (200 mg once a day orally), acyclovir (400 mg twice a day orally), and co-trimoxazole, and treatment of febrile neutropenia as per hospital policy. Engraftment was defined by absolute neutrophil count more than 500/μL for three consecutive days and platelet counts more than 20,000/μL for 7 days after last platelet transfusion. GVHD was graded as per Glucksberg criteria and was treated with intravenous methylprednisolone accordingly. After discharge the patients were regularly followed up in outpatient clinics.

Statistical Analysis

Survival analysis was done using Kaplan–Meier curve analysis using MedCalc version 2.0. Multivariate analysis was performed using Cox proportional regression analysis and log rank test for patients undergoing autologous and allogeneic transplants. Statistical calculation for comparison between matched sibling donor (MSD) and HID HSCT was done using chi-square test or Student's t-test as required.

Results

Out of the 516 patients, who underwent HSCT for hematological malignancies, 348 were males and 168 were females. Median age was 43 years (range: 2–75 years) (Table 1). Two hundred fifty-eight (50%) patients underwent autologous HSCT. Among allogeneic HSCT, 181 were MSD HSCT, 64 were HID HSCT, and 13 were matched unrelated donor (MUD) HSCT. The most common indication for allogeneic HSCT was AML (32.4%) and the most common indication for autologous HSCT was MM (35.8%). The most common RIC regimen used was Flu/Mel, and the most common MAC regimen used was Bu/Cy (Table 1). Grade 1 acute GVHD and grade 2 to 4 acute GVHD developed, respectively, in 4.3 and 26.8% patients undergoing allogeneic HSCT. All patients with grade 2 to 4 GVHD were treated with intravenous methylprednisolone 1 mg/kg twice a day as first line treatment. Second line treatment included etanercept (0.4 mg/kg twice a week), ruxolitinib (5–10 mg twice a day), or methotrexate. About 11% patients responded to steroids whereas 36.1% patient required two or more lines of treatment. Chronic GVHD was seen in 16.3% patients. Cytomegalovirus (CMV) reactivation was seen in 31.2% of patients and the patients were treated with intravenous ganciclovir (5 mg/kg twice daily) followed by oral valganciclovir. The 5-year overall survival (OS) and disease-free survival (DFS) for all HSCTs were 65 and 33%, respectively. Table 2 and Figs. 1 and 2 show the disease-specific 5-year OS and DFS. Among allogeneic HSCT patients, the 5-year OS was significantly better in the MSD group compared with the HID group (53.6% vs. 21.7%, p < 0.001), though the 5-year DFS was not significantly different between the two groups (42% vs. 35.7%, p = 0.247). The overall mortality was 30.8%. The most common cause of death was infection followed by relapse of the disease. Seven patients developed proven or probable fungal pneumonia based on bronchoalveolar lavage or chest computed tomography scan findings. Five patients developed posterior reversible encephalopathy syndrome and there was no death due to bleeding. Gram-negative bacterial infection was seen in 18.4% of patients and the most common bacteria grown were Escherichia coli, Pseudomonas aeruginosa, Klebsiella, and Enterococcus. Day +100 transplant-related mortality (TRM) of the total cohort was 16.6%.

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Fig. 1: The overall survival of all hematological malignancies.

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Fig. 2: The disease-free survival of hematological malignancies.

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In multivariate analysis, for allogeneic HSCT, factors impacting OS were chronic GVHD (p = 0.0272), engraftment (p < 0.0001), and Eastern Cooperative Oncology Group (ECOG) status (p = 0.0302), while diagnosis, acute GVHD, donor source, graft source, mucositis, veno-occlusive disease, and CMV reactivation were not significant. For DFS, significant factors were chronic GVHD (p = 0.0064) and engraftment (p < 0.0001), while acute GVHD, ECOG status, graft source, mucositis, veno-occlusive disease, and CMV reactivation were not significant. Primary graft rejection was seen in three patients that underwent HID, two with AML and one with acute lymphoblastic leukemia (ALL).

Discussion

India has a large population of 1.39 billion as per estimates in 2021, with increasing proportion of patients being diagnosed with hematological malignancies, requiring HSCT. In India, approximately 19,421 HSCT have been done till 2019 according to the Indian Society for Blood and Marrow Transplantation Registry (ISBMTR-2020). In 2019 alone 2,932 HSCT were performed in India and about one-third of those who underwent allogeneic HSCT were HID HSCT. With the increasing acceptance and availability of better supportive care, increasing number of patients are undergoing HSCT in developing countries, with improved outcomes and lesser cost of transplant.2 In our cohort of patients, MM was the most common indication for autologous HSCT followed by Hodgkin lymphoma (HL), whereas AML was the most common indication for allogeneic HSCT followed by ALL. There is scarcity of multicenter data from India, with only few single-center studies available (Table 3).

Conclusion

Autologous and allogeneic HSCTs are the curative treatment options for many high-risk and RR hematological malignancies. Though outcome of MSD allogeneic transplant is better than HID transplant, patients having only HID can still be considered for allogeneic HSCT for high-risk diseases. Infections and relapse of the disease post-HSCT are still the major obstacles in the successful outcome of HSCT.