Haploidentical Hematopoietic Cell Transplants in India

In this issue of the South Asian Journal of Cancer, Pallavi Mehta and Vishvdeep Khushoo have reported on their real-world experience with haploidentical (HI) hematopoietic cell transplantation (HCT) for hematological disorders.1

HCT commenced in India way back when a young girl with acute myeloid leukemia (AML) underwent allogeneic matched sibling HCT at Tata Memorial Hospital (TMH), Mumbai, Maharashtra, India.2 Thereafter, TMH continued to be at the forefront by doing the first umbilical cord blood transplantation and even the first HIHCT.3 Today, more than 100 centers offer HCT as standard therapy across India. It is estimated that so far, the Indian Society of Blood and Marrow Transplant has data of at least 3,200 HIHCT and 1,066 matched unrelated donor transplants (between 2012 and 2021). Estimate of annual national number of HCT done is 2,500 and HIHCT is 800 in various active centers from India. A quick PubMed search on HI, HCT, and India resulted in 147 hits, of which 8 articles were within the first 3 months of 2025.4 Clearly, HIHCT have become standard of care, and thanks to the widespread availability of HIHCT, every eligible patient now has the ability to receive potentially curative allogeneic transplantation. That outcome with HIHCT is now similar to every other standard of care option—human leukocyte antigen (HLA)-matched sibling donor transplantation, HLA-identical unrelated donor transplantation, and umbilical cord blood transplantation. In a study consisting of 58 patients with acute lymphoblastic leukemia, total marrow and lymphoid irradiation and cyclophosphamide resulted in a good outcome, especially for those undergoing HIHCT.5 Pallavi Mehta's data even showed that there was no statistical difference in progression-free survival (p = 0.796) and overall survival (OS) (p = 0.988) when comparing their patients with pretransplant complete remission 1 versus complete remission 2.1 We are sure that they will continue to analyze their patients for a longer follow-up and can also do additional evaluation of posttransplant immune reconstitution—two sets of data points that would strengthen their results further.

In some cases, allogeneic HCT is the only potentially curative option. Take the example of dyskeratosis congenital, which often results in marrow failure and even AML. Even though HCT is the only curative option, it is associated with a high mortality. This is because their chromosomal instability leads to high sensitivity to radiation as well as alkylating agents.6 Management includes treosulfan-reduced-intensity conditioning as well as modified PTCy-based prophylaxis against graft versus host disease (GVHD). A recent publication includes such a case with mutation in the DKC1 and RUNX1 genes. Interestingly, the maternal sides were careers and the paternal second-degree sibling was used as the HI donor.6

So, where do we go from here with HIHCT? Relapse still is the primary cause of death. And infection is primarily due to multidrug-resistant (MDR) bacteria or reactivation of cytomegalovirus (CMV)/Epstein-Barr virus. A report from Adyar included 21 patients undergoing HIHCT between 2014 and 2019. At that time 2-year OS was 38% and transplant-related mortality was also 38% (mainly due to MDR bacterial infection).7

Challenge of Infection Needs a Better Solution

Gram-negative infections and MDR have always been the most important barriers in hematopoietic stem cell transplantation (HSCT) in our country. Several centers have started adopting therapeutic, preemptive, or prophylactic granulocytes or pooled buffy coats to prevent and treat MDR. This strategy may need be looked at carefully in the Indian context.

While Clostridioides difficile infections can be common in the HCT setting, they can also be difficult to treat, especially in the HIHSCT setting. An interesting case documents how fecal microbiota transplant successfully overcame that infection that had failed vancomycin and metronidazole therapy. Incidentally, the fecal donor was also the donor of the HSC.8

Infection still remains a big challenge in HIHCT. One report regarding infection with CMV, tuberculosis, and MDR Fusarium sepsis reminds us that we need to be vigilant about every potential site harboring infectious agents, including skin, nails, and the prepuce.9 With the availability of generic letermovir in India things may get better at least with respect to CMV reactivations.

Graft versus Host Disease, Donor Selection, and Graft Rejection

A recent publication from Christian Medical College, Vellore, Tamil Nadu, India, showed that HCT is still associated with significant GVHD (acute 46.3%; chronic 69.4%); infections occurred in the majority (bacterial 24.6%, viral 20.1%, and invasive fungal 17.5%).10 Their multivariate analysis indicates that OS was poorer for older adults (hazard ratio [HR] 3.6, p = 0.006), those with minor blood group mismatch (HR 2.0, p = 0.028), when there was bidirectional blood group mismatch (HR 2.6, p = 0.010), and when using HIHCT (HR 2.2, p = 0.007).10

There is the perception regarding influence of dimorphism (-21 methionine [M] or threonine [T]) in HLA-B peptide (exon 1) on risk of GVHD. This is thought to be through HLA-E binding, which in turn regulates natural killer cell function and increases severity of GVHD. Should this factor be considered in donor selection? Pankaj Malhotra and colleagues performed high-resolution HLA-B genotyping in 89 HSCT patient-donor pairs.10 Their data indicated no significant influence for -21 HLA-B variant between HLA-identical versus haplo-HSCT either with or without GVHD.

HIHCT is associated with a 10% risk of graft rejection. In the rare instance when the HI donor is 100% homozygous at HLA-A, -B, -C, and -DQB1, there is zero mismatch with respect to GVHD and 2 to 5 mismatch for host versus graft disease (it depends on the haplotype of the donor). This can lead to unopposed alloreactivity with disastrous consequences. Navin Khattry's group from Advanced Centre for Treatment, Research and Education in Cancer reported two such cases, with graft rejection among 71 HIHCT done over 2 years.11

Adaptive Cell Therapy and Beyond

Success of HIHCT was initially based on appropriate conditioning with myeloablative and immunosuppressive regimen. Instead of selective T cell depletion, current focus is on adoptive cell therapies that enhance immunity against diseased cells (indication for HCT) and pathogens that can lead to life-threatening infections. For instance, switch gene-modified T cells have suicide genes (e.g., herpes simplex virus-derived thymidine kinase) that can be deleted if and when GVHD occurs.12 And now the focus is shifted to the role of CD4⁺Foxp3⁺ regulatory T cells, which can induce tolerance following allogeneic HCT. T cell-replete haplo-HCT uses one of three strategies—granulocyte colony-stimulating factor-primed grafts and or posttransplant immunosuppression (cyclophosphamide) and/or antithymocyte globulin.12 They have the potential to provide high chance of engraftment along with low incidences of severe GVHD. When associated with a lower nonrelapse mortality, who can argue against this approach? Further improvements are likely to be achieved with innovations like CAR-T (chimeric antigen receptor T cell) cells, bispecific antibodies, and CAR-NK cells.13 High CD45RA⁺ regulatory T cell percentage in the graft favors alloreactivity, nonrelapse mortality, as well as OS in patients receiving PTCy-based HI peripheral HCT.14 Age < 10 years, donor age > 45 years, and poor recovery of Tregs correlated with EA. Higher donor age was also associated with lower CD45RA.15 HCT after repleting T cells has also been used in India for hematological malignancies as well as benign conditions, including Wiskott–Aldrich syndrome.16

Is It Worth Doing Pharmacokinetics to Fine-Tune Conditioning?

Where is the scope to improve the outcome of patients treated with HIHCT? One interesting aspect is regarding cyclophosphamide conditioning. Its metabolite (carboxyethyl phosphoramide mustard) is potentially toxic. One Indian study has documented that its pharmacokinetics (median AUC) is directly associated with severe chronic GVHD and also impacts the GVHD relapse-free survival post-HIHSCT.17 This insight can help devise strategies to personalize therapy.

The Future

We leave the readers with the following questions that are critical and whose answers are likely to be available in the near future, to help us to improve the results of HIHCT:

1. Will indications for haplo-HSCT expand further?

2. Should pre-HSCT residual disease cells be eradicated pre-HIHCT?

3. How to identify subgroup of patients that will benefit most from of haplo-HSCT?

4. Which strategy will be most effective in reducing transplant-related mortality?