Haploidentical Hematopoietic Stem Cell Transplantation in India-Bridging the Gap

Hematopoietic stem cell transplantation (HSCT) is a curative option for various benign and malignant hematological conditions. Matched-related donors are available for 25–30% of patients. The various Indian stem cell donor registries are still nascent despite progress over the last few years. Only 15% of patients can get a desired match from these registries with a significant donor cost [1]. A matched unrelated donor (MUD) HSCT requires several weeks for donor search, confirmatory typing of the donor, availability of donor on an urgent basis, apheresis and final delivery of the product to the HSCT centre. This duration can be crucial for a patient with aplastic anemia or a high-risk malignancy who is in urgent need of a transplant.

Immediate availability of a haploidentical (haplo) donor from a family will reduce the need for bridging therapies, reduce transfusion and antimicrobial support that may otherwise be required while awaiting an unrelated donor. This will improve transplant outcomes and also reduce the financial burden [2]. Haplo-HSCT with post-transplant cyclophosphamide (PTCy) also offers potentially increased graft-vs-tumor effect, reduced graft versus host disease (GvHD) risk and easy availability for a donor lymphocyte infusion or a second HSCT [3].

The number of haploidentical HSCTs in India has increased from 62 (of 560 allogeneic HSCTs) in 2013 to 683 (of 1665 allogeneic HSCTs) in 2022 (ISBMT registry data-Personal Communication). In 2022, 26% of adult allogeneic and 35% pediatric allogeneic HSCTs were haploidentical. The number of MUD HSCTs in the corresponding period has increased from 76 to 157. An increase in the number of transplant centres from 37 to 114 during this period has certainly helped the cause.

The current issue publishes 2 articles on the outcomes of haplo HSCTs from 2 different regions of India. George et al. [4] report outcomes of 127 children receiving 138 transplants at a median age of 7.1 years. The main highlight of the study is the two-year survival rate of 55% which is comparable to the Western world data. They showed an improvement in day 100 non-relapse mortality (NRM), which decreased from 50% in 2010–13 to 18% in 2018–21. A high infectious disease burden of 93% is reported. As a shift to PTCy is made, there is a notable increase in viral (predominantly CMV reactivation) infections (76% of patients). Garg et al. [5] report infections as a cause of early mortality in 26% of patients. Rates of primary and secondary graft failure were 16%. Acute and chronic GVHD was only seen in 28% and 6% of the patients respectively which is far better than many published research articles. Despite this, a two-year survival rate of 43% is reported. Major shortcoming of both articles is their retrospective nature. Both cohorts had heterogeneous patient populations and included broader populations of benign and malignant disease. This of course led to varied myeloablative and reduced intensity conditioning regimes. Hence disease specific and conditioning specific outcomes are difficult to analyse as individual numbers were smaller.

The findings from these two independent centers and other reports from India in the last three years paint a vivid picture of the promise and potential of Haplo HSCT (Table 1). From improved engraftment rates to reduced incidences of GVHD, haplo-HSCT emerges as a viable and effective alternative for patients who might otherwise have limited options. As we celebrate these achievements, it is essential to acknowledge the work that lies ahead.

Table 1.

Highlights of publications on Haplo-HSCT from India in the last 5 years

Study (year)	Number	Median age (Range)	Infections	Graft failure	Engrafted	GVHD	Cause of death	Survival
George et al. [4]	Total: 127 Benign:61.5% AA: 46 PID: 21 Malignant: 38.5% AML: 15 ALL: 30	9.1 years (9 months-15 years)	92.7% Bact:31% Viral:76% Fungal:16%	Primary: 10.2%	113 (81.9%) Median: 16 days	Acute: 49.5% Chronic: 40.7%	Pre-engraftment: gram negative sepsis Day100 NRM Malignant Disease: 15.1% Benign Disease: 31.7%	OS (2 years): 54.9%
Garg et al. [5]	Total: 50 Benign: 12 (24%) AA: 6 Malignant: 38 (76%) AML: 16 ALL: 14	20 years (3–53 years)	GN-MDR: 19 (38%) Fungal: 2(4%) CMV reactivation: 33 (66%)	Primary: 3 (6%) Secondary: 5 (10%)	35 (70%) Neutrophil:16 days Platelet:18 days	Acute: 28% Chronic: 6%	Early TRM: 13 (26%) Late TRM: 7 (14%) Relapse related mortality @ day 100: 7 (14%)	OS (2 years): 43%
Arora et al. [12]	Total: 51 Benign:25 Thalassemia-9 SCA 5 AA 6 FA 2 PID 3 Malignant: 26 ALL 15 AML 6	7.5 years (1–18 years)	–	15.6%	42 (82.3%)	Acute: 29% Chronic: 37%	Relapse: 8/15 Chronic GVHD:3/15 Others 4/15	OS (34.5 months): 70% RFS:55%
Jaiswal et al. [13]	Total: 40 Benign: 40 AA: 24 PID: 2	10 years	CMV: 45%	5%	38 (95%)	Acute: 2.6% Chronic: 14.3%	NRM: 5%	OS: (4.6 years) 95%
Kharya et al. [14]	Total: 79 AA: 79	10 years (1–21)	Bacterial: 35(44.3%) Fungal: 5 (6.3%) Viral (non CMV): 12 (15.2%) CMV: 30 (37.9%)	Primary: 12 (16.43%) Secondary: 1 (1.63%)	Neutrophil:15 days Platelet: 18 days	Acute: 26.4% Chronic: 18.9%	TRM: 26 (33%) (all due to infectious complications)	OS (4 years): 61.6%
Lad et al. [15]	Total: 33 AML/MDS: 15 (45%) ALL: 15 (45%)	28 years (15–35 years)	–	–	Neutrophil:14.5 day Platelet: 13 day	Acute: 27% Chronic: 71%	NRM 35%	OS (1.9 year): 52%
Mehta et al. [16]	Total: 99 AML: 42 ALL: 28	31 years (9–62 years)	Culture positive: 42 (41.5%) CMV:65.3%	Primary: 9 (8.9%)	Neutrophil:15 day Platelet: 15.5 day	Acute: 33 (32.6%) Chronic: 71%	Sepsis: 27 (56.2%) Relapse: 10 (22.2%) GVHD: 4 (8.8%)	OS (1 year): 56.7%
Choudhary et al. [17]	Total: 40 Thalassemia: 19 Sickle cell anemia: 21	7 years (1–29 years)	CMV: 42.5%	Primary: 4 (9%) Secondary: 6 (14%)	Neutrophil:14 day Platelet: 17 day	Acute: 22.5% Chronic: 20%	D + 100 TRM: 20% Sepsis: 6(15%) Acute GVHD: 2(5%)	OS (14.3 months): 80%

AA, aplastic anaemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CMV, cytomegalo virus; FA, fanconi anemia; GVHD, graft versus host disease; GN-MDR, gram negative multidrug resistant; MDS, myelodysplastic syndrome; NRM, non-relapse mortality; OS, overall survival, PID, primary immune deficiency; RFS, relapse free survival; SCA, sickle cell anemia; TRM, transplant related mortality

The primary purpose of T-cell depletion has been to prevent GVHD, to avoid short and long-term immunosuppression and to enable early post-transplant immune augmenting therapies. The ex vivo techniques to remove T cells have evolved from the selection of CD34+ hematopoietic stem cell progenitors to the depletion of CD3+ cells to the depletion of alpha beta + T cells with CD45 RO added back [6]. Ex-vivo T-cell depletion strategies are time-consuming, technically challenging and costly. In adults with hematological malignancies, a T-cell replete haplo HSCT has been shown to be superior to T-cell depleted HSCT in terms of OS, NRM, chronic GVHD, immune reconstitution and even infective episodes which is an important consideration in resource constrained settings [7].

PTCY platform for T-Cell replete HSCT comes with a lot of inherent advantages like ease, simplicity, lower immediate donor-related and T-cell depletion expenses, lack of logistics and good manufacturing requirements for ex-vivo T-cell depletion. Even as one of the gaps in terms of the number of haplo HSCTs is being bridged, there is another gap to be bridged. Internationally the outcomes of MSD, MUD and haplo HSCTs are approaching similarity [8, 9]. This is not the case in India as yet. Some of the Indian studies in Table 1 had shorter follow-ups. It is possible that longer follow-ups will reduce survival even further. Infections have been a major deterrent to survival outcomes in India. Varla et al. [10] have shown that drug-resistant gram-negative infection especially carbapenem resistance is associated with high mortality in a group of 399 children who underwent allogeneic HSCT including 152 haplo HSCTs. Another study reported approximately 50% incidence of CMV reactivation in haploidentical HSCTs and it correlated with mortality [11].

Delayed immune reconstitution and subsequent infections are not uncommon and are a major cause of death after haploidentical transplantation. Relapses continue to reduce outcomes in haploidentical HSCT for malignant diseases. We need novel strategies to enhance immune recovery and the prevention of relapse. George et al. [4] have shown a learning curve where patients transplanted in recent times have improved survivals to 67% compared to 25% in the 2010–13 era. While the single-centre experiences presented in these articles are undoubtedly promising, ongoing research should continue to explore optimization strategies for PTCy administration and identify patient-specific factors that may improve treatment outcomes.

Funding

No financial support was obtained in this study.

Declarations

Competing interests

None to declare.