Haploidentical Stem Cell Transplantation for Hematological Disorders: Real-World Experience from India

Abstract

Pallavi Mehta

Haploidentical transplant (haploSCT) has its own unique complications; hence, we studied the outcome of haploSCT from a cancer hospital in India. We retrospectively analyzed the haploSCTs performed at our center between March 2015 and mid-August 2022 using posttransplant cyclophosphamide (PTCy). Ninety-nine patients (95 malignant and 4 nonmalignant) underwent 101 haploSCTs. Myeloablative (MA), nonmyeloablative (NMA), and reduced intensity conditioning (RIC) were used in 35 (34.6%), 43 (42.5%), and 23 (22.7%) transplants, respectively. The median CD34 +  was 5.9 (1.8–10) ×10⁶/kg. The median time to neutrophil and platelet engraftment was 15 (11–32) and 15.5 (9–120) days, respectively. There were 09 (8.9%) cases of primary graft rejection. Eighteen (17.8%) patients had a relapse. Acute graft versus host disease (GVHD) was observed in 33 (32.6%) cases. Blood cultures were positive in 42 (41.5%) transplants. Common viral infections were BK (47.3%) and cytomegalovirus (CMV; 65.3%). The median follow-up was 6 (0.5–89.5) months. Forty-eight (48.4%) patients had died at the last follow-up. The main causes of the death were sepsis (27 [56.2%]), relapse (10 [22.2%]), and GVHD (04 [8.8%]). The nonrelapse mortality was 37.3%. The median overall survival (OS) was 18 ± 11.46 (0–40.77) months. The 1-year OS was 56.7%, while the 2-year OS was 49.3%. We emphasize that haploSCT offers a reasonable hope of survival for patients, although infections remain a significant challenge based on our experience.

 

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Keywords

hematological disorders - haploidentical transplants - graft versus host disease - relapse - infections - survival

Introduction

Allogeneic stem cell transplantation (alloSCT) is a potentially curative treatment of a wide variety of malignant and nonmalignant disorders of hematopoiesis. Traditionally, the best outcomes of alloSCT have been reported when the donor is HLA matched.[1] As a matter of fact, each patient has only a 25% chance of being HLA matched with a sibling and with the small-size family concept now seen in many countries, patients have only about one-third chance of having an HLA-matched donor, which demands the need for alternate donors. Although, according to several studies, the outcomes with matched unrelated donor (MUD) transplants rival those with matched sibling donor (MSD) transplant, cost associated with MUD transplants are huge, which is a major limiting factor for resource-restricted countries.[2] With the emergence of haploSCT in the last decade, our wisdom on its shortcomings has expanded exponentially. An HLA-haploidentical donor is a related donor who shares exactly one HLA haplotype and differs by a variable number of HLA genes on the unshared haplotype, and the greatest edge is that it is almost always available for every patient. The Beijing Protocol was shown to be a reliable treatment strategy for haploidentical stem cell transplantation (haploSCT) patients.[3] The most commonly used and known John Hopkins Protocol incorporating posttransplant cyclophosphamide (PTCy) had shown that high-dose Cy substantially alleviates alloreactivity to the extent that outcomes are constantly improving.[4] However, until recently, various studies have proclaimed that haploSCT may not replace MSD transplants, but may be preferred to MUD transplants. Even so, future prospective comparisons with matched donors would be desirable.[5] [6] Nevertheless, it needs to be acknowledged that there is a discrepancy in the haploSCT outcomes when compared between developed countries and resource-limited countries. There is scarcity of data pertaining to haploSCT being performed in India. A study from South India had reported their experience of haploSCT in primary immune deficiency disorders in the pediatric population.[7] More recently, in regard to hematological malignancies, a study on 149 patients (including 158 haploidentical transplants) stated that haploSCTs are feasible to be performed, but infectious complications are the major challenge.[8] Also, not to forget that graft failure, nonrelapse mortality (NRM), GVHD, delayed immune reconstitution, and relapse remain significant concerns associated with haploSCTs.[9] One of the additional challenges in haploidentical donor selection could be the presence of donor-specific antibodies (DSA) in recipients, which mandates cumbersome desensitization techniques.[10] [11]

We are, therefore, presenting our data of over 7 years on the challenges and outcomes of haploSCT performed with PTCy in patients with hematological disorders.

 

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Patients and Methods

We performed a retrospective study in our bone marrow transplantation unit (BMTU) where all the patients with hematological disorders (benign and malignant) who underwent haploSCT with PTCy between 2015 and 2022 were included. All the patients were screened for anti-HLA antibodies, and only those donors who were nonreactive to the patient were taken as donors. PTCy was administered at a dose of 50 mg/kg/d on D + 3 and D + 4 of infusion of T-cell replete graft. All the patients received mesna in adequate doses along with forced alkaline diuresis. Mycophenolate mofetil (MMF) and calcineurin inhibitors (CNIs; cyclosporine or tacrolimus) were started on day +5. All patients received granulocyte colony-stimulating factor (G-CSF) from day +5 onward. Antifungal prophylaxis with posaconazole or voriconazole or echinocandins was administered as per the clinician's decision after considering previous history of fungal pneumonia and drug interactions with the conditioning regimen. Antiviral prophylaxis with acyclovir or valacyclovir was administered. Pneumocystis prophylaxis with co-trimoxazole was started once the stable engraftment was achieved. Chimerism was tested on days +30, +60, +100, 6 months, and 1-year posttransplant. In case of dropping chimerism, testing was done more frequently. Patients were followed up in the transplant clinic for monitoring of any symptoms and signs of GVHD, tapering of immunosuppression in case of no GVHD, and timely monitoring of disease status.

Data were collected from the medical records and the hospital information system. Data on the baseline demographics of the patients, donor characteristics, engraftment rates, peritransplant complications, graft versus host disease (GVHD), veno-occlusive disease (VOD), infections, relapse, NRM, and overall survival (OS) were captured and analyzed. The study was approved by the institutional review board and the ethical committee.

 

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Statistics

All continuous variables with normal distribution were represented by mean. Non-normally distributed continuous variables were calculated as median. Qualitative variables were represented by percentage. Descriptive statistics was used for the calculation of median with range. Survival analysis was done with the Kaplan–Meier curve. Data analysis was carried out by SPSS software. A p value of <0.05 was considered statistically significant.

 

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Results

Patient Characteristics

In total, 99 patients underwent 101 haploSCTs (including 2 patients who underwent 2 haploSCTs) between 2015 and 2022 at our center. Baseline demographics and clinical characteristics are described in [Table 1]. The median age at transplant was 31 (9–62) years. There were 70 (70.7%) males and 29 (29.2%) females. Common comorbidities associated were diabetes mellitus (5 [05%]), hypertension (5 [5%]), cardiac related (4 [4%]), and hypothyroidism (3 [03%]). Six (6%) patients had a history of chronic infections. Eleven (11%) patients had B-cell acute lymphoblastic leukemia (B-ALL), 9 (09%) patients had Philadelphia positive ALL, 5 (5%) patients had T-ALL, 3 (3%) patients had early T-cell precursor ALL, 40 (40.4%) patients had acute myeloid leukemia (AML), 1 (1%) patient had myeloid sarcoma, 1 (1%) patient had Philadelphia positive AML, 1 (1%) had mixed phenotypic leukemia, 9 (9%) patients had lymphoma (B-cell lymphoma = 2; T-cell lymphoma = 07), 10 (10.1%) patients had chronic myeloid leukemia (myeloid blast crisis = 3, lymphoid blast crisis = 3, mixed phenotype = 1, and T315I mutation = 3), 1 (1%) patient had acute undifferentiated leukemia, 1 (1%) patient had myelodysplastic syndrome, 1 (1%) patient had relapsed hemophagocytic lymphohistiocytosis (HLH) syndrome, and 2 (2%) patients had multiple myeloma (MM). In benign disorders, 1 (1%) patient had transfusion-dependent beta thalassemia and 2 (2%) patients had aplastic anemia. Most patients (54.4%) were in first complete remission (CR1) prior to transplant. Thirty-one (30.6%) patients were in second CR (CR2), 5 (4.9%) patients were beyond CR2 at the time of transplant, and 5 (4.9%) patients were taken for transplant with partial response. One (0.9%) patient had primary graft rejection and 2 (1.9%) patients had persistent disease prior to SCT. The median donor age was 30 (2.5–70) years. Seventy-one (70.2%) donors were males. Twenty-three (22.7%) transplants were from female donors to male recipients, 21 (20.7%) were from male donors to female recipients, 7 (6.9%) transplants were between female donors and female recipients, and 50 (49.5%) transplants were between male donors and male recipients. Sixteen (15.8%) transplants had the father as the donor, 8 (7.9%) patients had the mother as the donor, 57 (56.4%) patients had a sibling as the donor, and 20 (19.8%) patients had their children as donors. Fifty-three (52.4%) transplants were ABO matched, 23 (22.7%) transplants were major mismatched, 15 (14.8%) transplants were minor mismatched, and 10 (9.9%) transplants were bidirectional mismatched. Most of the patients and their donors (93%) were cytomegalovirus (CMV) seropositive, whereas in 7 (6.9%) transplants donors were seronegative. Twenty (19.8%) transplants had host versus graft (HVG) vector on HLA analysis, whereas 25 (24.7%) had graft versus host (GVH) vector. Twenty-three (22.7%) transplants had a class I match and 9 (8.9%) had a class II match.

Table 1 Characteristics, pretransplant status, and transplant variables

Variable	N (%)/median range
Total number of patients Total number of transplants (including 2 patients who underwent 2 haploSCTs)	n = 99 n = 101
Duration	2015 to 2022
Age (y)	31 (09–62)
Sex  Male  Female	70 (70.7%) 29 (29.2%)
Comorbidities (N = 99) Bronchial asthma Stroke Cardiac related Hypothyroid G6PD deficiency HTN Diabetes mellitus	22 (22.2%) 01 (4.5%) 01 (4.5%) 04 (18.1%) 03 (13.6%) 01 (4.5%) 05 (22.7%) 05 (22.7%)
Chronic infections (N = 99)  TB  Hepatitis B  Hepatitis C  HIV  Syphilis	06 (6.0%) 02 (33.3%) 01 (16.6%) 01 (16.6%) 01 (16.6%) 01 (16.6%)
Diagnosis (N = 99) B ALL PH + VE ALL T ALL ETP-ALL AML Myeloid sarcoma Philadelphia AML Mixed phenotype leukemia	11 (11.1%) 09 (9%) 05 (5%) 03 (3%) 40 (40.4%) 01 (1%) 01 (1%) 01 (1%)
Non-Hodgkin's lymphoma  B cell  T cell Hodgkin's lymphoma	02 (2%) 07 (7%) 01 (1%)
Chronic myeloid leukemia Chronic phase (T315I)	03(3%)
Blast crisis  Lymphoid  Myeloid  Mixed phenotype  Acute undifferentiated leukemia  Relapsed hemophagocytic syndrome (HLH)  Myeloma  MDS  Thalassemia  Aplastic anemia	03 (3%) 03 (3%) 01 (1%) 01 (1%) 01 (1%) 02 (2%) 01 (1%) 01 (1%) 02 (2%)
Year of transplant (N = 101)  2015  2016  2017  2018  2019  2020  2021  2022	13 (12.8%) 12 (11.8%) 19 (18.8%) 05 (4.9%) 09 (8.9%) 14 (13.8%) 11 (10.8%) 18(17.8%)
Status at transplant (N = 101) CR1 CR2 CR3 >CR3 PR1 PR2 Primary graft rejection Persistent disease Not applicable	55 (54.4%) 31 (30.6%) 02 (1.9%) 03 (2.9%) 03 (2.9%) 01 (0.9%) 01 (0.9%) 02 (1.9%) 03 (2.9%; 2 aplastic anemia and 1 thalassemia major)
Median age of donor age (y)	30 (2.5–70)
Donor sex  Male  Female	71 (70.2%) 30 (29.7%)
Female donor to male recipient Male donor to female recipient Same sex (female) Same sex (male)	23 (22.7%) 21 (20.7%) 07 (6.9%) 50 (49.5%)
Relationship with donor (N = 101)  Father  Mother  Brother  Sister  Daughter  Son  Maternal uncle	16 (15.8) 08 (7.9%) 39 (38.6%) 18 (17.8%) 05 (4.9%) 15 (14.8%) 01 (0.9%)
Blood group mismatch (N = 101)  Match  Minor mismatch  Major mismatch  Bidirectional	53 (52.4%) 15 (14.8%) 23 (22.7%) 10 (9.9%)
CMV status (N = 101)  D +/R+  D–/R+  D +/R-  D–/R–	94(93%) 06 (5.9%) None 01 (0.9%)
Vector direction  GVH  HVG	25 (24.7%) 20 (19.8%)
HLA class matches  Class I match  Class II match	23 (22.7%) 09 (8.9%)
Conditioning regimen (N = 101) Myeloablative RIC Nonmyeloablative	35 (34.6%) 23 (22.7%) 43 (42.5%)
FluTBI (800 cGy) FluBuCy FluMelTBI (200 cGy) FluCyTBI (200 cGy) FluMel Flu FluCy FluBu FluTBI (200 cGy) rATG	14 (13.8%) 20 (19.8%) 21 (20.7%) 40 (39.6%) 02 (1.9%) 01 (0.9%) 01 (0.9%) 01 (0.9%) 01 (0.9%)
Graft mobilized	101 (100%)
Source of stem cell  PBSC	101 (100%)
Median dose of CD34 (×106/kg)	5.9 (1.8–10)
Engraftment days  Neutrophils  Platelets	15 (11–32) 15.5 (9–120)

Abbreviations: SCT, Stem cell transplantation; HTN, Hypertension; B ALL, B-cell Acute Lymphoblastic Leukemia; PH+ ALL, Phildelphia positive Acute Lymphoblastic Leukemia; T-ALL, T Acute Lymphoblastic Leukemia; ETP-ALL, Early T-cell precursor Acute Lymphoblastic Leukemia; AML, Acute Myeloid Leukemia; CR, Complete Remission; PR, Partial Remission; D, Donor; R, Recipient; GVH, Graft versus Host; HVG, Host versus Graft; RIC, Reduced Intensity Conditioning; Flu, Fludarabine; Bu, Busulphan; Cy, Cyclophosphamide; Mel, Melphalan; TBI, Total Body Irradiation.

 

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Transplant Details:

Myeloablative (MA), nonmyeloablative (NMA), and reduced intensity conditioning (RIC) regimens were used in 35 (34.6%), 43 (42.5%), and 23 (22.7%) transplants, respectively. Stem cell source was G-CSF-mobilized peripheral blood stem cells (PBSCs) in all patients. Median CD34+ stem cell dose was 5.9 (1.8–10) × 10⁶/kg. Postinfusion of stem cells, cytokine release syndrome (CRS) was observed in 89 (88.1%) transplants (grade 1 = 32 [35.9%], grade 2 = 47 [52.8%], grade 3 = 9 (10.1%), and grade 4 = 1 (1.1%)]. The median time to neutrophil and platelet engraftment was 15 (11–32) and 15.5 (9–120) days, respectively. There were 9 (8.9%) cases of primary graft rejection. Chimerism at day + 30 was complete in 77 (76.2%) transplants, whereas mixed chimerism was observed in 4 (3.9%) transplants. Death prior to engraftment occurred in 11 (10.8%) transplants.

 

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Peritransplant and Posttransplant Complications

VOD was seen in 5 (4.9%) transplants ([Table 2]). Severity of VOD according to the European Society for Blood and Marrow Transplantation (EBMT) criteria[12] was mild, moderate, and severe in 2 (40%), 1 (20%), and 2 (40%) transplants. Common regimen-related toxicities (RRT) were renal impairment (19 [18.8%]), hepatic impairment (6 [5.9%]), cardiac dysfunction (3 [2.9%]), pulmonary toxicities (2 [1.9%]), and neurological complications (2 [1.9%]). Hemorrhagic cystitis (HC) was seen in 7 (6.9%) cases, cause being cyclophosphamide in 4 (57.1%) and BK virus in 3 (42.8%) transplants. Other bleeding site complications were seen in 6 (5.9%) cases. CMV reactivation requiring empirical therapy was seen in 66 (65.3%) transplants. CMV disease was seen in two (1.9%; CMV pneumonia = 1, CMV colitis = 1) transplants. Transplant-associated thrombotic microangiopathy (TA-TMA) was observed in 17 (16.8%) patients, which required discontinuation of CNIs. Posttransplant HLH was also noted in two (1.9%) transplants.

Table 2 Rejections, toxicities, infections, and treatment outcomes

Variable	N (%)/
Rejections  Primary  Secondary	11 (10.8%) 09 (8.9%) 02 (1.9%)
Toxicities  Bleeding   PV bleeding   Epistaxis   Hematemesis   Gum bleeding	06 (5.9%) 03 (50%) 01 (16.6%) 01 (16.6%) 01 (16.6%)
Regimen-related toxicities  Cardiac   Acute CHF   Pericardial effusion  Liver   Deranged LFT  Lung   Interstitial pneumonitis  Renal   Deranged KFT  Neurological   Axonal demyelinating polyneuropathy   Tonic clonic seizures	03 (2.9%) 2 (66.6%) 1 (33.3%) 06 (5.9%) 02 (1.9%) 19 (18.8%) 02 (1.9%) 01 (50%) 01 (50%)
Oral + abdominal mucositis  Grade 1/2  Grade 3/4 Cytokine release syndrome  Grade 1  Grade 2  Grade 3  Grade 4 Veno-occlusive disease  Mild  Moderate  Severe Hemorrhagic cystitis  Due to cyclophosphamide  Due to BK virus HLH CMV  CMV viremia (required empirical treatment)  CMV disease Thrombotic microangiopathy anemia	12 (11.8%) 17 (16.8%) 89 (88.1%) 32 (35.9%) 47 (52.8%) 09 (10.1%) 01 (1.1%) 05 (4.9%) 02 (40%) 01 (20%) 02 (40%) 07 (6.9%) 04 (57.1%) 03 (42.8%) 02 (1.9%) 68 (67.3%) 66 (65.3%) 02 (1.9%) 17 (16.8%)
Infections Febrile neutropenia Culture positive bacterial infections In blood Gram negative Sensitive  Klebsiella  Escherichia coli  Pseudomonas  Acinetobacter Resistant  Carbapenem-resistant (CR) klebsiella  ESBL klebsiella  CR E. coli  CR pseudomonas  Acinetobacter	74 (73.2%) 54 (53.4%) 42 (41.5%) 35 (83.3%) 20 (57.1%) 11 (55%) 5 (25%) 3 (15%) 1 (5%) 15 (42.8%) 10 (66.6%) 1 (6%) 2 (13.3%) 1 (6%) 1 (6%)
Gram positive Sensitive Staphylococcus Enterococcus Resistant  MRSA	07 (16.6%) 06 (85.7%) 05 (83.3%) 01 (16.6%) 01 (14.2%)
In urine  Klebsiella  Enterococcus  E. coli  Streptococcus	12 (11.8%) 05 (41.6%) 04 (33.3%) 02 (16.6%) 01 (8.3%)
Stool infection  Clostridioides difficile  Cryptosporidium Syphilis Invasive fungal infections Viral infections  BK virus  COVID-19  EBV  Adenovirus  HHV 6	11 (10.8%) 04 (36.3%) 07 (63.6%) 01 (0.9%) 16 (15.8%) 19 (18.8%) 09 (47.3%) 05 (26.3%) 01 (5.2%) 03 (15.7%) 01 (5.2%)
Graft versus host disease (GVHD; N  = 101) Acute GvHD  Grade 1  Grade 2  Grade 3  Grade 4	33 (32.6%) 03 (9%) 19 (57.5%) 02 (6%) 09 (27.2%)
Site  GI  Skin  GI + skin  GI + oral  GI + skin + liver  Skin + oral No. of steroid refractory patients	13 (39.3%) 08 (24.2%) 09 (27.2%) 01 (3%) 01 (3%) 01 (3%) 06 (18.1%)
Chronic GvHD  Severity   Mild   Moderate   Severe  Site   Skin + oral   Skin + oral + ocular   Skin   Oral + skin+ pulmonary   Hepatic + ocular + skin + nails + joints   Oral + liver   Liver + skin + ocular No. of steroid refractory patients	12 (11.8%) 05 (41.6%) 04 (33.3%) 03 (25%) 02 (16.6%) 01 (8.3%) 02 (16.6%) 04 (33.3%) 01 (8.3%) 01 (8.3%) 01 (8.3%) 01 (8.3%)
Day +30 chimerism  Complete  Mixed  Primary rejection  Death before engraftment	77 (76.2%) 04 (3.9%) 09 (8.9%) 11 (10.8%)
Relapse  BM  CNS	18 (17.8%) 16 (88.8%) 02 (11.1%)
Rejection  Primary  Secondary	11 (10.8%) 09 (81.8%) 02 (18.1%)
DLI  Relapse  Falling chimerism	05 (4.9%) 05 (100%) None
Overall mortality rate at last follow-up (N = 99)   < 30 d  30–100 d   > 100 d	48 (48.4%) 18 (37.5%) 11 (22.9%) 19 (39.5%)
Nonrelapse mortality (NRM)   < 30 d   30–100 d   > 100 d	37 (37.3%) 18 (48.6%) 08 (21.6%) 11 (29.7%)
NRM <100 d	26/99 (26.2%)
Cause of death  Sepsis  Relapse  GVHD  VOD  Fungal pneumonia  Primary graft rejection  HHV6 encephalitis	27 (56.2%) 10 (22.2%) 04 (8.8%) 02 (4.4%) 02 (4.4%) 02 (4.4%) 01 (2.2%)
Median follow-up (mo)  Alive in CR at last follow-up  Alive in relapse at last follow-up  Lost to follow-up after relapse/rejection  Lost to follow-up in CR	42 (42.4%) 01 (1.0%) 07 (7.0%) 01 (1.0%)
Median PFS of the entire cohort	Not reached 5 y estimated OS is 60 + 8%
Median EFS of the entire cohort	39 mo (95% CI: 5.3–72.6 mo) 5 y estimated OS is 32 + 8%
Median OS of the entire cohort	18 mo (95% CI: 0–40.7 mo) 2 y estimated OS is 49.3%

Abbreviations: PV, Per vaginal; CHF, Congestive Heart Failure; LFT, Liver function test; KFT, Kidney function test; HLH, Hemophagocytic lymphocytic histiocytosis; CMV, Cytomegalovirus.

Infections were the major challenge in our cohort. Fifty-four (53.4%) patients had culture-positive bacterial infections (gram negative = 42 [41.5%], gram positive = 12 [11.8%]). Blood culture was positive in 42 (41.5%) transplants, whereas 12 (11.8%) patients had a positive urine culture along with urinary symptoms. In patients with positive blood culture, 35 (83.3%) cases had gram-negative bacteria and 7 (16.6%) cases had gram-positive infection. Among the gram-negative bacteria, antibiotic sensitivity pattern was pan-sensitive for 20 (57.1%) cases, whereas resistant bacteria were observed in 15 (42.8%) cases, the commonest being carbapenem-resistant (CR) klebsiella (66.6%). Among the gram-positive bacteria, antibiotic resistance was seen in only one (14.2%) case. Stool infection was also observed in 11 (10.8%) cases (Clostridium difficile = 4 [36.3%], Cryptosporidium = 7 [63.6%]). One (0.9%) patient had active syphilis infection. Invasive fungal infections were observed in 16 (15.8%) cases. Viral infections encountered were BK virus (9 [47.3%]), COVID-19 (5 [26.3%]), adenovirus (3 [15.7%]), Epstein–Barr virus (EBV; 1 [5.2%]), and human herpesvirus 6 (HHV6; 1 [5.2%]).

Acute GVHD was observed in 33 (32.6%) transplants, where grade 1, 2, 3, and 4 GVHD was seen in 3 (9%), 19 (57.5%), 2 (6%), and 9 (27.2%) patients, respectively. The most common site involved was the gastrointestinal tract (GIT; 13 [39.3%]), followed by skin (8 [24.2%]). Six (18.1%) patients had steroid refractory disease. Chronic GVHD was observed in 12 (11.8%) patients, of which 5 (41.6%) had mild, 4 (33.3%) had moderate, and 3 (25%) had severe GVHD. Common sites involved were oral mucosa, skin, and pulmonary. One (8.3%) patient had steroid refractory chronic GVHD.

 

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Transplant Outcomes

Forty-eight (48.4%) patients had died at the last follow-up ([Table 2]). Deaths at less than 30 days, between 30 and 100 days, and beyond 100 days were 18 (37.5%), 11 (22.9%), and 19 (39.5%), respectively. Causes of death were sepsis (27 [56.2%]), relapse (10 [22.2%]), GVHD (4 [8.8%]), VOD (2 [4.4%]), fungal pneumonia (2 [4.4%]), primary graft rejection (2 [4.4%]), and HHV6 encephalitis (1 [2.2%]). Thirty-seven (37.3%) of 99 transplants (who had completed at least 100 days of follow-up) had NRM. NRM at less than 30 days, between 30 and100 days, and beyond 100 days was 18 (48.6%), 8 (21.6%), and 11 (29.7%), respectively. Eighteen (17.8%) patients relapsed (medullary = 16, CNS = 2) and the median days at relapse was 253 (60–835) days. Five (4.9%) patients received donor lymphocyte infusion (DLI) for relapse. Two (18.1%) patients had secondary graft rejection. After a median follow-up of 6 (0.5–89.5) months, 42 (42.4%) patients were alive in remission and 1 (1%) patient was alive in relapse. Eight (8%) patients (after relapse = 7, in CR = 1) were lost to follow-up. The median OS of the entire cohort is 18 ± 11.46 (0–40.77) months. One-year OS for the entire cohort is 56.7%, while the 2-year OS is 49.3%. The estimated 1-year progression-free survival (PFS) and event-free survival (EFS) for the cohort were 76.70 and 48.50%, respectively ([Fig. 1]). There was no statistically significant difference in PFS (p = 0.796) and OS (p = 0.988) in patients with pretransplant CR1 versus CR2 versus CR > 2 status.

Fig 1 (a) Overall survival (OS) of the entire cohort (1-year OS: 56.7%). (b) Progression-free survival of the entire cohort (1-year OS: 76.7%). (c) Event survival of the entire cohort (1-year OS: 48.5%).

 

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Discussion

Compelled by the lack of universal availability of donors for many patients, the option of haploSCT was explored. In the beginning, haploSCT was associated with inferior outcomes due to high probability of GVHD and graft rejection leading to compromised OS. With the introduction of PTCy strategy, which results in in vivo selective T-cell depletion, these problems have been taken care of to a large extent.[13] In particular, haploSCT for hematological malignancies remains a challenge because of the more aggressive nature of the disease, accumulation of comorbidities due to prior therapies, and significant posttransplant complications. In addition, it is a difficult decision for clinicians in case of older individuals where most patients have at least a child available as donor, making haploSCT a readily available option for them. Additionally, there are challenges with haploSCT due to HLA disparity, which leads to delayed immune reconstitution.[14] [15] The above-mentioned approach of PTCy has revolutionized the use of haploSCT in United States and many European countries.[16] [17] Even developing countries are capable of doing haploSCT with this strategy as it overcomes the need for graft manipulation, which demands special expertise and cell separation devices. Various studies from developed countries have compared the outcome of haploSCT with MSD and MUD and had shown outcomes equivalent to MUD or even MSD.[18] [19] [20] [21] [22] There is a scarcity of literature from developing countries; hence, demonstrating similar outcomes is a challenge.

In India, a study by Jaiswal et al conducted on 40 haploidentical transplants involving both malignant and benign disorders over 3 years showed NRM at day + 100 of 15% and OS at 2 years of 55%. The major cause of NRM mentioned was infection with CR gram-negative bacilli accounting for 90% of the deaths.[23] Another study from India, although done on primary immunodeficiency patients only (n =16), had shown 37.5% mortality with OS of 62.5% with a median follow-up of 23.3 months.[7] In another study by George et al where 149 patients underwent 158 haploidentical transplants for both malignant (n = 85) and nonmalignant (n = 73) indications, the 1-year OS was 44% and 2-year OS was 39%.[8] In comparison, a study by Bacigalupo et al on 459 consecutive patients with hematologic malignancies elicited a 4-year survival of 45% in the MSD group and 52% in the haploSCT group.[24] In another study conducted in China, the OS and disease-free survival and relapse-free survival after MSD were significantly superior to those after haploSCT, although there was no significant difference in the transplant-related mortality (TRM) rate between the two.[5]

In the current retrospective study, 99 patients underwent haploidentical transplants for both malignant (95 [95.9%]) and nonmalignant (4 [4%]) indications with conditioning received as MA (34.6%), NMA (42.5%), and RIC (22.7%). Primary graft rejection was seen in nine (8.9%) patients, which is almost similar to the rate of 8% reported by George et al.[8] In our cohort, acute and chronic GVHD were seen in 33 (32.6%) and 12 (11.8%) patients, with grade 3/5 acute GVHD seen in 11 (10.8%) and severe chronic GVHD in 3 (2.9%) cases. Our results are similar in the rates of development of acute GVHD (grade 3/4) in a study by Jaiswal et al,[23] reported as 9.3%. Similarly, chronic GVHD was seen in 10% patients in their study, which coincides with our results. George et al had also reported acute GVHD in 32% patients.[8] Comparably, Bacigalupo et al had showed an acute GVHD (grade 3/4) rate of 14%, with a trend toward less moderate to severe chronic GVHD in their haploSCT group.[24] Relapses were seen in 18 (17.8%) patients in our cohort. In the above-mentioned study by Bacigalupo et al, cumulative incidence of relapse was 35% in the haploSCT group.[24]

In our experience, infections were a major problem with bacteremia seen in 42 (41.5%) cases (out of these, 83% were gram negative) and viral infections in 19 (18.8%) cases and the commonest virus was BK (8.9%). In another Indian study, gram-negative bacteremia has been reported as 41% and viral infections (CMV and BK) were seen in 68% patients.[8] In our cohort, viral infections including BK and CMV were seen in 76% patients. The major cause of NRM was infection (56.2%). Similarly, George et al had realized that infectious complications were the major challenge with haploSCT.[8] In contrast, Bacigalupo et al had reported infection-related mortality as low as 11%.[24] In our study, the overall TRM was 37.3% and TRM at 100 days was 26.2%. The 1-year OS for the entire cohort was 56.7%, while the 2-year OS was 49.3%. One-year PFS and EFS were 76.7 and 48.5%, respectively. In the study by George et al, 1-year OS was 44.1% and 2-year OS was 39.2%.[8] The Perugia group had reported 40% NRM with common causes being CMV and aspergillus.[25] [26] The Durham group achieved 10.2% TRM at day 100 and 40% at 2 years of follow-up.[27] Other significant posttransplant complications observed were CRS (88%; in contrast to another Indian study that reported CRS in 75% patients[23]), VOD (4.9%), TMA (16.8%), HC (6.9%), and posttransplant HLH (1.9%). Although neither our study nor any other Indian studies have made a comparison between haploidentical, MSD, and MUD transplants, there have been reports of comparison among the three groups in Western literature. A recent meta-analysis including 30 studies elicited that haploSCTs were associated with increased all-cause mortality and NRM compared with MSD, but similar in comparison to MUD.[6]

We acknowledge that there are shortcomings in our study, as the follow-up period was short. Long-term follow-up is required to reflect again on our results in the near future. In addition, we could not include data on posttransplant immune reconstitution due to unavailability of data.

 

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Conclusion

HaploSCTs are an attractive option in alternate donor transplants. However, these are still associated with significant all-cause mortality and NRM with substantial GVHD rates. We are aiming to reduce our NRM rates but still facing the demons of resistant infections. Real-world experience from developing countries is still striving to achieve the optimistic potential highlighted in the Western literature.

 

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Conflict of Interest

None declared.

Acknowledgments

We acknowledge all the staff and team members of the Department of Hematology and Bone Marrow Transplant Unit, Rajiv Gandhi Cancer Institute and Research Centre, India, for their help in performing this study.

Author Contributions

P.M. was responsible for conceptualization, methodology, and writing and preparation of the original draft. Formal analysis and investigation, and writing, reviewing, and editing of the manuscript were done by P.M. and V.K.

Compliance with Ethical Standards

The manuscript is written as per the guidelines of journal and is not under consideration for publication in any other journal. This study was approved by the Institutional Review Board of the hospital. This is a retrospective study. Only data from hospital medical records were collected and no human participants were included; hence, no formal informed consent was required to conduct the study.

• References

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Publikationsverlauf

Artikel online veröffentlicht:
27. September 2023