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      The impact of Host vs. Graft mismatches on rejection of haploidentical bone marrow transplants in thalassemia patients using posttransplant cyclophosphamide

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          Abstract

          To the Editor: Blood or marrow transplantation can cure patients with transfusion-dependent thalassemia (TDT) [1] and normalize their long-term health-related quality of life [2]. In regions where TDT is most prevalent, 38–60% of transplant candidates may find a fully matched-related donor [3], thus a substantial proportion of patients require alternative donors. The use of posttransplant cyclophosphamide (PTCy) as well as ex vivo T-cell depletion methods have allowed to safely perform transplants across HLA barriers [4–6]. Because of its simplicity and inexpensiveness, PTCy seems a particularly attractive option for centers in lower-middle-income countries (LMIC) in South-East Asia where TDT is the most frequent life-threatening noncommunicable disorder of childhood and a major financial burden to families and health care systems [7]. Outcomes using partially matched-related donors (PMRD) with the PTCy approach have been shown to be comparable with those using unrelated or related fully matched donors [5, 8], but unrelated donors in LMIC are often unavailable and/or unaffordable. In the PMRD transplantation context the relevance of donor-specific antibodies (DSA) is well established [9], less so that of different degrees and types of HLA mismatches which, in fact, are not generally considered relevant [10]. We retrospectively assessed the impact of DSA as well as that of Host vs. Graft (HVG) set ups, i.e., when the recipient is homozygous for one or more HLA specificities while the donor is not, so that for those HLA specificities the recipient has the potential to react towards the unshared allele of the donor but not vice versa. A total of 28 consecutive partially matched-related BMTs where analyzed, these were performed between March 2017 and December 2018 in three centers in India: The South-East Asia Institute for Thalassemia in Jaipur, Rajasthan (20 cases), the People Tree Hospitals in Bangalore, Karnataka (seven cases), and the Care Institute for Medical Sciences in Ahmedabad (one case). Selection criteria included a diagnosis of TDT, lack of a fully matched-related donor, age at BMT <15 years (range 1.5–13.5 years, median 5.3), no significant hepatosplenomegaly (<2 cm from costal margin) or serum ferritin >5000 ng/mL pre-BMT. None of the patients underwent a liver biopsy and thus would be considered Pesaro class I–II given the absence of hepatomegaly [1]. A common online electronic medical record system and collaboration platform where data were entered prospectively on a daily basis (BMTPlus®, Jagrity Innovations, Bangalore, India, www.bmtplus.net) [11], and a single transplant approach approved by centers’ IRB was used. The preparative regime, modified from Anurathapan at al. [5], is outlined in Supplementary Fig. 1. All caretakers provided informed consent to share personal data as well as for the BMT procedure. All patients received G-CSF-primed (5 µg/kg twice daily from day −5 to −1) bone marrow with a total nucleated cell dose ranging from 12.1 to 52.9 × 108/recipient kg (median 16.3). Post-BMT all blood products were irradiated with ≥25 Gy. Autologous marrow was cryopreserved in all cases. Chimerism was monitored at least at 1, 2, 4, and 8 months by molecular (STR) analysis or Y chromosome cytogenetics or fluorescent in-situ hybridization when informative. All patients and immediate family members were HLA-typed by sequence-based high-resolution typing confirmed in two independent samples in different laboratories. All but one patient were evaluated for DSA status. Data were collected and analyzed on 31 May 2019. Fisher’s exact tests were used to compare proportions and Mann–Whitney nonparametric test were used to compare continuous distribution values. Kaplan–Meier survival curves were compared using the log-rank (Mantel–Cox) test. All P values are two-tailed. Statistical analysis was performed using GraphPad Prism version 5.00 for Windows, GraphPad Software, San Diego, California, USA, www.graphpad.com. Six out of twenty-five patients (24%) had a rejection, with no significant differences in terms of sex, maternal vs. paternal donor, or cell dose between patient who rejected and those who did not (see Table 1). A total of 4 patients out of 27 evaluated for DSA where positive with mean fluorescent intensity >2000, 2/6 in the rejection group (33%) and 2/21 in the nonrejection one (9%). In the rejection group 3/6 (50%) had a HVG set up (patient characteristics are summarized in Table 2). Actuarial rejection proportion went from 5% in patients with neither DSA-positivity nor HVG set up, to 56% in those with either one, see Supplementary Fig. 2. There was no overlap between DSA-positive patients and those with HVG set up. Among patients who did not reject 4/22 (18%) had a HVG set up, all with unilateral homozygosities at the A locus, in 2 the donor was DRB1 and DQB1 compatible, in 1 was also B and C compatible, and in 1 was DRB1 and DQB1 unilaterally homozygous, thus there was a concomitant HVG and GHV set up. Both DSA-positive patients who did not reject had a GVH set up. None of the patients who rejected had a GVH set up. Of the 21 thalassemia-free patients, 18 (86%) have >95% donor chimerism, 2/22 (9%) of engrafted patients developed grade III or IV GHVD, no case of extensive chronic GHVD has been observed so far. One patient died of grade IV GVHD and had a GVH set up, otherwise there was no apparent correlation between GVH set up and actual occurrence of GVHD. At a median follow up of 13 months (range 5.7–26.4) transplant-related mortality was 24% vs. 17% in DSA+ HVG+ and DSA− HVG− patients respectively with a P value of 0.53. Table 1 Data summary of patients who rejected vs. those who did not Patients who rejected Patients who did not reject P Total patients 6 22 Median age (range) 6.5 (3.4–10) 4.4 (1.5–13.5) 0.40 Sex 4 males, 2 females 16 males, 6 females 1 Donor 5 mother, 1 father 13 mother, 6 father 1 Marrow cell dose ×108/kg 17.3 (16–21.2) 16.2 (12.1–52.9) 0.52 Marrow white cell count/µL 55,445 (31,730–75,600 68,215 (34,790–252,100) 0.15 Table 2 Patients characteristics UPN Age at BMT Sex Donor FU Pre-BMT Blood Tx Cell dose (×108/kg) Day to ANC 500 Day to plt 20,000 DSA HLA notes DSA + or HVG + Latest donor chimerism Rej Acute GVHD CMV activation Status Notes INA16034 4.3 F Mother 26.4 79 23 17 16 Neg A compatible No 100 No 2 Yes A&TF INA15054 2.2 M Father 25.0 28 15.38 17 15 Neg A compatible No 61 No 0 Yes A&TF INA15007 3.9 F Mother 17.2 69 18.5 14 12 Not done B & DPB1 compatible No 100 No 1 No A&TF INA15020 3.4 M Mother 18.4 57 21.7 24 15 Neg No 99 No 2 No A&TF INA12018 8.9 M Mother 13.7 120 15.4 19 20 Neg DRB1, DQB1 & DPB1 compatible No 100 No 0 No A&TF Possible IFD INA13107 8 M Mother 16.2 90 20.5 26 14 Neg DQB1 GVH vector No 100 No 0 No A&TF MAS INA12057 9.4 M Mother NA 201 16.05 26 35 Neg DRB1, DQB1 & DPB1 compatible No 100 No 0 No TRM BK virus HC, ICH INA17022 5.1 F Mother 13.0 50 13.7 24 18 Neg No 100 No 1 No A&TF INE16041 5.9 F Mother 12.2 117 52.9 18 18 Neg B, C, DRB1 & DQB1 GVH vector No 97 No 0 No A&TF INE17035 13.5 M Mother NA 147 12.14 20 25 Neg DRB1, DQB1 & DPB1 compatible No 97 No 0 No TRM Probabble IFD INA10055 11.5 M Father 11.2 198 13.28 24 27 Neg DRB1, DQB1 & DPB1 compatble, A HVG vector No 100 No 2 No A&TF INA17041 2 M Mother 10.3 20 14.12 13 16 Neg A, C, DRB1, DQB1 & DPB1 compatible No 100 No 2 No A&TF INE15024 3 M Mother 9.5 36 44.4 14 18 Neg DRB1 compatible, DQB1 GVH vector No 100 No 0 No A&TF AFC17001 3.4 M Mother 8.5 57 18.4 NA NA Neg DPB1 compatible No 0 d + 30 0 No A&T PGF-PP, Probable IFD INA11012 9.5 F Mother 7.5 204 16 17 39 Neg C compatible No 100 No 0 No A&TF 2nd BMT after MRD rejection, MAS, SOS INA13015 10.7 M Father 6.5 232 16 18 19 Neg No 100 No 2 No A&TF INA13128 7 M Father 6.1 144 14.3 20 16 Neg DRB1 & DQB1 GVH vector No 98 No 0 No A&TF INM17025 3.9 M Mother 5.7 69 23.8 18 19 Neg B, C, DRB1 & DQB1 compatible, A HVG vector No 84 No 0 No A&TF Responded to DLI for EMC INA17009 2.1 M Father NA 12 16.26 19 18 Neg A, C, DPB1 GVH vector No NA No 4 No TRM Severe GVHD-Sepsis INA14043 3.5 M Father 10.9 60 19.13 23 16 Pos DRB1 & DQB! GVH vector, A HVG vector Yes 100 No 2 Yes Dead Death unrelated to BMT INA16078 5.8 M Mother 18.9 115 16.3 NA NA Neg C compatible, DRB1 HVG vector Yes 0 d + 29 0 No A&T PGF-EAR INE16076 4.2 F Mother 18.3 76 14.6 21 29 Neg DRB1 & QB1 compatible, A HVG vector Yes 100 No 0 Yes A&TF INA16041 5.5 M Mother NA 108 20.16 21 19 Pos C compatible Yes 3 d + 43 0 No TRM SGF INC15040 8.3 F Mother 14.2 175 16 NA NA Pos Yes 0 d + 25 0 Yes A&T PGF-PP, Provem IFD INA17120 1.5 M Mother 14.1 12 18.9 20 36 Pos A GVH vector Yes 100 No 1 No A&TF INE17044 10 F Father 13.0 170 21.21 35 54 Neg DRB1 & DPB1 HVG vector Yes 0 d + 20 0 No A&T PGF-PP, SOS INA17021 7.3 M Mother 11.8 90 16.21 NA NA Neg A HVG vector Yes 0 d+25 0 No A&T PGF-PP INA15003 4.6 M Mother NA 86 17.4 NA NA Neg A HVG vector Yes 100 No 3 No TRM MAS FU follow-up, Rej rejection, A&TF alive and thalassemia-free, A&T alive with thalassemia, TRM transplant-related mortality, MAS macrophage activation syndrome, HC hemorrhagic cystitis, ICH intracranial hemorrhage, IFD invasive fungal disease, PGF primary graft failure, PP persistent pancytopenia, SOS synusoidal obstructive syndrome, EMC early mixed chimerism (<day +60), EAR early autologous reconstitution, SGF secondary graft failure Thalassemia seems an ideal model to study the role of immunogenetic factors in the HVG direction because of its homogeneity, functional immune system and exposure to multiple transfusions resulting in higher potential for rejection compared with the hematological malignancy context. The observation that HLA HVG disparities can affect rejection in thalassemia patients has been previously reported in the unrelated setting [12] but not in the haploidentical-related one. A factor which might have contributed to not having identified this HLA vector effect previously in haploidentical BMT is that high-resolution typing is not routinely employed for related donor identification [13], while high-resolution mismatches may have the same clinical significance as low-resolution ones [14]. In fact, the identification of a HLA vector is based on the assumption of true homozygosity of one or more HLA alleles. We believe that even if PTCy is quite effective in inducing tolerance, some degree of escape still remains since GHVD is not infrequent albeit generally mild and manageable. The same maybe true in the HVG (rejection) direction. In conclusion, these findings may have important practical implications for the selection of partially matched donors for nonmalignant conditions in which rejection is a potential issue. With all the limitations of a small case series, in our experience the presence of a HVG set up in the context of thalassemia seems as impactful on rejection as that of DSA. The potential implication is that in this context it might be advisable to get high-resolution HLA typing and possibly consider the use of unrelated donors in the presence of unilateral recipient’s HLA homozygosities. This occurrence maybe more frequent in populations with high consanguinity or close ethnicity, like in the Indian subcontinent. The impact of HLA vectors in the HVG or GVH direction in haploidentical transplantation for thalassemia may deserve to be assessed in larger studies. Supplementary information Supplemental Fig 1 Supplemental Fig 2

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          Most cited references14

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          Global epidemiology of haemoglobin disorders and derived service indicators

          To demonstrate a method for using genetic epidemiological data to assess the needs for equitable and cost-effective services for the treatment and prevention of haemoglobin disorders. We obtained data on demographics and prevalence of gene variants responsible for haemoglobin disorders from online databases, reference resources, and published articles. A global epidemiological database for haemoglobin disorders by country was established, including five practical service indicators to express the needs for care (indicator 1) and prevention (indicators 2-5). Haemoglobin disorders present a significant health problem in 71% of 229 countries, and these 71% of countries include 89% of all births worldwide. Over 330 000 affected infants are born annually (83% sickle cell disorders, 17% thalassaemias). Haemoglobin disorders account for about 3.4% of deaths in children less than 5 years of age. Globally, around 7% of pregnant women carry b or a zero thalassaemia, or haemoglobin S, C, D Punjab or E, and over 1% of couples are at risk. Carriers and at-risk couples should be informed of their risk and the options for reducing it. Screening for haemoglobin disorders should form part of basic health services in most countries.
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            The European Society for Blood and Marrow Transplantation (EBMT) Consensus Guidelines for the Detection and Treatment of Donor-specific Anti-HLA Antibodies (DSA) in Haploidentical Hematopoietic Cell Transplantation

            Haploidentical donors are now increasingly considered for transplantation in the absence of HLA matched donors or when an urgent transplant is needed. Donor-specific anti-HLA antibodies (DSA) have been recently recognized as an important barrier against successful engraftment of donor cells, which can affect transplant survival. DSA appear more prevalent in this type of transplant due to higher likelihood of alloimmunization of multiparous females against offspring’s HLA antigens, and the degree of mismatch. Here we summarize the evidence for the role of DSA in the development of primary graft failure in haploidentical transplantation and provide consensus recommendations from the European Society for Blood and Marrow Transplant Group on testing, monitoring and treatment of patients with DSA receiving haploidentical hematopoietic progenitor cell transplantation.
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              Bone marrow transplantation in patients with thalassemia.

              We reviewed the results of transplantation of allogeneic marrow from HLA-identical donors in patients with beta-thalassemia who were less than 16 years old. Among the 222 consecutive patients who had received transplants since 1983, survival and event-free-survival curves leveled off about one year after transplantation, at 82 and 75 percent, respectively. Pretransplantation clinical characteristics were examined for their impact on survival, event-free survival, and the recurrence of thalassemia in the 116 consecutive patients who were treated with our current regimen, in use since June 1985. In a multivariate analysis, portal fibrosis and either the presence of hepatomegaly or a history of inadequate chelation therapy were significantly associated with reduced probabilities of survival and event-free survival. The patients were divided into three classes on the basis of the presence of hepatomegaly or portal fibrosis (class 1 had neither factor, class 2 had one, and class 3 had both). For class 1 patients the three-year probabilities of survival, event-free survival, and recurrence were 94, 94, and 0 percent, respectively. For class 2 patients the probabilities were 80, 77, and 9 percent, and for class 3 patients 61, 53, and 16 percent. We conclude that for patients under 16 years of age, transplantation of bone marrow from an HLA-identical donor offers a high probability of complication-free survival, particularly if they do not have hepatomegaly or portal fibrosis.
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                Author and article information

                Contributors
                lawrence.faulkner@cure2children.org
                Journal
                Bone Marrow Transplant
                Bone Marrow Transplant
                Bone Marrow Transplantation
                Nature Publishing Group UK (London )
                0268-3369
                1476-5365
                30 September 2019
                30 September 2019
                2020
                : 55
                : 9
                : 1824-1828
                Affiliations
                [1 ]South East Asia Institute for Thalassemia, Jaipur, India
                [2 ]People Tree Hospitals, Bangalore, India
                [3 ]GRID grid.488743.4, Care Institute for Medical Sciences, ; Ahmedabad, India
                [4 ]Sankalp India Foundation, Bangalore, India
                [5 ]Cure2Children Foundation, Florence, Italy
                Author information
                http://orcid.org/0000-0003-1014-3702
                http://orcid.org/0000-0003-4864-6479
                Article
                692
                10.1038/s41409-019-0692-0
                7452814
                31570780
                b7b10281-12f9-45a0-8627-8a6d1139f331
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 6 January 2019
                : 15 June 2019
                : 3 August 2019
                Funding
                Funded by: Sankalp India Foundation, Bangalore, India Cure2Children Foundation, Florence, Italy Fondazione Umberto Veronesi, Milan, Italy
                Categories
                Correspondence
                Custom metadata
                © Springer Nature Limited 2020

                Transplantation
                risk factors,genetics research
                Transplantation
                risk factors, genetics research

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