Human Leukocyte Antigen-matched Unrelated Donor Research Articles

Haploidentical and matched unrelated donor allogeneic hematopoietic stem cell transplantation offer similar survival outcomes for acute leukemia.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has emerged as an effective approach for acute leukemia, primarily due to the inherent difficulty in finding human leukocyte antigen-matched unrelated donors (MUD). Nevertheless, it remains uncertain whether haplo-HSCT and MUD-HSCT can provide comparable outcomes in patients with acute leukemia. This study aimed to assess the overall survival (OS) and leukemia-free survival (LFS) outcomes between the MUD-HSCT and haplo-HSCT groups. This retrospective analysis encompassed adult patients with acute leukemia undergoing the initial allo-HSCT. Among these 85 patients, we stratified 33 patients into the MUD-HSCT group and 52 to the haplo-HSCT group. The primary outcomes were OS and LFS. The median OS was not reached in the haplo-HSCT group, while it reached 29.8 months in patients undergoing MUD-HSCT (p = .211). Likewise, the median LFS periods were 52.6 months in the haplo-HSCT group and 12.7 months in the MUD-HSCT group (p = .212). Importantly, neither the OS nor LFS showed substantial differences between the MUD-HSCT and haplo-HSCT groups. Furthermore, univariate analyses revealed that haplo-HSCT did not demonstrate a significantly higher risk of worse LFS (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.25; p = .216) or OS (HR, 0.67; 95% CI, 0.36-1.26; p = .214) than MUD-HSCT. Notably, a high European Group for Blood and Marrow Transplantation risk score (HR, 1.44; 95% CI, 1.10-1.87; p = .007) and non-complete remission (HR, 2.48; 95% CI, 1.17-5.23; p = .017) were significantly correlated with worse OS. Haplo-HSCT may serve as an alternative to MUD-HSCT for the treatment of acute leukemia, offering similar survival outcomes.

Posttransplant cyclophosphamide versus antithymocyte globulin in patients with acute lymphoblastic leukemia treated with allogeneic hematopoietic cell transplantation from matched unrelated donors. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

The aim of this study was to compare two immunosuppressive strategies, based on the use of either rabbit antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCY), as a prophylaxis of graft-versus-host disease (GVHD) for patients with acute lymphoblastic leukemia (ALL) in first complete remission who underwent hematopoietic cells transplantation from matched unrelated donors. Overall, 117 and 779 adult patients who received PTCY and ATG, respectively, between the years 2015 and 2020 were included in this retrospective study. The median patient age was 40 and 43years in the PTCY and ATG groups, respectively, and 37% and 35% of patients, respectively, had Philadelphia chromosome-positive ALL. In univariate analysis, the cumulative incidence of acute and chronic GVHD did not differ significantly between the study groups. The cumulative incidence of relapse at 2years was reduced in the PTCY group (18% vs. 25%; p=.046) without a significant impact on nonrelapse mortality (11% vs. 16% in the ATG group; p=.29). The rates of leukemia-free survival (LFS) and overall survival were 71% versus 59%, respectively (p=.01), and 82% versus 74%, respectively (p=.08). In multivariate analysis, the receipt of ATG compared with PTCY was associated with a reduced risk of extensive chronic GVHD (hazard ratio, 0.54; 95% confidence interval, 0.3-0.98; p=.04) and an increased risk of low LFS (hazard ratio, 1.57; 95% confidence interval, 1.01-2.45; p=.045). The receipt of ATG compared with PTCY, despite the reduced risk of extensive chronic GVHD, is associated with inferior LFS in adults with ALL who undergo hematopoietic cell transplantation from 10/10 human leukocyte antigen-matched unrelated donors. These findings warrant verification in prospective trials.

HLA gamma block matching in unrelated hematopoietic stem cell transplantation and the development of graft versus host disease

The human leukocyte antigen (HLA) genes routinely typed for hematopoietic stem cell transplantation (HSCT) are HLA-A, -B, -C, -DRB1 and -DQB1. HLA mismatches (MM), which have been associated with many post-transplantation complications, including acute graft-versus-host disease (GvHD), sometimes occur when a fully matched donor is not available. Gamma block (GB) is located in the central HLA region between Beta and Delta blocks and contains many inflammatory and immune regulatory genes, including the C4 gene. C4 was proposed as a marker when predicting haplotype matching due to positive linkage disequilibrium (LD) with its surrounding loci. Our aim was to investigate the association between GB matching in patients and their 9/10 HLA matched unrelated donors (UD) and the occurrence of GvHD. Patients and their UDs were typed using the PCR-SSP kit that detects 25 SNPs within GB. Gamma block mismatch occurred in 25 (75.8%) of the 33 studied patient-UD pairs. There was a significant difference in GvHD occurrence between Gamma type matched (GT-M) and mismatched (GT-MM) patient-UD pairs (p=0.0302). The probability of GvHD occurrence had also shown an increase, although insignificant, along with the number of GT-MM between patient-UD pairs (p=0.0913). These results suggest that GT matching could be useful in reducing the risk of post-HSCT complications.

Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors

AbstractAfter the transplantation of unmodified marrow from human leukocyte antigen-matched unrelated donors receiving cyclosporine (CSP) and methotrexate (MTX), the incidence of acute graft-versus-host disease (GVHD) is greater than 75%. Tacrolimus is a macrolide compound that, in previous preclinical and clinical studies, was effective in combination with MTX for the prevention of acute GVHD. Between March 1995 and September 1996, 180 patients were randomized in a phase 3, open-label, multicenter study to determine whether tacrolimus combined with a short course of MTX (n = 90), more than CSP and a short course of MTX (n = 90), would reduce the incidence of acute GVHD after marrow transplantation from unrelated donors. There was a significant trend toward decreased severity of acute GVHD across all grades (P = .005). Based on the Kaplan-Meier estimate, the probability of grade II-IV acute GVHD in the tacrolimus group (56%) was significantly lower than in the CSP group (74%;P = .0002). Use of glucocorticoids for the management of GVHD was significantly lower with tacrolimus than with CSP (65% vs 81%, respectively; P = .019). The number of patients requiring dialysis in the first 100 days was similar (tacrolimus, 9; CSP, 8). Overall and relapse-free survival rates for the tacrolimus and CSP arms at 2 years was 54% versus 50% (P = .46) and 47% versus 42% (P = .58), respectively. The combination of tacrolimus and MTX after unrelated donor marrow transplantation significantly decreased the risk for acute GVHD than did the combination of CSP and MTX, with no significant increase in toxicity, infections, or leukemia relapse.

Extramedullary Gastric Relapse of Acute Myeloid Leukemia After Allogenic Hematopoietic Stem Cell Transplantation.

CASE REPORT A 63-year-old man presented with abdominal discomfort and dyspepsia for 2 weeks. Four years prior, he had a diagnosis of acute myeloid leukemia (AML) with maturation and received induction chemotherapy. He had undergone allogenic hematopoietic stem cell transplantation (allo-HSCT) from a human leukocyte antigen-matched unrelated donor and maintained a complete hematologic remission. Esophagogastroduodenoscopy revealed mucosal edema with erythema and subepithelial hemorrhage, which resembled a snakeskin pattern in the fundus of the stomach (Figure 1). An endoscopic biopsy specimen taken from this lesion showed infiltration of leukemic cells that were positive for myeloperoxidase. The laboratory findings demonstrated a leukocyte count of 3,400/μL, a hemoglobin level of 11.3 g/dL, and a platelet count of 65,000/μL. Bone marrow biopsy showed approximately 10% myeloblasts, which were positive for CD34. He was diagnosed with relapsed AML, and salvage chemotherapy with fludarabine, cytarabine, and granulocyte colony-stimulating factor was begun. After 8 months, his symptoms resolved and follow-up esophagogastroduodenoscopy revealed a complete resolution of previously noted lesion and the obtained biopsy specimen showed no leukemic cells (Figure 2).Figure 1.: Esophagogastroduodenoscopy revealed mucosal edema with erythema and subepithelial hemorrhage, which resembled a snakeskin pattern in the fundus of the stomach.Figure 2.: A follow-up esophagogastroduodenoscopy revealed complete resolution of previous noted lesion.Extramedullary gastrointestinal relapse, despite its rarity, should be considered as a cause of gastrointestinal symptoms in patients with AML who have undergone allo-HSCT. Relapse after allo-HSCT for leukemia commonly occurs in bone marrow, and extramedullary relapse is rare. Extramedullary gastric relapse of AML has been rarely reported in the literature. In reported cases, patients usually have vague and nonspecific symptoms such as abdominal discomfort, dyspepsia, nausea, and gastrointestinal bleeding. It should be noted that these symptoms can also occur in patients with graft-versus-host disease. Therefore, endoscopy and accurate pathological diagnosis are important for differential diagnosis and appropriate treatment. DISCLOSURES Author contributions: J. Hong wrote the article and approved the final manuscript. Y. Joo approved the final manuscript and is the article guarantor. Financial disclosure: None to report. Informed consent was obtained for this case report.

Results of Unrelated Donor Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Europe on Behalf of Paediatric Diseases (PDWP) and Inborn Errors Working Parties (IEWP) of the EBMT

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is, to date, the only curative treatment for sickle cell disease (SCD). Because a human leukocyte antigen (HLA) matched sibling donor is not always available, alternative stem cell sources such as unrelated or haploidentical related donors have been explored. The likelihood of finding a 10/10 (HLA-A, B, C, DRB1 and DQB1) matched donor varies among ethnic groups, with the lowest probability among individuals of African descent. To date, few series of SCD patients transplanted with an unrelated donor (UD) have been reported, but the high rates of rejection and chronic graft versus host disease (cGvHD) have limited its widespread application. Patients and methods: We report the results of a retrospective, registry based, survey on 70 UD HSCT performed in patients (pts) with SCD from UD in 22 European Society for Blood and Marrow Transplantation (EBMT) centers between 2005 and 2017. Data were collected from the EBMT database and missing information was updated by the centers. Median follow up was 38 (range 2-154) months. Most pts were HbSS (n=54; 78%), had positive serology for CMV (80%), and a Karnofsky score >80% (98%). Eighteen pts had a major ABO incompatibility. Recurrent vaso-occlusive crisis (n=58), cerebral vasculopathy (n=23) and acute chest syndrome (n=24) were the main indications for HSCT. Red blood cell (RBC) transfusions pre-HSCT were reported in 97% of pts of whom 53% received more than 20 transfusions; 14% of the transfused pts had RBC alloantibodies. Hydroxyurea pre-HSCT was used in 65% of pts. Median age at HSCT was 9.6 years (range 2-43) with 87% of pts being ≤ 16 years. Stem cell source was bone marrow (BM) in 55 pts (79%) and peripheral blood (PBSC) in 15 (21%). The median number of infused TNC /kg was 3.6 x 108 for BM and 7.1 x 108 for PBSC; the median number of infused CD34/kg was 4.4 x 106 for BM and 8.3 x 106 for PBSC. HLA matching at high resolution typing was 10/10 (HLA-A, B, C, DRB1 and DQB1) in 31, 9/10 in 17 and 8/10 in 4 of the patient-donor pairs; intermediate resolution typing was available for 10 (10/10 or 9/10) and the HLA information was missing for the remaining 8 patient-donor pairs. The most frequent conditioning regimens were fludarabine-thiotepa-treosulfan (64%) and busulfan- cyclophosphamide (12%). GvHD prophylaxis was cyclosporine plus methotrexate in 59%. Anti-thymocyte globulin was used in 90% and alemtuzumab in 9% of pts. Results: The cumulative incidence (CI) of neutrophil engraftment at 60 days was 93% (95% CI 76-100), with median time to engraftment of 18 days; platelet engraftment at 180 days was 90% (95% CI 83-98) with a median time of 20 days. Ten pts had graft failure (5 primary and 5 secondary) of whom 6 had a second transplant and were all alive at last FU (median 9.5 months after second HSCT). The CI of grade II-IV aGVHD at 100 days was 23% (95% CI 15-36), and 8 pts (11%) had grade III-IV. Acute GVHD was more frequent in patients who received PBSC (PBSC 42.9%, BM 18.2%, p=0.062). Three-year CI of cGVHD was 23% (95% CI 15-36), 7 pts (10%) had limited and 9 (13%) extensive cGvHD. Three-year overall survival (OS) was 90±4%; three-year event free survival (EFS) (considering death and graft failure as events) was 76±6%; HLA matching between donor and recipient was the most important factor for OS and EFS. Considering only pts-donor pairs with high resolution HLA typing available (n=52), 3-year OS was 96±4% in 10/10 group compared to 77±11% in 9/10 plus 8/10 group (p 0.065), 3-year EFS was 85±7% vs 62±12% (p 0.040), respectively. No significant differences between the groups were observed in CI of neutrophil engraftment, aGVHD and cGVHD. Conclusion: UD HSCT is a valid option for SCD patients who lack an HLA-identical sibling donor. Nevertheless, efforts are still needed to improve outcomes after UD HSCT. Our results indicate that using a 10/10 HLA matched UD improves both OS and EFS compared to donors with 1 or more mismatches; so, when such a matched unrelated donor is not found, using an haplo relative or an unrelated cord blood as donor source should be evaluated. A prospective trial is in preparation to evaluate the use of haploidentical donors for HSCT in SCD (EudraCT number: 2018-002652-33). Disclosures No relevant conflicts of interest to declare.

Human leukocyte antigen-matched unrelated donor search experience for hematological disorder patients requiring transplant: scenario for Indian patients

Abstract Introduction: Human leukocyte antigen (HLA)-matched unrelated donor (MUD) is the source of MUD transplantation (MUDT) for about 70% of patients who do not have matched related donor. To facilitate MUD search globally, there are 75 stem cell registries with more than 28 million donors registered (as of January 2017). Out of these donors, India has an insignificant representation of approximately 0.23 million. Further, Indians express high genetic variations, making it difficult to find MUD for an Indian patient. Aims and Objectives: The aim of this study is to analyze the MUD search for hematological disorder patients requiring transplant. An attempt was made to observe the MUD scenario for Indian patients requiring MUDT from accessible stem cell registries. Methods: A total of 558 patients approached Genebandhu registry and Chimera Transplant Research Foundation for MUD search over a period of 4 years requiring MUDT were included in this study. High resolution of HLA-A, -B, -C, -DRB1, and -DQB1 was used to perform MUD search through proprietary software called Prometheus and Bone Marrow Donors Worldwide (BMDW) search tool. Results: Out of 558 patients, MUD was located only for 135 (24.19%) patients. Out of these 135 patients, 91 (16.30%) patients found an MUD in global database and only 44 (7.88%) patients within India. Conclusion: This study demonstrates that building a large Indian database will not only help in increasing the chances of finding an MUD for maximum number of patients within India but also provide cost-effective treatment, in a society where cost is a vital factor.

Tyrosine kinase inhibitors improve long-term outcome of allogeneic hematopoietic stem cell transplantation for adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia.

This study aimed to determine the impact of tyrosine kinase inhibitors given pre- and post-allogeneic stem cell transplantation on long-term outcome of patients allografted for Philadelphia chromosome-positive acute lymphoblastic leukemia. This retrospective analysis from the EBMT Acute Leukemia Working Party included 473 de novo Philadelphia chromosome-positive acute lymphoblastic leukemia patients in first complete remission who underwent an allogeneic stem cell transplantation using a human leukocyte antigen-identical sibling or human leukocyte antigen-matched unrelated donor between 2000 and 2010. Three hundred and ninety patients received tyrosine kinase inhibitors before transplant, 329 at induction and 274 at consolidation. Kaplan-Meier estimates of leukemia-free survival, overall survival, cumulative incidences of relapse incidence, and non-relapse mortality at five years were 38%, 46%, 36% and 26%, respectively. In multivariate analysis, tyrosine-kinase inhibitors given before allogeneic stem cell transplantation was associated with a better overall survival (HR=0.68; P=0.04) and was associated with lower relapse incidence (HR=0.5; P=0.01). In the post-transplant period, multivariate analysis identified prophylactic tyrosine-kinase inhibitor administration to be a significant factor for improved leukemia-free survival (HR=0.44; P=0.002) and overall survival (HR=0.42; P=0.004), and a lower relapse incidence (HR=0.40; P=0.01). Over the past decade, administration of tyrosine kinase inhibitors before allogeneic stem cell transplantation has significantly improved the long-term allogeneic stem cell transplantation outcome of adult Philadelphia chromosome-positive acute lymphoblastic leukemia. Prospective studies will be of great interest to further confirm the potential benefit of the prophylactic use of tyrosine kinase inhibitors in the post-transplant setting.

Effect of Early Posttransplantation Tacrolimus Concentration on the Development of Acute Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation from Unrelated Donors

Only limited data are available regarding the relationship between blood concentration of tacrolimus and its efficacy in preventing acute graft-versus-host disease (aGVHD). We retrospectively evaluated the effects of the whole blood concentration of tacrolimus, which was measured by an automated microparticle enzyme immunoassay, early after allogeneic hematopoietic stem cell transplantation (HSCT) upon the development of aGVHD. Sixty patients, who underwent allogeneic HSCT from serologically human-leukocyte antigen-matched unrelated donors and received continuous infusion of tacrolimus with short-term methotrexate for GVHD prophylaxis, were included in this study. The target range of the blood concentration of tacrolimus was set at 10 to 20 ng/mL, and the level was maintained within this range in all patients. However, the mean blood concentration of tacrolimus during the third week after HSCT was significantly associated with the grades of aGVHD (17.3 ± 2.1 in patients with grades 0-I vs 15.9 ± 2.8 in II-IV and 14.8 ± 2.1 in III-IV; P < .05 and <.01, respectively). Multivariate analysis also demonstrated that higher age (≥35) of donor(odds ratio [OR] = 4.28) and lower mean blood concentrations of tacrolimus during the second (OR = 0.75; 95% confidence interval [CI]: 0.58-0.98) and third weeks (OR = 0.76; 95% CI: 0.58-0.98) after HSCT were significant risk factors for grades II-IV aGVHD (P < .05). We conclude that the early posttransplantation blood concentration of tacrolimus had a significant impact on the development of moderate-to-severe aGVHD after allogeneic HSCT from an unrelated donor.

Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Sociéte Française de Greffe de Moelle et de Thérapie Cellulaire

This retrospective report assessed the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard myeloablative conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT) using human leukocyte antigen-matched unrelated donors (HLA-MUD), on the incidence of acute and chronic graft-vs-host disease (GVHD). In this series of leukemia patients, 120 patients (70%) did not receive ATG ('no-ATG' group), whereas 51 patients received ATG ('ATG' group). With a median follow-up of 30.3 months, the cumulative incidence of grade 3-4 acute GVHD was 36% in the no-ATG group and 20% in the ATG group (P = 0.11). The cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively; P = 0.0017). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of extensive chronic GVHD (relative risk) = 7.14, 95% CI: 1.7-33.3, P = 0.008). At 2 years, the probability of nonrelapse mortality, relapse, overall and leukemia-free survivals was not significantly different between the no-ATG and ATG groups. We conclude that the addition of ATG to GVHD prophylaxis resulted in decreased incidence of extensive chronic GVHD without an increase in relapse or nonrelapse mortality, and without compromising survival after myeloablative allo-SCT from HLA-MUD.

Prolonged Agammaglobulinemia Despite Unaltered B-Cell Lymphopoiesis After Peritransplant-Rituximab Administration in a Child

With the following report, we aim to increase the awareness of severe alteration of B-cell maturation leading to agammaglobulinemia in patients who received anti-CD20 therapy after transplantation. A 18-month-old child received an allogeneic hematopoietic-stem cell transplantation (HSCT) from a 9/10 human leukocyte antigen-matched unrelated donor, as therapy for juvenile myelomonocytic leukemia. He had previously received (i) hydroxyurea, low dose-aracytine, and VP16, (ii) aracytine and mitoxantrone, and (iii) aracytine and amsacrine. Conditioning regimen consisted of busulfan-cyclophosphamide, melphalan, and antithymocyte globulin. The number of infused nucleated cells was 16×108/kg. Short-course methotrexate and cyclosporin were used as graft-versus-host disease (GVHD) prophylaxis. Engraftment was confirmed on day 23. Simultaneously, the patient developed cutaneous grade II–III acute GVHD successfully treated by intravenous (IV) methylprednisolone (PDN) (2 mg/kg daily). On day 61, Epstein-Barr virus (EBV)-polymerase chain reaction (PCR) became positive in the blood and remained at high levels despite immunosuppression taper off. Posttransplant lymphoproliferative disorder was diagnosed on clinical history, EBV PCR, and both pathological and immunohistological staining on adeno-tonsilar tissue samples. Rituximab (Mabthera, Roche, France) was administered weekly (375 mg/m2; six infusions). This therapy steadily induced EBV-PCR negativation and clinical symptoms improved. Hundred percent donor-type chimerism was evidenced since day 33 and still evidenced at M40. Around day 90, acute GVHD (grade III) developed in the skin and eyes requiring PDN escalation. Then, GVHD improved and PDN was tapered off. No additional major infectious complication was noticed until now (M40) and heamatologic remission was maintained. As shown in the Figure 1, immunological investigations revealed undetectable immunoglobulin M (IgM) and IgA levels since M12 and IV Igs were required until now because any attempt to interrupt the treatment led to IgG defect. In contrast, B-cell count recovered within the usual delays. Furthermore, full recovery of CD4-T-cells at M12 was accompanied with normal count of CD45RA+/CD62L+/CD4+ naive cells (377/mm3) and T-cell function as measured by in vitro proliferative responses to tetanus toxoid and purified peptide derivative recovered at M15 (92,605 cpm; index: 27 for tetanus toxoid after vaccination and 31,325 cpm/index: 43 for purified peptide derivative).FIGURE 1.: Recovery of humoral and cellular immunity post-HSCT. Serum Ig were monitored by nephelemetry from 6 months before HSCT (M-6) to 40 months (M40) post-HSCT and cell counts were evaluated by flow cytometry as previously described (1) from transplantation (M0) to month 40 post-HSCT. Results are expressed as gram per liters (Ig) and cell number per cubic millimeter (B-cells, T-cells, T-CD4, T-CD8, and natural killer-cells). Immunoglobulin substitution (IV Ig) was started at the time of transplantation (M0) and the patient received rituximab (375 mg/m2; six infusions) at month 3 and half post-HSCT. Horizontal bars indicate the lower limit of normal values in immunocompetent children of 4 years (n=8).A selective defect in B-cell maturation was suspected. It was confirmed by the observation of decreased percentage of CD27+ blood B-cells, that is, 2.7% (2–3 times less than age-matched healthy HSCT donors). The possibility of incidious humoral deficiency in the donor or in the patient before HSCT was excluded by normal B-cell count and elevated titers of EBV-antibodies prior-HSCT in the former and normal levels of IgM, IgA, and IgG before therapy in the later. Rather, EBV infection, combined with altered immunity-related to HSCT and peritransplant rituximab infusion, might be involved in the etiopathogeny of this agammaglobulinemia. Indeed, progressive hypogammaglobulinemia, a common finding after EBV-infection in other immunoregulatory disturbances (2–5), is similarly associated with decreased CD27+ memory B-cells levels (6). Also defective CD27+ B-cells count have been previously reported in patients who received rituximab (7, 8). Valérie Guérin Laboratory of Immunology Robert Debré Hospital Assistance Publique-Hôpitaux de Paris University Paris VII Paris, France Karima Yakouben Brigitte Lescoeur Department of Hematology Robert Debré Hospital Assistance Publique-Hôpitaux de Paris University Paris VII Paris, France Béatrice Pédron Laboratory of Immunology Robert Debré Hospital Assistance Publique-Hôpitaux de Paris University Paris VII Paris, France Jean-Hugues Dalle André Baruchel Department of Hematology Robert Debré Hospital Assistance Publique-Hôpitaux de Paris University Paris VII Paris, France Ghislaine Sterkers Laboratory of Immunology Robert Debré Hospital Assistance Publique-Hôpitaux de Paris University Paris VII Paris, France