Unrelated Allogeneic Bone Marrow Transplantation Research Articles

Human leukocyte antigen (HLA) haplotype matching in unrelated single HLA allele mismatch bone marrow transplantation.

The role of matching human leukocyte antigen (HLA) haplotypes in unrelated allogeneic bone marrow transplantation (allo-BMT) remains unclear. Here, we imputed the HLA haplotypes of 3657 patients who received unrelated single HLA allele-mismatched allo-BMT, included from the Transplant Registry Unified Management Program (TRUMP) database, the Japanese registry program for hematopoietic transplantation, using mathematical methods. We successfully imputed the HLA haplotypes of both patients and donors in 1365 cases (37.3%) with ≥90% probability. Of the patients, 1326 (97.1%) and 39 (2.9%) were categorized into one-haplotype-matched and no-haplotype-matched groups, respectively. Disease-free survival was significantly worse in the no-haplotype-matched group. Multivariate analyses revealed that no-haplotype-match was an independent risk factor for reducing disease-free survival (hazard ratio, 1.54 [95% confidence interval: 1.01-2.36]; p = 0.047). However, the overall survival did not significantly differ between the groups. The incidence of grade III-IV acute and chronic graft-versus-host disease did not significantly differ between the groups. Furthermore, there were no significant differences in the cumulative incidences of relapse and non-relapse mortality between the groups. Our findings suggest that imputing haplotypes using a mathematical approach can help to avoid transplanting patients with donors who do not share matching haplotypes, thereby improving the outcome of allo-BMT.

Donor Lymphocyte Infusion for Relapsed Hematological Malignancies after Unrelated Allogeneic Bone Marrow Transplantation Facilitated by the Japan Marrow Donor Program

To evaluate the safety and efficacy of donor lymphocyte infusion (DLI), we retrospectively analyzed 414 recipients who received unrelated DLI (UDLI) for the treatment of relapsed hematological malignancy after unrelated bone marrow transplantation (BMT). UDLI was administered for acute myelogenous leukemia (n = 184), myelodysplastic syndrome (n = 69), acute lymphocytic leukemia (n = 57), chronic myelogenous leukemia (CML, n = 36), lymphoid neoplasms (n = 38), adult T cell leukemia/lymphoma (n = 18), and multiple myeloma (n = 12). Sixty-five patients (16%) were in cytogenetic/molecular relapse and 349 (84%) were in hematological relapse after BMT. In total, 266 out of 414 (64%) patients received chemotherapy and/or molecular-targeted agents in combination with UDLI. The median time from BMT to UDLI was 244 days. The median number of infused CD3+ cells was 3.51 × 107/kg. Response and survival rates were evaluated at 100 days after UDLI. Complete response was obtained in 37 (57%) of 65 patients with cytogenetic/molecular relapse and in 69 (20%) of 349 patients with hematological relapse (P < .001). Two hundred forty-seven patients (60%) were alive, whereas 110 (26%) had died because of disease progression, 26 (6%) because of infections, 12 (3%) because of graft-versus-host disease (GVHD), and 13 (3%) because of organ failure. Multivariate analysis identified molecular/cytogenetic relapse, GVHD after UDLI, and CML but not combination with chemotherapy as significant prognostic factors. These results indicate that UDLI may have efficacy in relapsed patients with CML, low tumor burden, or occurrence of GVHD after UDLI.

Adoptive transfer of food allergy via unrelated allogeneic bone marrow transplant

Adoptive transfer of food allergy via unrelated allogeneic bone marrow transplant

Cold autoimmune hemolytic anemia complicated with relapsed myelodysplastic syndrome after allogeneic hematopoietic cell transplantation

Myelodysplastic syndrome (MDS) is known to often be complicated by a range of autoimmune diseases. We herein present a case with MDS complicated by cold autoimmune hemolytic anemia (cold AIHA). The patient was a 51-year-old woman. She was diagnosed with MDS (refractory cytopenia with multilineage dysplasia) in May 2009. In January 2010, she underwent unrelated allogeneic bone marrow transplantation but was re-admitted in October 2010 for treatment of relapsed MDS. Despite daily transfusions of red blood cells, her anemia failed to improve. Her laboratory examinations showed a low haptoglobin level and elevation of indirect bilirubin and LDH. The direct Coombs test was positive at a low and at room temperature and cold agglutinin was negative. After confirming the diagnosis of cold AIHA, all transfusion fluids were warmed but her anemia still failed to improve. In addition to the warmed transfusion fluids, we administered corticosteroids, immunosuppressive agents and high-dose intravenous immunoglobulin infusions. This management strategy ameliorated the patient's hemolytic anemia. To our knowledge, MDS cases complicated by cold AIHA are rare. Our patient thus provides a valuable contribution to medical knowledge.

Adenovirus Pneumonia Presenting with Nodular Shadows on Chest X-ray in Two Unrelated Allogeneic Bone Marrow Transplant Recipients

Adenoviruses are increasingly recognized as important pathogens following allogeneic stem cell transplantation. We herein report two cases of disseminated adenovirus infection that presented with nodular shadows on chest X-ray after allogeneic bone marrow transplantation from unrelated donors. Both patients died of respiratory failure. Autopsies revealed adenovirus infection of multiple organs. Adenovirus infection should be suspected when nodular lung lesions of unknown origin appear in allogeneic stem cell transplant recipients.

Normal Blood and Bone Marrow Wt1 Expression Level in Extramedullary Relapse in AML Patient

AbstractAbstract 4825Wilms' tumor gene 1 (WT1) that encodes a transcription factor has elevated expression in 90% of AML. High level of WT1 gene expression in bone marrow and peripheral blood of patients with AML indicates the presence of leukemia tumor burden. Thus, quantifying assessment of the level of WT1 could predict relapse. It is important to monitor a universal marker in the absence of target molecular genetic abnormalities in the disease onset. There are few data related to extramedullary relapses. Here we describe the patient with extramedullary relapse without concomitant elevation of WT1 expression.The patient is 22 year old male with the first early bone marrow and CNS relapse of AML. Cytogenetics- (45XY, t (3, 5) (q29; q15), −7, der (7), add (11) (p15)). Blast cells immunophenotype was CD45 + CD34 + CD38 + CD117 +. There was high blast count with high expression of WT1 level (Tabl 1). And there was no expression of other molecular genetic prognostic markers. Therapy with high dose of cytarabine with intrathecal administration of cytotoxic drugs was conducted. The complete hematological and cytogenetic remission was achieved after the first induction. Also there was no any blast cell in the CSF, WT1 expression decreased by 1,87 log (WT1 level became normal). Consolidation of remission with three similar courses with high doses of cytarabine was conducted. Extramedullary relapse during bone marrow and CNS remission with unilateral lesion of the lacrimal gland and the periorbital area( 2.8 × 3.4×4.6 cm )was diagnosed in 6 month. Relapse was confirmed by histological and immunochemical study of the left lacrimal gland biopsy, blasts phenotype was similar to the phenotype of bone marrow blasts at AML onset. WT1 level in bone marrow and peripheral blood remained within normal limits: 15.5 WT1/104 ABL copies and 13.4 WT1/104 ABL copies respectively. Therapy with high dose cytarabine and mitoxantrone was used as an induction. After this therapy a local remission was diagnosed according to MRI. Consolidation courses were followed by a course of radiotherapy to the area of the left orbit. Bone marrow remission and low-level expression of WT1 remained to be normal. Thereafter the patient has undergone unrelated allogeneic bone marrow transplantation. Conclusion.We have described isolated AML relapse without elevation of WT1. A possible reason for normal level of expression of WT1 in patients with extramedullary relapse may be a small amount of the extramedullary formation, its location and features of blood supply of the body area.Table 1Blast count in bone marrowWT1/104 ABL copies in bone marrowAt the diagnosis58%3560,6After the induction1%50,8After the first consolidation course1,4%26,7After the second consolidation course0,4%9,6After the third consolidation course0,4%3,04Follow-up2,4%14,3Follow-up1,4%17,7Extramedullary relapse1,4%15,5Day 14 of ≪HDAC≫3,4%29,4After ≪HiDAC≫6%49,2Follow-up before radiotherapy1,6%15Follow-up after radiotherapy32 [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Frequent Loss of HLA Alleles From Hematopoietic Stem Cells in Patients with Hepatitis-Associated Aplastic Anemia

Abstract 2407 Background:Hepatitis-associated aplastic anemia (HAA), a subset of acquired AA which accounts for 5% of all AA, is thought to have an immune-mediated pathogenesis. Although the attack by CD8+ T cells may be responsible for both hepatitis and bone marrow failure, the exact mechanisms underlying the development of HAA, as well as the reason for the time lag from its onset to that of hepatitis remain unclear. We recently found HLA-class I allelic loss from leukocytes due to copy-number neutral LOH in chromosome 6p (6pLOH) in 15% of AA patients, and identified four class I alleles (HLA-A*02:01, A*02:06, A*31:01, and B*40:02) that are overrepresented in AA, based on the finding that the missing HLA haplotype of 6pLOH(+) patients frequently contained one of the four alleles. Such immunologically-selected hematopoiesis caused by HLA allelic loss may be more common in patients with HAA than in non-HAA patients because HAA presents with homogenous pathophysiology, and a kinetic analysis of the HLA-missing leukocytes may help to understand the immune pathophysiology of HAA. Objectives/Methods: To gain insight into the immune pathophysiology of HAA, 17 patients with HAA (11 males and 6 females) aged 1 to 63 (median 23 years) whose 10 HLA allelic data were available were analyzed for this study. Blood samples from seven of the 17 patients were examined for the presence of 6pLOH and leukocytes lacking HLA-A antigens using Affymetrix® 500K SNP arrays and flow cytometry (FCM) using allele-specific monoclonal antibodies. For three HAA patients whose blood samples before therapy were available, peripheral blood was serially examined for the presence of HLA-A missing leukocytes. The frequency of high risk HLA alleles in HAA patients were compared to those of non-HAA patients and of 6,629 registries from the Japan Marrow Donor Program who had received an unrelated allogeneic bone marrow transplant. Results: 6pLOH was detected in 4 (57%) of the 7 HAA patients, which was more frequently than in non-HAA patients (12%, P=5.1 × 10−4). Granulocytes with unilateral HLA-A expression were detectable in all four patients at a frequency of 23% to 99%. The loss of HLA-A expression in the 6pLOH(+) cases was found in multiple lineages of leukocytes, including granulocytes, monocytes, B cells, and to a lesser extent, in T cells and NK cells. The missing HLA haplotypes of the 4 patients included at least one of the four high risk alleles. The frequency of patients possessing one or more of the high risk alleles was 77% in HAA patients, 64% in non-HAA patients, and 52% in the control population (P=0.03 for HAA vs. control; P=0.25 for HAA vs. non-HAA; P=2.0 × 10−8 for AA vs. control). In one patient who developed severe hepatitis and AA simultaneously, HLA-A missing leukocytes were not detectable before ATG, but all granulocytes that appeared 16 days after ATG therapy lacked an HLA-A antigen. On the other hand, in two patients who developed AA 1 month and 2 months after the onset of hepatitis, HLA-missing leukocytes were detectable before therapy at a frequency of 31% and 37%. The percentages remained unchanged in both a patient who responded to ATG (Figure) and another non-responding patient. Conclusions: HLA allelic loss from leukocytes and the high risk class I alleles were more strongly associated with HAA than idiopathic AA, suggesting that cytotoxic lymphocyte (CTL) attack against hematopoietic stem cells (HSCs) is involved in the pathogenesis of HAA. A 2-step mechanism may explain the time lag between hepatitis and the onset of AA; CTLs simultaneously attack hepatocytes and HSCs, but it takes several weeks or months until the secondary immune response can suppress HSCs enough to develop pancytopenia, because subsequent cytokine secretion is needed to cause BM failure. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation

Mycophenolate mofetil (MMF) has been widely used for prophylaxis against graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-SCT). However, no clear advantage over methotrexate has been reported, other than reduced incidence of mucositis. We speculated that the wide inter-individual variation of plasma mycophenolic acid (MPA) levels veiled the benefits of MMF. Data from 36 unrelated allogeneic bone marrow (allo-BMT) and cord blood transplantation (CBT) were analyzed retrospectively based on MPA area under the curve (AUC(0-24h)). In allo-BMT, high AUC(0-24h) (>30μgh/ml) resulted in no incidence of grade II-IV acute/extensive chronic GVHD and tended to show higher overall and disease-free survival, lower relapse rates, and non-relapse mortality. In CBT, AUC(0-24h) less than 30μgh/ml was sufficient for low incidence of acute/chronic GVHD and high survival. Strong correlation between AUC(0-24h) and C(2h), plasma MPA concentration at 2h after administration was observed. Single point assessment of C(2h) was shown to provide a useful surrogate of AUC(0-24h) to predict GVHD incidence. The results of this study suggest that individualized MMF dosing in a donor source-dependent fashion may be important for maximizing the benefit of MMF in allo-SCT.

非血縁者間同種骨髄移植を施行し良好な経過をとっているNF-1に合併した若年性骨髄単球性白血病 (JMML) の2例

非血縁者間同種骨髄移植を施行し良好な経過をとっているNF-1に合併した若年性骨髄単球性白血病 (JMML) の2例

Successful allogeneic bone marrow transplantation for myelodysplastic syndrome complicated by severe pulmonary alveolar proteinosis

Pulmonary alveolar proteinosis (PAP) is a rare disorder characterized by the abnormal accumulation of alveolar surfactant protein in alveolar spaces. We report herein a rare case of myelodysplastic syndrome (MDS-RAEB) complicated by severe PAP, and successful allogeneic bone marrow transplantation (BMT) for both disorders. An unrelated BMT was planned for a 48-year-old male with advanced MDS-RAEB. Just before the initiation of the conditioning regimen for unrelated BMT in March 2007, he developed dyspnea. A diagnosis of PAP was made based on findings of chest X-ray, CT scanning, and the fluid obtained by bronchoalveolar lavage. To improve his dyspnea and improve BMT safety, whole lung lavage (WLL) was performed twice, with the partial improvement of PAP. Unrelated allogeneic BMT was performed in September 2007. We had to perform a third WLL because of the worsening of PAP on day 26 after BMT. Despite many infectious complications after BMT, GVHD was relatively mild. PAP had almost disappeared 6 months after BMT. He was well with favorable hematopoiesis 20 months after the BMT without any specific treatment. There has been no report of an MDS patient with PAP in whom 3 WLL procedures were performed before and after allogeneic BMT.

Chronic active Epstein–Barr virus infection with mosquito allergy successfully treated with reduced‐intensity unrelated allogeneic bone marrow transplantation in a boy

EBV-infected T-/NK cells play an important role in the pathogenesis of mosquito allergy, and the prognosis of most patients with mosquito allergy is poor without proper treatment. We describe a 13-yr-old boy who had CAEBV with mosquito allergy and was successfully treated with BMT from an unrelated donor after reduced-intensity preconditioning. Because combination chemotherapy failed to achieve CR, we performed unrelated BMT to reconstitute normal immunity and eradicate any residual EBV-infected cells. To reduce complications after BMT, we selected a reduced-intensity preconditioning regimen consisting of fludarabine, l-phenylalanine mustard, and antithymocyte Ig instead of a conventional myeloablative preconditioning. Although grade II acute GVHD developed, it was successfully controlled with immunosuppressive therapy. After 27 months, the patient has been well without any signs of CAEBV, and the EBV DNA has been undetectable with real-time PCR analysis. We conclude that RIST from the bone marrow of an unrelated donor is indicated for some patients who have CAEBV that is refractory to chemotherapy and who have no HLA-matched related donors or cord blood as a source of stem cells.

Post-transplant plasmacytoma without Epstein–Barr virus infection occurring rapidly after unrelated allogeneic bone marrow transplantation

Post-transplant lymphoproliferative disorders (PTLD) represent a heterogenous group of lymphoid proliferations that develop as a consequence of immunosuppressive therapy in recipients of solid organ or bone marrow (BM) transplantation (BMT). PTLD range from benign hyperplastic lesions to lymphoid neoplasm including plasma cell tumors, and they are mostly Epstein–Barr virus-related [1, 2]. In contrast to the high incidence of post-transplant lymphomas, PTLD manifesting as plasma cell tumors such as multiple myeloma and extranodal plasmacytoma are extremely rare [3]. We report a case of plasmacytoma without evidence of Epstein–Barr virus (EBV) infection which developed rapidly after bone marrow transplantation. A 45-year-old Japanese male with myelodysplastic syndrome (MDS, RAEB-1) received myeloablative allogeneic bone marrow transplantation due to progressive pancytopenia and episodes of recurrent infection. Pretransplant evaluation did not detect plasma cell proliferation in bone marrow aspirate and clot sections, monoclonal gammopathy on serum protein electrophoresis, or splenomegaly on the computed tomography (CT) scan (Fig. 1a). The serum IgG, IgA and IgM values were 1,160, 188, and 123 mg/dl, respectively. These were within the normal range. The conditioning regimen comprised conventional TBI and CY. He had no available HLA-identical family donors. He received an infusion of unmanipulated bone marrow containing 3.6 9 10/kg nucleated cells from a minor ABO-incompatible, one allele-mismatched (HLA DRB1) (disparities in the rejection direction), unrelated male donor. Tacrolimus and short-term MTX were administered for GVHD prophylaxis. Treatment with G-CSF was initiated on day ?5. On day ?7, severe stomatitis and febrile neutropenia (FN) developed. Immediate treatment was started with broad-spectrum antibiotics and an anti-fungal agent. The patient engrafted (ANC[500/mm) on day ?18 after the transplant. However, a platelet count above 5 9 10/mm was not observed. Along with recovery of the neutrophil count, stomatitis and FN improved. Cytomegalovirus (CMV) antigenemia developed on day ?28. Treatment with ganciclovir was started and CMV antigenemia disappeared. The patient did not develop acute graft-versus-host disease (GVHD). On day ?36, a fever of unknown origin and bilateral lower limb pain developed. Radiograph of bilateral lower limb did not show any abnormality including osteolytic lesion. These symptoms did not resolve despite the administration of broad-spectrum antibiotics and an anti-fungal agent. The neutrophil count began to decrease on day ?42. On day ?49, the serum IgG was 1,028 mg/dl, which was within the normal range. K. Kawakami (&) H. Mitani M. Nakao Division of Hematology, Suzuka General Hospital, Yasuzuka-cho, Suzuka, Mie 1275-53, Japan e-mail: Kawakei@cocoa.ocn.ne.jp

Escape of Minor Histocompatibility Antigen-Restricted Anti-Leukemia Immunity Associated with Loss of Specific HLA-I Locus Expression in a Leukemia Patient after an Intensive Immunotherapy.

Differential graft versus host response after bone marrow transplantation (BMT) is key to leukemia patient survival. The development of specific graft versus leukemia response targeting tissue-specific minor histocompatibility antigens (mHAgs) is a novel therapeutic approach to treating hematopoietic malignancies. A pilot intensive immune cell therapy was applied to an acute myeloid leukemia (AML) patient who relapsed around day 43 after receiving unrelated allogeneic BMT with three allele disparities for HLA-A, C and DQB1. The patient received more than thirty infusions of dendritic cell-co-cultured donor-derived immune cells including cytotoxic T lymphocytes (CTL) generated against AML lysate-pulsed dendritic cells (DC), AML-DC fusion, and DC pulsed with HLA-A*2402-restricted ACC1Y mHAg epitope. The latter was expressed by recipient but not by donor hematopoietic cells. ACC1Y-peptide-major histocompatibility complex (MHC) multimer staining detected CTL in the patients peripheral blood at different time points during treatment. Four months after the first mHAg-CTL infusion, CTL-resistant AML cells were detected in relapsed pleural effusion and peripheral blood. Further analysis of the relapsed AML cells revealed complete loss of surface class I HLA-A*2402 and class II HLA molecules. Although the AML-specific immune cells were effective in killing the original AML in CTL assays in vitro, the late relapsed AML became resistant to the early AML-primed CTL. This result suggests that rapidly evolving AML cells may escape the intensive anti-leukemia allo-immune pressure including the mHAg-specific CTL through selective loss of A*2402 expression - the ACC1Y-restricted HLA locus. As the patient suffered ongoing multi-focal extramedullary relapse in muscles, sub-mucosal tissue, intestine, spinal cord, and brain, rare cancer cells resistant to mHAg-specific CTL could evolve quickly. Our study indicates that immune escape through diminished HLA expression, which resulted in lack of cancer cell killing by AML-specific immune cells, including the mHAg-restricted CTL, had developed during the therapy. Therefore, leukemia patients with high load of AML or multi-focal extramedullary relapse may not endure prolonged benefit from a single arm immune cell therapy.

Acute Myelomonocytic Leukemia with Dysplastic Bone Marrow Eosinophils Showing t(5; 17)(q13;q11) and a Secondary Chromosomal Aberration, inv(16)(p13q22)

inv(16)(p13q22) is associated with de novo acute myelomonocytic leukemia with dysplastic bone marrow eosinophils (AMML Eo), which has a relatively favorable clinical course with a longer remission duration and better survival prospects. On the other hand, t(5; 17)(q13;q11), although relatively rare, has been reported to be a component of complex chromosomal abnormalities in myelodysplastic syndromes and secondary acute myeloid leukemia (AML). We treated a 29-year-old woman with the first reported case of de novo AMML Eo with inv(16)(p13q22) in addition to t(5; 17)(q13;q11). Although she attained complete remission (CR) immediately after induction therapy, the disease recurred 1 year after the completion of consolidation therapies. She underwent HLA-matched unrelated allogeneic bone marrow transplantation (UBMT), together with a myeloablative conditioning regimen, after achieving a second CR and has survived without a recurrence for more than 24 months since UBMT. In general, certain secondary chromosomal abnormalities are associated with the phenotype of the disease, which retains its essential biologic characteristics established by the primary abnormality. Accordingly, the primary nature of the leukemic cells in this case differs from the findings for core-binding factor AML with inv(16)(p13q22). We believe this report is the first of de novo AMML Eo with t(5; 17)(q13;q11) showing as a secondary chromosomal aberration with inv(16)(p13q22).

Identification of Non-Permissive HLA Allele Mismatch Combinations and Amino Acid Substitution Responsible for Acute Graft-Versus-Host Disease in Unrelated Allogeneic Bone Marrow Transplantation.

Background: In the allogenic hematopoietic stem cell transplantation from unrelated donors (UR-HSCT), an effect of HLA locus mismatch in allele level on clinical outcome has been clarified. However, the effect of each HLA allele mismatch combinations is little known, and its molecular mechanism to induce acute graft versus host disease (aGVHD) remained to be elucidated.Methods: Consecutive 4866 patients transplanted with T cell replete marrow from a serologically HLA-A, -B and -DR antigen-matched donor through Japan Marrow Donor Program were registered in this cohort study. All HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles were retrospectively typed in 2171 pairs, and partly in the other pairs. The impact of the HLA allele mismatch combinations in HLA six loci and amino acid substitution positions in HLA-C and HLA-DPB1 locus on aGVHD and survival was analyzed using a multivariable Cox regression model.Results: Significant high-risk HLA allele mismatch combinations compared with match for severe aGVHD were identified; four in HLA-A allele (donor A*0206- patient A*0201 (n=108) hazard ratio (HR): 1.77, A*0206-A*0207 (n=20) : 3.24, A*2601-A*2603 (n=32): 1.96, A*2602-A*2601 (n=24): 2.18), six in HLA-B (B*1507-B*1501 (n=14): 2.95, B*4002-B*4003 (n=14): 2.44, B*4002-B*4006 (n=85): 1.69, B*4003-B*4006 (n=7): 3.85, B*4006-B*4002 (n=60): 1.62, B*4403-B*4402 (n=4) : 5.78), 11 in HLA-C, six in HLA-DRB1, zero in HLA-DQB1 and two in HLA-DPB1. Amino acid substitutions of position 80 of HLA-C at which donor had Asp80 and patient Lys80 (Asp80-Lys80) and Ser77-Asp77 were first elucidated as significant risk factors for severe aGVHD. These two amino acid substitutions were completely linked, and HR for severe aGVHD was 1.49 (1.01–2.21). As position 80 is ligand for NK cell receptor KIR2DL as a result, further analysis was performed in the KIR2DL ligand match in the GVH vector population. Notably, particular amino acid substitution at positions 95, 156 and 163 of HLA-C was a significant risk factor for severe aGVHD. HR of Leu95-Ile95, Arg156-Leu156, Leu156-Trp156, Trp156-Leu156 and Thr163-Leu163 substitutions were 1.74 (95%CI: 1.06–2.86), 2.10 (1.16–3.81), 5.22 (1.65–16.4), 4.64 (1.04–20.7) and 1.82 (1.11–2.99), respectively. The amplitude of hydropathy scales were 0.7, 8.3, 4.7, 4.7 and 4.7, respectively. Amino acid substitutions of any other positions of HLA-C were not significant risk factors. When analyzing the location of amino acid substitution in HLA-C, residues located in the T-cell receptor contact have marginal impact on severe aGVHD (HR: 1.45 trend P=0.096), and no other locations were significant. In HLA-DPB1 mismatch combinations, there was no obvious tendency to associate the positons of amino acid substitutions with severe aGVHD and grades 2–4 aGVHD.Conclusion: These findings provide evidences to elucidate the mechanism of aGVHD on the base of HLA molecule. Furthermore, the identification of non-permissive and possible permissive mismatch would be beneficial for the selection of suitable donor and international donor exchange for UR-HSCT.

Economic analysis of unrelated allogeneic bone marrow transplantation: results from the randomized clinical trial of T-cell depletion vs unmanipulated grafts for the prevention of graft-versus-host disease

Unrelated-donor marrow transplantation is a potential option for transplant candidates lacking a compatible related donor. The T-cell Depletion Study compared the 3-year disease-free survival for patients receiving T-cell-depleted (TCD) donor marrow (n = 203) vs unmanipulated donor marrow with methotrexate and cyclosporine (M/C) (n = 207). Hospital costs during index admission were documented with billing data, while hospital costs during subsequent 6-month follow-up were estimated from case report forms. Patients with index admission billing were included in the analysis (TCD = 119, M/C = 127). Total hospital length of stay (LOS) was similar across groups, with medians 47.0 days for TCD and 52.0 days for M/C (P = 0.72). Total hospital costs were comparable, 145,115 dollars vs 141,981 dollars (P = 0.63) for TCD and M/C, respectively. However, controlling for site and patient characteristics, TCD was associated with a 12.1% reduction in LOS for the index admission (95% CI -19.4%, -4.3%). Independent of treatment, HLA matching (6/6) was associated with an 8.6% (95% CI -17.4%, +1.2%) reduction in the index admission LOS, while cost was lower by 15.8% (95% CI -26.7%, -3.3%). Treatment costs were similar for TCD and M/C study groups. Savings on reduced cost for treating acute graft-versus-host disease were likely offset by increase in serious infections in the TCD arm.

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens

The role of T-cell depletion (TCD) to prevent graft-versus-host disease (GVHD) after matched unrelated donor allogeneic bone marrow transplant (MUD BMT) remains undefined. Most studies employ total body irradiation and pan TCD. Between March 1993 and June 2002, we treated 33 relapsed acute myelogenous leukemia (AML) patients with busulfan-based preparative regimens and selective TCD. The preparative regimen consisted of busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and VP-16 50 mg/kg in all but one patient who only received busulfan and cyclophosphamide. Donor marrow was depleted of CD8+ T cells by immunomagnetic bead separation. The patients were also treated with cyclosporine and methylprednisolone or FK-506 and mini-dose methotrexate. Four (15%) of 33 patients developed graft failure or rejection. However, three of these patients were serologically mismatched at HLA-Cw. Although 67% of evaluable patients developed acute GVHD, severe grade III-IV acute GVHD only developed in 19%. The severity of acute GVHD correlated with the degree of CD8+ TCD. Median relapse-free survival was 5 months among 20 patients treated with active AML, and 28 months among 13 patients treated in complete remission. Our results confirm that MUD BMT with CD8+ TCD for AML is a potentially curative treatment option.

Cytomegalovirus and adenovirus infections and diseases among 75 paediatric unrelated allogeneic bone marrow transplant recipients.

Viral infections remain a major complication of allogeneic bone marrow transplantation. A population of children who underwent unrelated allogeneic bone marrow transplantation in a single centre has been followed-up for viral infections and diseases. We describe the detection of cytomegalovirus (CMV) and adenovirus among 75 children transplanted between 1989 and 2000. CMV was detected among 22 patients (29%) and adenovirus among 19 patients (25%); they were associated with clinical diseases in 10 and 8 patients, respectively. Four patients had adenovirus and CMV coinfection. The obvious risk factor for CMV infection is seropositivity of the recipient prior to transplantation. Adenovirus is detected significantly more frequently when conditioning regimen includes anti-thymocyte or anti-lymphocyte globulin. Diseases associated with adenovirus have been correlated with a significantly higher mortality rate, stressing the need for the implementation of a systematic virological survey for this virus and for the evaluation of therapeutic protocols including new molecules.

Evaluation of bone marrow involvment by FDG-PET for refractory Hodgkin lymphoma treated by unrelated allogeneic bone marrow transplantation

Evaluation of bone marrow involvment by FDG-PET for refractory Hodgkin lymphoma treated by unrelated allogeneic bone marrow transplantation

Donor T-lymphocyte infusion for unrelated allogeneic bone marrow transplantation with CD3+ T-cell-depleted graft.

In T-cell-depleted allogeneic bone marrow transplantation (TCD-BMT) using unrelated donors, the role of donor lymphocyte infusion (DLI) for survival and disease control has not been defined. In a study of 116 patients (92 matched, 24 mismatched) who received CD3+ T-cell-depleted marrow graft, sequential infusions of escalated doses of donor T lymphocytes up to 1 x 10(6) CD3+ cells/kg were prospectively investigated. T cells were administered while patients were on cyclosporine, provided >or=grade II acute graft-versus-host-disease (GVHD) had not occurred. Acute GVHD of >or=grade II occurred in 27 of 110 (25%) patients before DLI and in 39 of 79 (49%) patients after DLI. In total, 12 of 27 (44%) patients without DLI and 44 of 72 (61%) patients who received DLI developed chronic GVHD. A total of 19 patients died of GVHD, with 17 of acute and two of chronic GVHD. Overall survival (OS) and event-free survival (EFS) at 5 years were 27 and 21%, respectively. The 2-year incidence of relapse was 14%. In multivariate analysis, only chronic GVHD was a good prognostic factor for both OS: hazard ratio (HR) 1.4, P=0.04, and EFS: HR 1.6, P=0.01. Both acute and chronic GVHD were favorable prognostic factors for relapse probability: HR 1.9 for both, P=0.02, 0.01, respectively. The 1-year cumulative incidence of transplant-related mortality (TRM), excluding cases of GVHD, was 42%. The two most common causes of 1-year non-GVHD death were viral infection (9%) and idiopathic pneumonia syndrome (12%). Although the incidence of relapse was low, the study suggests that the current scheme of DLI in unrelated TCD-BMT would not improve survival unless TRM decreases significantly.