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  • 1
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1949-1949
    Abstract: Abstract 1949 Introduction Transmission of hepatitis B virus (HBV) may occur (de novo HBV infection) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HBsAg-positive donors into HBsAg-negative recipients. Increased HBV associated complications will cause high morbidity and mortality post-transplantation in such patients. China is an endemic area for HBV infection. The exclusion of HBsAg positive donors will greatly limit the application of HSCT. There are few published data on allo-HSCT from HBsAg-positive donors when no other alternatives can be available. Recently great advances in anti-HBV therapy and prophylaxis have been achieved. The efficacy of allo-HSCT combined with anti-HBV prophylaxis in such patients remains unknown. In the current study, we performed a retrospective analysis of the virologic and clinical outcomes of allo-HSCT from HBsAg-positive donors into HBsAg-negative recipients under active prophylactic anti-HBV therapy. Methods From 2005 to 2010, a total of 10 HBsAg-negative recipients undergoing allo-HSCT from HBsAg-positive donors in our single center were included as an observation group. We performed a matched case-controlled analysis, in which each HBsAg-positive transplantation was paired with 3 control subjects selected from among all seronegative transplantation defining as a matched control group (30 patients). Patients were matched on age, underlying disease, disease stage, conditioning regimen and donor type. All the enrolled patients underwent HLA-matched related (20% each group) and HLA-mismatched related (haploidentical, 80% each group) transplantation. For haploidentical HSCT, conditioning regimen consisted of Ara-C, busulfan (Bu), cyclophosphamide (Cy), Me-CCNU and ATG. For HLA-matched related HSCT, the conditioning regimen consisted of Bu and Cy. GVHD prophylaxis consisted of cyclosporine A, mycophenolate mofetil and short-term methotrexate. Anti-HBV therapy consisted of lamivudine or entecavir for HBsAg positive donors. Marrow harvest and HSCT were performed until donor's serum HBV-DNA became undetectable. Hepatitis B immunoglobulin (HBIg) of 400 IU were administered to the recipients within 24 hours, 1 month and 2 months after stem cell infusion, respectively. HBsAb titers were detected once a month. If the titer was lower than 200IU/L, HBIg was injected rapidly. All the patients were followed-up weekly and HBV serology was detected once a month. Reults After transplantation, 1 and 0 patient developed HBV-related hepatitis in observation group and matched control group (P 〉 0.05). The HBV-related hepatitis patient became positive for HBsAg 1 year post-transplantation with serum HBsAb loss. Interestingly, this patient became negative for HBsAg and positive for HBsAb after donor lymphocyte infusion due to the primary disease relapse. To date, none of the enrolled recipients in our study became positive for HBsAg. Veno-occlusive disease (VOD) is another kind of hepatic complication. One and 0 patient developed VOD in observation group and matched control group respectively (p 〉 0.05). The presence of HBcAb in the absence of HBsAg in serum indicates past exposure to HBV. Despite the presumed resolution of the HBV infection in these patients, a minute amount of HBV DNA remains in the liver. So we analyzed HBcAb and HBsAb levels in the serum in both groups 1 year post-transplantation. Nine (90.0%) and 6 (20.0%) patients became positive for both HBcAb and HBsAb in observation group and matched control group respectively (p 〈 0.01), suggesting possible occult HBV infection in recipients transplanted from HBsAg-positive donors. We also compared clinical outcomes between 2 groups. The incidence of aGVHD was 40.0% in obervation group and 30.0% in matched control group (p 〉 0.05). The 1 year overall survival (OS) were 60.0% and 63.3% in observation group and matched control group respectively (p 〉 0.05). The 1 year non-relapse mortality (NRM) were 10.0% and 13.3% in observation group and matched control group respectively (p 〉 0.05). Conclusions Our data support that allo-HSCT from HBsAg-positive donors into HBsAg-negative recipients is a safety and practicable regimen under active prophylactic anti-HBV therapy, but these recipients are possibly complicated with occult HBV infection. A long-term prospective follow-up study on such patients is imperative currently. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 2
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 5116-5116
    Abstract: Abstract 5116 Multiple myeloma (MM) is a malignant neoplasm of plasma. The rates of complete remission (CR) or very good partial remission (VGPR) for patients received conventional chemotherapy are still low with median overall survival about 3 years. Here we report our results with combination therapy based on bortezomib in the Chinese population and investigat the efficacy and safety of Bortezomib-based therapies in previously untreated MM patients. Metohds: Between 1st Feb. 2006 and 31st Dec. 2010, 102 consecutive newly-diagnosed patients with symptomatic MM were treated with combination therapies based on bortezomib. Sixty-four patients were male and 38 were female. Median age was 59 years (range 31–86 years). Forty-two patients were stage 3 according to the International Staging System, 36 patients were stage 2 and 24 patients were stage 1. The combinations included dexamethasone (BD group ), dexamethasone plus subsequent thalidomide (BDT group ) and dexamethasone plus cyclophosphamide (BDC group ) or epirubicin (BDA group ) based on bortezomib. Thirty-five patients were in BDT group, 19 in BD group, 32 in BDC group and 16 in BDA. All patients received a median of three cycles of therapy (range 1–5 ). The IMWG criteria was used for response evaluation and toxicities were evluated according to the NCI Common Toxicity Criteria version 3. Results: The efficacy of the triplet combination therapy based on bortezomib including BDT, BCD and BAD were better than BD group, with response rate greater than or equal to partial remission(≥PR) 85.7%, 90.6%, 93.7% and 68.4%, respectively. The efficacy of BDA and BDC group were significantly superior to BD group (P=0.048,0.050). Bortezomib in combination with chemotherapy was highly effective as treatment for symptomatic multiple myeloma, even only after one cycle. The efficacy for patients received one cycle of BDT, BD, BCD and BAD was 65.7%, 42.1%, 65.6% and 62.5%, respectively. Patients treated with BD had suboptimal responses to those received BDT, BCD and BAD treatment and one cycle of BCD was superior to one cycle of BD (P=0.019).The median follow-up time was 17m (1–60m), including 31m (1–60m) for 35 patients in BDT group and 16m (2–29m) for the remaining 67 patients. The median progression-free survival (PFS ) of BDT group was 15m (9.8–20.2m ) while BD group was 12m (8.1–15.8m), BCD group was 13m (5.9–20.1m ), and BAD group was 12m (7.8–16.2m ), without significant difference. The median overall survival (OS ) of BDT group was 35m (13.2–56.8m ) while BD, BCD and BAD groups was not reached yet. There was no significant difference in OS among groups, but BCD and BAD were superior to BD group (P=0.104, 0.142 ). The frequent treatment-emergent adverse events includes hematologic adverse events such as neutropenia, anemia, thrombocytopenia and the non-hematologic adverse events like fatigue, infection, constipation, diarrhea, pleural effusion and ascites, herpes zoster and peripheral neuropathy. Patients treated with BDT were more likely to show peripheral neuropathy than those treated with BD, BCD and BAD (91.4% vs 73.6%, 68.7%, 74.9% ), but there is no statistical significant difference (P = 0.131), Grade 2 or 3 peripheral neuropathy was occurred in 45.7% of BDT group significantly higher than BD, BCD and BAD groups. (21.0%, 15.7% and 18.7%, P = 0.028 ). Other related adverse events in all the groups had no significant difference. Routine anticoagulation or anti-thrombsis were not used. Only 1 patient suffered from DVT/PE but did well with treatment. Conclusions: Our preliminary experience in Chinese patients indicated that combination chemotherapy based on bortezomib is highly effective in newly-diagnosed multiple myeloma and BDC, BDA or BDT regimens may be more superior to BD in Chinese population. There were relative lower rates of DVT/PE in the Chinese patients with MM received combination chemotherapy based on bortezomib. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 3
    In: The American Journal of the Medical Sciences, Elsevier BV, Vol. 345, No. 2 ( 2013-02), p. 88-93
    Type of Medium: Online Resource
    ISSN: 0002-9629
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
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  • 4
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    Ivyspring International Publisher ; 2014
    In:  International Journal of Biological Sciences Vol. 10, No. 2 ( 2014), p. 192-199
    In: International Journal of Biological Sciences, Ivyspring International Publisher, Vol. 10, No. 2 ( 2014), p. 192-199
    Type of Medium: Online Resource
    ISSN: 1449-2288
    Language: English
    Publisher: Ivyspring International Publisher
    Publication Date: 2014
    detail.hit.zdb_id: 2179208-2
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  • 5
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 156-156
    Abstract: Introduction Although steady progress of effective chemotherapy in childhood acute lymphoblastic leukemia (ALL) carried with exceeding 80% of individuals now cured, the majority of adult patients with ALL are not cured by chemotherapy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option. However, relapse remains the most leading cause of death after allo-HSCT. Adverse genetic alterations are generally accepted to be responsible for treatment failure and relapse. Several structural chromosomal alterations including rearrangement of the myeloid-lymphoid or mixed-lineage leukemia gene (MLL) and Philadelphia chromosome (Ph), have been mostly found in relapsed ALL. However, many Ph-negative (Ph-) ALL patients with normal karyotype , lacking known risk factors, also experienced relapse. The underlying pathologic determinants leading to relapse and prognostic markers in these cases remain poorly understood. More importantly, allo-HSCT is a distinct treatment option from tradtional chemotherapy and has 2 important forms to eliminate and select on malignant cells. The malignant cells that go on to causing relapse must initially survive ablation of chemotherapy before allo-HSCT and conditioning regimen in allo-HSCT. Then, after allo-HSCT, they must survive the effect of graft-versus- leukemia (GVL) reaction. Following this rationale, we hypothesized that there may be pivotal genetic causes confer leukemic cells a fitness advantage to undergo huge selective pressures and expand after allo-HSCT. To elucidate the genomic basis underlying relapse after allo-HSCT to aid to discover novel predictive biomarkers and identify therapeutic targets, we carried out the first whole-exome sequencing analysis in longitudinal matched samples from diagnosis to relapse after allo-HSCT in adult patients with the most common subtype of ALL, Ph- B-cell ALL (B-ALL). Methods Whole-exome sequencing was conducted for 9 genomic DNA samples from 3 relapsed cases with Ph- B-ALL (discovery cohort) at 3 specific time points including: diagnosis, complete remission (CR) after induction chemotherapy before allo-HSCT, relapse after allo-HSCT to discover candidate relapse-associated mutated genes. We identified putative somatic mutations by comparing each tumor ( diagnostic samples or relapsed samples) to normal (CR samples) from the same patient. To confirm candidate somatic gene mutations, screen relapse-associated gene mutations and define the frequency of somatic mutations identified by whole-exome sequencing analysis, we further carried out target genes whole coding regions sequencing in an ALL extended validation cohort including 58 adult Ph- B-ALL cases, where 27 patients experienced relapse at a median time of 6.5 (range 2-33) months after allo-HSCT and 31 patients did not relapse after allo-HSCT at a median follow-up for 34 (range 12–56) months. Results (1) We discovered novel associations of recurrently mutated genes (CREBBP, KRAS, PTPN21) with the pathogenesis of adult Ph- B-ALL relapse after allo-HSCT, which were mutated in at least two relapsed cases, but were not mutated in non- relapsed patients. (2) The generation of high-depth whole-exome sequencing data in longitudinal matched samples from diagnosis to relapse after allo-HSCT in initial 3 patients allowed us to directly assessed the evolution of somatic mutations. Our data suggested that in the progression of leukemia relapse after allo-HSCT, the relapse clone had a clear relationship to the diagnosis clone, either arising from a subclone already exsiting in the diagnostic tumor, or originating from a common preleukemic progenitor with the diagnosis clone. In the latter pattern, the relapse clone acquires new genetic alterations while retaining some but not all of the alterations found in the diagnostic tumor. In contrast, in some cases, leukemia recurrences afer allo-HSCT may be composed of second malignancies with completely distinct sets of mutations from the primary tumor. Conclusions Our study is the first to explore genetic basis of adult Ph- B-ALL from diagnosis to relapse after allo-HSCT over time, which will provide novel genetic biomarkers on risk “index” to improve individualized treatment intensification and intervention strategies, and potential therapeutic targets for Ph--ALL relapse after allo-HSCT. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 6
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1303-1303
    Abstract: Abstract 1303 Background: Leukemia relapse arising in cells of donor origin in the transplant recipient, called donor cell leukemia (DCL), is a rare disease entity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The precise etiological mechanisms of DCL are unravelled and almost all the reported cases do not suggest a common mechanism. Careful analyses of the mechanisms with respect to the oncogenic transformation of donor-derived cells might provide a valuable insight into understanding of leukemogenesis.We aimed to assess whether those genetic mutations implicated in the development of common forms of AML contribute to the “leukemization” of donor cells in DCL. Methods: (1) A 36-year-old male was diagnosed with AML-M4. Cytogenetic evaluation demonstrated an abnormal clone 46 XY, del (9) (q11 q34) in 10/10 cells. The patient underwent `allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from a HLA-identical sister. Short tandem repeats (STR) analyses on day +28 showed complete donor chimera. Thirteen months after SCT, bone marrow aspiration revealed leukemia relapse. STR analyses showed still absolute donor chimera. The karyotype of bone marrow cells of the patient showed a new clonal chromosome abnormality: 45,XX, der(15;22) (q10;q10) in 10/10 cells, which was completely identical to the karyotype of the donor. Molecular evaluation suggested the patient developed DCL from a HLA-identical sibling. The examination of the donor's bone marrow showed normal and no malignant clone was detected by flow cytometry and fluorescence in-situ hybridization analyses. The donor remains healthy during a 25-month follow-up. (2) A series of archival stained bone marrow slides of the patient, including at the times of diagnosis, CR after one course of induction chemotherapy, lasting CR, before SCT, 1 month, 9 months and 12 months after SCT, samples of mononuclear-cell-enriched bone marrow at the times of relapse and CR after relapse, and buccal mucosal swab specimen during remission were available. (3) Buccal mucosal swab specimen and samples of mononuclear-cell-enriched peripheral blood and bone marrow were available from the donor. (4) Genomic DNA was extracted and analyzed for mutations in fms-related tyrosine kinase 3 gene (FLT3), neuroblastoma RAS viral oncogene homolog gene (NRAS), the CCAAT enhancer-binding proteinα gene (CEBPA), myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and nucleophosmin gene (NPM1). Results: (1) DNA obtained from the patient during diagnosis was found to exhibit three different mutations in CEBPA, the gene encoding the crucial granulocytic differentiation factor C/EBPα. The mutation1 was the duplication of a cytosine residue at nucleotide 247 (247dupC) which resulted in the corresponding protein terminating prematurely at codon106 (Gln83fsX106). The mutation2 was a 6-bp duplication comprised nucleotides 584 to 589 (584—589dup) which resulted in an internal tandem duplication of amino acids 195 to 196 (His195—Pro196dup) in the protein. The mutation3 was a 3-bp duplication comprised nucleotides 914 to 916 (914—916dup) which resulted in the duplication of amino acids 305 (Gln305dup) in the protein. The 584—589dup mutation was remain found in DNA from the patient during lasting remission before SCT and from his buccal swab specimen, indicating this mutation should be germ-line mutation. In contrast, other two mutations were not found in the patient during remission and buccal swab specimen, indicating these two mutations should be somatically acquired. (2) The 584—589dup germ-line mutation was also found in DNA from peripheral blood cells, bone marrow cells and buccal swab specimen from the donor. (3) Donor-derived cells in the patient at the times of 1 month, 9 months and 12 months after SCT only exhibited the single germ-line mutation. When the patient relapsed with DCL, donor-derived leukemic cells were found to develop two somatic mutations in CEBPA in the patient microenvironment, which were completely identical to those observed in the patient with de novo leukemia. No other mutations were identified in FLT3, NRAS, MLL and NPM1 genes. Conclusions: Our findings suggest that multiple mutations of CEPBA impairing C/EBPα function may be sufficient to induce AML and a single mutation of CEBPA is not leukemogenic, but is the first step and predisposed to development of other mutations, ultimately inducing AML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 7
    In: Leukemia Research, Elsevier BV, Vol. 37, No. 9 ( 2013-9), p. 1046-1051
    Type of Medium: Online Resource
    ISSN: 0145-2126
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 752396-8
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  • 8
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4211-4211
    Abstract: Abstract 4211 Isolated extramedullary relapse (EMR) of acute leukemia (AL) is a rare occurrence although it appears to be more common following allogeneic stem cell transplantation (allo-SCT). To characterize what has been observed in isolated EMR, we investigated a total of 287 consecutive AL patients (144 acute myeloid leukemia, 138 acute lymphocytic leukemia and 5 acute mixed lineage leukemia) who underwent allo-SCT. Forty-seven (16.4%) patients experienced relapse after allo-SCT. 12 cases (4.2%) experienced relapse of extramedullary sites without concomitant bone marrow involvement. Isolated EMR accounted for 25.5% of the overall initial relapse. The time to relapse after allo-SCT was longer in the extramedullary sites than in the marrow (median, 10 months vs. 5.5 months, P 〈 0.05,). Sites of EMR varied widely including central nervous system, skin, bone, pelvis and breasts. The variables considered for univariate analysis included donor gender, age, primary disease, disease status, cytogenetics/molecular abnormalities, preconditioning regimen, donor type, HLA match, aGVHD and cGVHD. The variables that showed significant correlation with isolated EMR were the cytogenetics abnormalities at diagnosis. The prognosis for patients who develop EMR remained poor but was relatively better than that after bone marrow (BM) relapse (overall survival, 10 vs. 18 months, P 〈 0.05). Compared with local or single therapy, patients treated with systemic in combination with local treatment could yield favorable prognosis. Three patients survived 63, 55 and 49 months after transplant respectively, of whom two received DLI with subsequent chemotherapy and (or) irradiation and one had surgery with subsequent chemotherapy. In conclusion, we observed a significant number of isolated EMR of AL after allo-SCT and intensive approaches combined of local and systemic therapy can produce favorable response which may cure a percentage of these patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
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  • 9
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 5273-5273
    Abstract: Objective: Between October 2010 to May 2014, 59 patients who diagnosed as FLT3-ITD positive aAML were analyzed. All the patients were signed informed consents to agree to provide their clinical information to this study. Informed consents were approved by Ethics Committee. Peripheral white cell count at diagnose; complete remission (CR) rate; the percentage of progressing to refractory leukemia and the response to allogenic stem cell transplantation (allo-SCT) were analyzed. Better therapeutic strategy was explored. Methods: Diagnosis was made according to the French-American-British classification system or World Health Organization diagnostic classification criteria. FLT3-ITD mutation was detected by polymerase chain reaction (PCR) and gel electrophoresis. Refractory leukemia is defined as fail to achieve CR after two courses of conventional chemotherapy, or with a short ( 〈 6–12 months) CR1 duration, or patients who have relapsed at least twice. Results: 59 patients were diagnosed as Flt3-ITD mutation positive aAML in our centre during the last 44months, including 30 males and 29 females, with an average age at 42.2y. Flt-ITD mutation can be detected in 1/59 of M0 (1.7%); 6/59 of M1 (10.1%); 20/59 of M2 (33.8%); 9/59 of M3 (15.2%); 5/59 of M4 (8.5%); 14/59 of M5 (23.7) and 1/59 of M6 (1.7%). 23.7% (14/59) patients had high white blood cell counts (>100*10E9/L) at diagnose. After induction chemotherapy, 50% (27/54) cases achieved CR. 53.4% (23/43, 16 cases were lost follow-up) patients met the criteria of refractory leukemia. 12 patients received allo-SCT, including 8 refractory leukemia cases. The average time from diagnose to transplantation is 6.5 months (3 to 12 months). 1 patient relapsed at 3 months after allo-SCT who was diagnosed refractory leukemia before allo-SCT, all other 11 cases remained CR with the longest follow-up time at 26 months (3 to 26 months). For the left 15 refractory leukemia cases who did not received allo-SCT, the 1-year OS rate for the 12 cases is 50% (6/12), but the 1-year EFS rate is 0 (0/12) (3 cases were lost follow-up). Conclusion: FLT3-ITD mutation was reported to be detected in around 30% of aAML. Flt3-ITD mutation is an independent high-risk factor for aAML. Based on retrospective data from 59 cases in our centre, FLT3-ITD mutation positive aAML patients can be characterized as high white blood cell count at diagnose, lower CR rate and higher refractory leukemia percent. allo-SCT can achieve persistent remission in part of patients, even in refractory leukemia patients. Our study also implied that the CR1 is the ideal stage for FLT3-ITD mutation positive aAML patient to receive allo-SCT. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 10
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1938-1938
    Abstract: Abstract 1938 Background: Toll-like receptors (TLRs) are transmembrane proteins on the surface of immune cells that detect conserved molecular motifs known as “microbe-associated molecular patterns” from a variety of organisms. They interact with several adapter proteins to activate transcription factors, leading to the production of inflammatory cytokines and the activation of adaptive immunity. Current evidence suggests that common polymorphisms in TLR genes have been associated with the susceptibility to autoimmune disease and several infections, their association with outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has yet to be explored. Methods: We unselectively included all patients undergoing allo-HSCT in our Bone Marrow Transplantation Center between January 2001 and March 2009 if donor and patient DNA were available. All the patients and their donors were from a homogeneous genetic background. We analyzed 10 single nucleotide polymorphisms (SNPs) in the TLR1gene (rs4833095 C/T, rs5743565 A/G), TLR2gene (rs11938228 A/C, rs3804099 C/T), TLR3 gene (rs3775291 A/G, rs3775296 G/T), TLR8gene (rs3764880 A/G, rs2159377 C/T) and TLR9 gene (rs352139 G/A, rs352140 C/T) in 2 independent cohorts. The initial cohort consisted of 138 pairs of patients and their unrelated donors (URDs). The second cohort consisted of 102 pairs of patients and their HLA-identical sibling donors. Results: (1) We found that two SNPs in donor side, TLR9 +1174 G/A (rs352139) and TLR9 +1635 C/T (rs352140), influenced the risk of aGVHD. The association was particularly strong in the URD transplantation cohort. Multivariate analysis confirmed that an unrelated donor with the TLR9 +1174 variant allele (A allele) was an independent risk factor for aGVHD (P= 0.009, RR= 3.123). In contrast, an unrelated donor with the TLR9 +1635 variant genotype (TT) was protective (P= 0.067, RR= 3.457). The same effect was observed in the sibling transplantation cohort, although the incidence of clinically significant aGVHD in this cohort was low overall and the association was not statistically significant. (2) Since cytomegalovirus (CMV) reactivation and disease continued to be important complications post-HSCT, and CMV infection is of special concern in the Chinese population. The incidence of asymptomatic infection is high. The episodes of major infection were focused on early CMV infection post-HSCT. Early CMV infection refers to antigenemia or disease with onset by day 100 after transplantation. In the present study cohorts, all patients and almost all donors were CMV seropositive (CMV-specific immune globulin G positive, CMV-IgG(+)) before HSCT and only one donor from the Taiwan Tzu Chi Stem Cells Center was CMV seronegative. All patients received CMV prophylaxis treatment and those experiencing pre-transplantation CMV recurrent infection received preemptive treatment. Of the total of 240 patients, 134 (55.8%) had experienced early CMV infection with a median onset of 27 days (range 2–64) post-HSCT. Patients who received stem cells from donors with the TLR9 +1635 variant genotype (TT) had a reduced incidence of grades II–IV aGVHD, however, they experienced early CMV infection more frequently than those with the wild-type genotype (CT or TT) in both the URD transplantation cohort (TT: 80% vs. CT or CC: 59.3%, Gray's test p =0.02) and the sibling transplantation cohort (TT: 66.7% vs. CT or CC: 41.7%, Gray's test p=0.03), although a higher incidence of early CMV infection was observed in the URD transplantation cohort (63% vs. 46%, Gray's test p = 0.025). Multivariate analysis confirmed unrelated donors (p =0.046, RR = 1.438, 95%CI,1.007–2.053), patients experiencing recurrent CMV infection pre-transplantation (p = 0.004, RR = 0.597, 95%CI, 0.419–0.849) and donors with the TLR9 +1635 TT genotype (p=0.005, RR=0.561, 95%CI, 0.376–0.836) all contributed to the development of early CMV infection. Conclusion: There is increasing evidence for a role for TLR9 in the pathogenesis of aGVHD and viral infection. These result is the first report of donor TLR9 gene polymorphic features with the risk of aGVHD and early CMV infection, which are located within the promoter region and coding polymorphisms and may influence transcriptional regulation and the amino acid exchange of the TLR9 gene. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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