HLA-matched Unrelated Bone Marrow Transplantation Research Articles

Impact of MRD on clinical outcomes of unrelated hematopoietic stem cell transplantation in patients with Ph+ ALL: A retrospective nationwide study.

Measurable residual disease (MRD) status before transplantation has been shown to be a strong prognostic factor in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, the outcomes of unrelated hematopoietic stem cell transplantation based on the MRD status have not been fully investigated. In this retrospective study, we compared the outcomes of 715 consecutive adults with Ph+ ALL in complete remission who underwent unrelated cord blood transplantation (UCBT) (single-unit UCBT, n = 232 [4/6, 5/6, and 6/6 HLA match]), HLA-matched unrelated bone marrow transplantation (UBMT; n = 292 [8/8 HLA match]), or HLA-mismatched UBMT (n = 191 [7/8 HLA match]). In the MRD+ cohort, adjusted 3-year leukemia-free survival rates were 59.8%, 38.3%, and 55.5% after UCBT, HLA-matched UBMT, and HLA-mismatched UBMT, respectively. In the MRD- cohort, the corresponding rates were 65.3%, 70.4%, and 69.7%, respectively. The MRD+ HLA-matched UBMT group had a significantly higher risk of relapse than the MRD+ HLA-mismatched UBMT group (hazard ratio [HR] in the MRD+ HLA-mismatched UBMT group, 0.33; 95% confidence interval [CI] 0.15-0.74) and the MRD+ UCBT group (HR in the MRD+ UCBT group, 0.38; 95% CI 0.18-0.83). Furthermore, HLA-matched UBMT had a significant effect of MRD on death (HR 1.87; 95% CI 1.19-2.94), relapse or death (HR 2.24; 95% CI 1.50-3.34), and relapse (HR 3.12; 95% CI 1.75-5.57), while UCBT and HLA-mismatched UBMT did not. In conclusion, our data indicate Ph+ ALL patients with positive MRD may benefit from undergoing UCBT or HLA-mismatched UBMT instead of HLA-matched UBMT to reduce leukemic relapse.

Sequence Variations Within HLA-G and HLA-F Genomic Segments at the Human Leukocyte Antigen Telomeric End Associated With Acute Graft-Versus-Host Disease in Unrelated Bone Marrow Transplantation.

Acute graft-versus-host disease (aGVHD) is defined as a syndrome of an immunological response of graft to the host that occurs early after allogeneic hematopoietic stem cell transplantation (HCT). This disease is frequently observed even in HCT matched for human leukocyte antigen (HLA) alleles at multiple gene loci. Although the HLA region represents complex and diverse genomic characteristics, detailed association analysis is required for the identification of uncharacterized variants that are strongly associated with aGVHD. We genotyped three loci, OR2H2, HLA-F-AS1, and HLA-G, that are located in the 460 kb of HLA telomeric region and statistically analyzed the genotypes including HLA-DPB1 with clinical and transplantation outcomes using 338 unrelated bone marrow transplantation (UR-BMT) patient–donor pairs who were matched for HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 (HLA-10/10). Multivariate analyses demonstrated that HLA-F-AS1 and HLA-DPB1 mismatches were associated with grade II–IV aGVHD (hazard ratio (HR), 1.76; 95% CI, 1.07–2.88; p = 0.026; and HR, 1.59; CI, 1.02–2.49; p = 0.042, respectively). There was no confounding between HLA-F-AS1 and HLA-DPB1 (p = 0.512), suggesting that the HLA-F-AS1 mismatch has a strong effect on aGVHD independently of HLA-DPB1. Moreover, a stratified analysis suggested possible associations of HLA-F-AS1, HLA-DPB1, and/or HLA-G mismatches with grade II–IV aGVHD and the more severe grade III–IV aGVHD. These findings provide new insights into understanding the molecular mechanism of aGVHD caused by HLA-matched UR-BMT.

Graft-versus-host disease-free, and relapse-free survival in Japanese patients with hematological malignancies

Graft-versus-host disease (GVHD) -free, relapse-free survival (GRFS) is an important, composite endpoint for clinical trials, which provides a patient-centered measure of transplant success. This review discusses the results of the Japanese Transplant Registry study. This large-scale study examined 23,302 patients with hematological malignancy and characterized GRFS according to a variety of graft sources. The GRFS rate at 1 year was 41% in all patients. GRFS was superior in patients undergoing bone marrow transplantation compared to peripheral blood stem cell transplantation, owing to lower risk of developing grades III-IV acute and chronic GVHD. The best GRFS rates were observed in patients that received HLA-matched related bone marrow transplants; however, this was not the case in HLA-mismatched donors. GRFS after single-cord blood transplantation was almost comparable with HLA-matched unrelated bone marrow transplantation, possibly due to the low risk of chronic GVHD. Other factors associated with increased GRFS rates included female patients; use of anti-thymocyte globulin prophylaxis for standard-risk disease; recent transplantations; gender combinations other than from a female donor to a male patient; absence of prior autologous transplantation; myeloablative conditioning; negative cytomegalovirus serostatus; and use of tacrolimus-based GVHD prophylaxis. These results provide valuable information for deciding the best choice of graft sources and type of GVHD prophylaxis to be used.

ALDH2 Polymorphism Has a Significant Impact on Transplant Related Mortality after HLA-Matched Bone Marrow Transplantation

Background:Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme known to degrade acetaldehyde metabolized from ethanol, is also involved in critically important biological processes such as drug metabolism and DNA repair in hematopoietic stem cells. Based on its role in these biological processes, we hypothesized that a functional ALDH2Glu504Lys polymorphism, which is highly prevalent in East Asian populations, could affect the outcome of hematopoietic transplant recipients. Here, we investigated the association between recipient and donor ALDH2 polymorphism and the clinical outcomes of bone marrow transplantation (BMT).Methods.:We analyzed the Japanese national registry data for 409 patients who underwent allogeneic BMT from an HLA-matched unrelated donor through the Japan Marrow Donor Program. The probability of overall survival (OS) was estimated according to the Kaplan-Meier method. The probabilities of relapse, transplant-related mortality (TRM), engraftment, and graft-versus-host disease (GVHD) were estimated based on cumulative incidence curves. Competing events were death without relapse for relapse, relapse for TRM, death without engraftment for engraftment, and death without GVHD for GVHD. To evaluate the impact of recipient and donor ALDH2 polymorphism on transplant outcomes, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for potential confounders. The Cox proportional hazards model was used to evaluate the effect on OS, whereas Fine and Gray's proportional hazards model was used for the other endpoints.Results.:The median follow-up period in survivors was 6.3 years (range, 0.3-13.1 years). The unadjusted 3-year OS rate was 51% (95% CI, 43%-57%) in Glu/Glu genotype recipients, 52% (43%-60%) in Glu/Lys genotype recipients, and 43% (25%-60%) in Lys/Lys genotype recipients. We did not observe a statistically significant association between the recipient ALDH2 polymorphism and OS. The cumulative incidence of unadjusted 3-year TRM was 28% (21%-34%) in Glu/Glu genotype recipients, 25% (18%-33%) in Glu/Lys genotype recipients, and 50% (29%-68%) in Lys/Lys genotype recipients. The recipient ALDH2 Lys/Lys genotype was significantly associated with a higher TRM, with a HR relative to Glu/Glu genotype of 2.45 (95% CI = 1.22-4.90, P = 0.01). Among the causes of TRM, the incidence rate of organ failure in recipients with the Lys/Lys genotype was twice as high as in recipients with the Glu/Glu genotype (5.9 vs. 3.0 per 1,000 person-days). A statistically significant association between the recipient ALDH2 polymorphism and relapse or GVHD was not observed. With regard to engraftment, the cumulative incidence of platelet engraftment at day 50 was 82% (76%-87%) in Glu/Glu genotype recipients, 80% (72%-85%) in Glu/Lys genotype recipients, and 65% (47%-78%) in Lys/Lys genotype recipients. Compared to the recipient Glu/Glu genotype, the recipient Lys/Lys genotype was marginally significantly associated with delayed platelet engraftment (HR = 0.60, 95% CI = 0.43-1.03, P = 0.06). In contrast, donor ALDH2 polymorphism did not show any significant association with transplant outcomes.Conclusions:We observed poor TRM and delayed platelet engraftment in HLA-matched unrelated BMT recipients with ALDH2 Lys/Lys genotype. Taken functional significance of this polymorphism, our results might indicate that recipient ALDH2 polymorphism could affect the metabolism of chemotherapeutic agents leading to higher TRM and delayed platelet engraftment. DisclosuresNo relevant conflicts of interest to declare.

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups.

Graft-versus-host disease-free relapse-free survival, which is defined as the absence of grade III-IV acute graft-versus-host disease, systemically treated chronic graft-versus-host disease, relapse, and death, is a novel, meaningful composite end point for clinical trials. To characterize risk factors and differences in graft-versus-host disease-free relapse-free survival according to a variety of graft sources, we analyzed 23,302 patients with hematologic malignancy that had a first allogeneic transplantation from 2000 through 2013 using the Japanese national transplant registry database. The 1-year graft-versus-host disease-free relapse-free survival rate was 41% in all patients. The rate was higher after bone marrow transplantation than after peripheral blood stem cell transplantation due to the lower risks of III-IV acute and chronic graft-versus-host disease. The rate was highest after HLA-matched sibling bone marrow transplantation. The rate after single cord blood transplantation was comparable to that after HLA-matched unrelated bone marrow transplantation among patients aged 20 years or under, and was comparable or better than other alternative graft sources among patients aged 21 years or over, due to the low risk of chronic graft-versus-host disease. Other factors associated with better graft-versus-host disease-free relapse-free survival include female patients, antithymocyte globulin prophylaxis (for standard-risk disease), recent years of transplantation, sex combinations other than from a female donor to a male patient, the absence of prior autologous transplantation, myeloablative conditioning, negative cytomegalovirus serostatus, and tacrolimus-based prophylaxis. These results provide important information to guide the choice of graft sources and are benchmarks for future graft-versus-host disease prophylaxis studies.

Comparison of Cord Blood Transplantation with Unrelated Bone Marrow Transplantation in Patients Older than Fifty Years

We retrospectively compared the transplantation outcomes for patients 50 years or older who received umbilical cord blood transplantation (UCBT) with those who received unrelated bone marrow transplantation (UBMT) for hematologic malignancies. A total of 1377 patients who underwent transplantation between 2000 and 2009 were included: 516 received 8/8 HLA allele-matched UBMT, 295 received 7/8 HLA allele-matched UBMT, and 566 received 4/6 to 6/6 HLA-matched UCBT. Adjusted overall survival (OS) was significantly lower in those who underwent UCBT than those who underwent 8/8 HLA–matched UBMT but was similar to that of 7/8 HLA–matched UBMT (the 2-year OS after 8/8 HLA–matched UBMT, 7/8 HLA–matched UBMT, and UCBT were 49% [95% confidence interval (CI), 45% to 55%], 38% [95% CI, 32% to 45%], and 39% [95% CI, 34% to 43%], respectively). However, adjusted OS was similar between 8/8 HLA–matched UBMT and UCBT receiving ≥.84 × 105 CD34+ cells/kg among those with acute myeloid leukemia and those with acute lymphoblastic leukemia (the 2-year OS was 49% [95% CI, 43% to 55%], and 49% [95% CI, 41% to 58%], respectively). These data suggest that UCB is a reasonable alternative donor/stem cell source for elderly patients with similar outcomes compared with UBM from 8/8 HLA–matched unrelated donors when the graft containing ≥.84 × 105 CD34+ cells/kg is available.

Expanding the spectrum of recombination-activating gene 1 deficiency: A family with early-onset autoimmunity

Expanding the spectrum of recombination-activating gene 1 deficiency: A family with early-onset autoimmunity

Impact of a single human leucocyte antigen (HLA) allele mismatch on the outcome of unrelated bone marrow transplantation over two time periods. A retrospective analysis of 3003 patients from the HLA Working Group of the Japan Society for Blood and Marrow Transplantation

A previous Japanese study revealed that a human leucocyte antigen (HLA)-A or -B allele mismatch was associated with higher overall mortality, whereas an HLA-C or -DRB1 allele mismatch did not affect mortality after serologically matched unrelated bone marrow transplantation (BMT). This study reanalysed 3003 adult patients who underwent unrelated BMT from a serologically HLA-A, -B, or -DR matched unrelated donor between 1993 and 2009 using the latest database, that included 1966 HLA-matched unrelated BMT and 187, 31, 524, and 295 unrelated BMT with a single HLA-A, -B, -C, or -DRB1 allele mismatch, respectively. As opposed to our previous findings, HLA-C and -DRB1 mismatches had a significant negative impact [hazard ratio (HR) 1·35, P < 0·001, and HR 1·45, P < 0·001] on survival in the period 2000-2009. The negative impact of each single HLA allele mismatch was not significantly different among the HLA-A, -B, -C, and -DRB1 mismatches (P = 0·79). An interaction test revealed that the effects of single HLA-C and -DRB1 allele mismatches significantly differed over the two time periods (P = 0·032 and P = 0·0072, respectively). In conclusion, the impact of a single HLA allele mismatch changed over time. In the recent cohort, the negative impact of HLA-DRB1 and -C mismatches became apparent.

Hemophagocyctic lymphohistiocytosis developed in a Japanese boy with Chédiak-Higashi syndrome

Chédiak-Higashi syndrome (CHS) is one of the primary immunodeficiency syndromes accompanied by oculocutaneous albinism. It is characterized by existence of giant granule of neutrophils, and development of symptoms of hemophagocytic lymphohistiocytosis. CHS is a rare disorder and recognition of the disease is indispensable for its diagnosis. In our case, a four-month-old boy, virus-associated hemophagocytic syndrome (VAHS) was suspected from generation of fever, hepatosplenomegaly, and existence of atypical lymphocytes on admission. However, elevation of serum AST, LDH and ferritin were quite slight as VAHS, and rapid exacerbation of the findings was not seen. Associated virus was undetected. He was finally diagnosed as CHS developing hemophagocyctic lymphohistiocytosis based on the existence of a giant granule of neutrophils in the peripheral blood smear and oculocutaneous albisum and laboratory findings. Clinical outcome was successful after receiving HLA-matched unrelated bone marrow transplantation.

The Association of a Single Nucleotide Polymorphism in the Chemokine CXCL10 Gene with Transplant Outcomes After HLA-Matched Unrelated Bone Marrow Transplantation for Low Risk Hematologic Malignancies

Abstract 2048CXCL10, also known as interferon gamma inducible protein 10, is a chemokine secreted by several cell types including monocytes, endothelial cells and fibroblasts that plays important roles in the stimulation and migration of natural killer cells and T cells. The single nucleotide polymorphism (SNP) rs3921 located in the 3'-untranslated region of the CXCL10 gene has been reportedly associated with acute GVHD and with invasive aspergillosis after allogenic stem-cell transplantation. In this study, we analyzed the impact of rs3921 polymorphism on transplant outcomes in patients undergoing unrelated HLA-matched myeloablative bone marrow transplantation (BMT) through the Japan Marrow Donation Program. The CXCL10 genotypes were retrospectively analyzed in a cohort of 652 pairs of patients with hematologic malignancies and their unrelated donors. The genotype frequencies of GG, CG and CC were 1%, 13% and 86% in recipients and 1%, 12% and 87% in donors (P=0.62). The recipient GG or CG genotype was associated with significantly better overall survival (OS; P=0.02; Fig1). No difference was noted in transplant-related mortality, disease relapse or graft-versus-host disease in relation to the recipients' polymorphism. The multivariate analysis showed that in patients with low risk disease, the recipient GG or GC genotype remained statistically significant for better OS (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.30 to 1.01; P=0.05). The donor CXCL10 genotypes did not significantly influence the transplant outcomes. These results suggest an association of the recipient GG or GC genotypes with better transplant outcomes after unrelated HLA-matched BMT. These findings could therefore be useful in creating therapeutic strategies such as risk-adapted management of transplanted patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A Single Nucleotide Polymorphism in the NLRP3 Gene Is Associated with Acute Graft-Versus-Host Disease After HLA-Matched Unrelated Bone Marrow Transplantation,

Abstract 4073NOD-like receptor family, pyrin domain containing 3 (NLRP3) is an innate immune receptor that exerts functions in the regulation of inflammation and apoptosis. Recent studies have shown that the single nucleotide polymorphism (SNP) rs10754558 (C>G) at the 3’ untranslated region of NLRP3 gene is functional and is associated with various immunological diseases. Allele G is linked with a higher activity of NLRP3 than allele A, and plays important roles in increased susceptibility to allergic reactions and in protection of HIV infection. This study retrospectively examined the impact of the NLRP3 genotype of a total 659 recipients with hematologic malignancies and their unrelated donors on the clinical outcomes in unrelated HLA 12/12 matched bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The genotype frequencies of G/G, G/C and C/C were 19%, 50% and 31% in recipients and 18%, 49% and 32% in donors (P =0.79). The donor G/G or G/C genotype was associated with a significantly higher incidence of grades III to IV acute graft-versus-host disease (GVHD; 15% vs. 7%, P =0.004; Fig 1B) and a trend toward a higher incidence of grades II to IV acute GVHD (34% vs. 27%, P =0.06; Fig 1A), while no significant differences between the G/G genotype and G/C genotype were seen. The donor G/G or G/C genotype remained statistically significant in the multivariate analysis for the development of grades III to IV acute GVHD (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.22 to 3.90; P =0.009) as well as a trend toward an association with grades II-IV acute GVHD (HR, 1.31; 95% CI, 0.96 to 1.80; P =0.09). The recipient NLRP3 genotype did not significantly influence the transplant outcomes. These results suggest an association of the donor NLRP3 genotype with the development of acute GVHD after unrelated BMT. Genotyping for the NLRP3 rs10754558 could be useful in donor selection and risk-adapted management of transplanted patients, and may furthermore offer some novel therapeutic insights into the mechanisms of acute GVHD. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

A Functional Variation In the NKG2D Gene Regulates NKG2D Receptor Expression and Is Associated with Better Transplant Outcomes After Fully-HLA-Matched Unrelated Bone Marrow Transplantation

AbstractAbstract 221A functional variation in the NKG2D gene regulates NKG2D receptor expression and is associated with better transplant outcomes after fully-HLA-matched unrelated bone marrow transplantationNKG2D, an activating receptor expressed by NK cells and some T cells, plays important roles in both immunity to microbial infections and cancer immune surveillance. A single nucleotide polymorphism (SNP rs1049174) in the 3′-untranslated region (3′UTR) of the NKG2D gene determines two genotypes, HNK1 genotype with high NK cytotoxicity, and the LNK1 genotype with low NK cytotoxicity. Individuals with the HNK1 genotype have reduced risk of cancer (Cancer Res 2006; 66(1):63-70). In the present study, we analyzed the impact of SNP rs1049174 on transplant outcomes after HLA-matched unrelated bone marrow transplantation. The NKG2D genotypes were retrospectively analyzed in a cohort of 360 pairs of patients and their unrelated donors transplanted through the Japan Marrow Donor Program. The donor HNK1 genotype was associated with lower transplant related mortality (TRM) in patients with standard risk (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.35–0.97; P=0.04) (Fig.1). The donor HNK1 genotype was also associated with a trend toward better OS (HR, 0.69; 95% CI, 0.46–1.04; P=0.08). The host NKG2D genotypes did not significantly influence the transplant outcomes. NK cells from HNK1 donors expressed higher levels of NKG2D on the cell surface, and also expressed higher levels of NKG2D mRNA. Luciferase reporter gene constructs transfected into NK cells showed that the LNK1 construct more effectively attenuated gene expression compared with the HNK1 construct (60% vs. 35%). Bioinformatics tools predicted an interaction between the rs1049174 SNP motif with the micro-RNA-1245 (miR1245). Next, in an mRNA/miRNA binding assay, the LNK allele showed higher affinity to the miR1245 than the HNK1 allele. Moreover transfection of NK cells possessing the LNK1 allele with a miR1245 mimic resulted in 25 fold decrease in mRNA NKG2D level versus only 2 fold decrease in mRNA NKG2D expression in HNK1 allele derived NK cells, thus suggesting that the 3′UTR SNP may regulate the expression of NKG2D through its binding to the putative repressor miR1245. These findings provide evidence that the NKG2D 3′UTR polymorphism is functional, and that the NK cells from donors with the HNK1 genotype exert higher cytotoxicity through their increased expression of NKG2D, thereby resulting in an improved outcome for bone marrow transplantation. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Significant Impact of IL-17A Gene Polymorphism On Transplant Outcomes After HLA-Fully-Matched Unrelated Bone Marrow Transplantation.

Abstract 2305Poster Board II-282IL-17 plays an active role in autoimmune diseases and organ transplant rejection through its mediating proinflammatory responses and inducing inflammatory cytokine and chemokine production. This study examined the impact of donor and recipient polymorphism in the IL-17A gene on the clinical outcomes in unrelated HLA-fully-matched myeloablative bone marrow transplantation (BMT) through the Japan Marrow Donor Program. The IL-17A polymorphism (rs2275913, G197A) was retrospectively analyzed in a total 145 recipients with hematologic malignancies and their unrelated donors. In patients with standard risk disease, the donor IL-17A-197A genotype was associated with significantly improved OS (adjusted HR, 0.32; 95% CI, 0.13-0.79; p=0.01) and reduced transplant related mortality (TRM) (adjusted HR, 0.27; 95% CI, 0.11-0.67; p=0.005), but no impact on disease relapse or the development of grades II-IV acute GVHD or chronic GVHD. Patients with standard risk disease receiving transplants from donors with the 197A genotype had better 5-year OS (71% vs. 40%, p=0.02; Figure) and lower 5-year TRM rate (27% vs. 60%, p=0.02). The IL-17A polymorphism did not significantly influence the transplant outcomes in patients with high risk disease. These results suggest transplantation from IL-17A-197A positive donor is advantageous in improving OS and reducing TRM after HLA-matched unrelated BMT for standard risk hematologic malignancies. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Mapping of susceptibility and protective loci for acute GVHD in unrelated HLA-matched bone marrow transplantation donors and recipients using 155 microsatellite markers on chromosome 22

Despite matching donors and recipients for the human leukocyte antigens (HLAs) expressed by the major histocompatibility genomic region of the short arm of chromosome 6, several recipients still develop acute graft-versus-host disease (aGVHD) after bone marrow transplantation (BMT). This is possibly due to non-HLA gene polymorphisms, such as minor histocompatibility antigens (mHas) and genes coding for cytokines. However, a detailed genetic background for aGVHD has not yet been established. To find novel susceptibility and/or protective loci for aGVHD, a whole genome-wide association study of donors and recipients needs to be performed. As the first step to such a study, we retrospectively analyzed polymorphisms of 155 microsatellite markers spread across the long arm of chromosome 22 in 70 pairs of HLA-matched unrelated BMT donors and recipients. We performed individual typing and then compared the markers' allele frequencies (1) between all the aGVHD (grades III and IV GVHD) and GVHD-free (grade 0 GVHD) groups in donors and recipients and (2) between the aGVHD and aGVHD-free groups in donor/recipient pairs that were matched and mismatched for the microsatellite marker's allele. Screening of the microsatellite markers revealed five loci with a significant difference between the aGVHD and GVHD-free groups and revealed eight loci on chromosome 22, where the microsatellite allele mismatched markers were associated with aGVHD. This screening analysis suggests that several aGVHD-associated susceptible and protective loci exist on chromosome 22, which may encompass novel gene regions that need to be elucidated for their role in aGVHD.

BK VIRUS-ASSOCIATED FATAL RENAL FAILURE FOLLOWING LATE-ONSET HEMORRHAGIC CYSTITIS IN AN UNRELATED BONE MARROW TRANSPLANTATION

The human polyomavirus BK (BKV)-associated hemorrhagic cystitis (HC) has been a frequent and seldom life-threatening complication after bone marrow transplantation (BMT). The authors report a male with myelodysplastic syndrome, who developed BKV-associated late-onset HC 12 days after HLA-matched unrelated BMT. His urine contained epithelial cells with intranuclear inclusion bodies suggestive of BKV infection and was positive for BKV in polymerase chain reaction. He did not respond to any treatment for HC. In addition, he developed BKV-associated acute renal failure on day 26, followed by hepatic veno-occlusive disease on day 42. This is the first case in which BKV may be associated with fatal progressive renal failure.

Beyond Our Pages

Beyond Our Pages

SOMNOLENCE SYNDROME IN A CHILD FOLLOWING 1200-cGy TOTAL BODY IRRADIATION IN AN UNRELATED BONE MARROW TRANSPLANTATION

Neurological complications may occur following intensive chemotherapy and hematopoietic cell transplantation. Postirradiation somnolence syndrome has been observed in children with acute lymphoblastic leukemia who received central nervous system preventive therapy with 1800-2400 cGy cranial irradiation. The authors report a 16-year-old boy with chronic myelogenous leukemia in chronic phase, who developed symptoms compatible with thes omnolence syndrome (SS) 6 weeks following HLA-matched unrelated bone marrow transplantation (BMT). The preparative regimen consisted of 1200 cGy total body irradiation (TBI), cytosine arabinoside and cyclophosphamide. The patient developed lethargy and low-grade fever, with intermittent rhythmical delta activity in electroencephalograph. Here covered spontaneously without specific therapy 3 weeks after developing symptoms. This is the first report describing that as low as 1200 cGy TBI can induce SS in a child. After allogeneic BMT, some patients develop neurological symptoms. The authors suggest that somnolence syndrome should be included in differential diagnosis in these patients.

Coagulation abnormalities and thrombotic microangiopathy following bone marrow transplantation from HLA-matched unrelated donors in patients with hematological malignancies.

Thrombotic microangiopathy is a well-known heterogeneous disorder that occurs as a complication of allogenic bone marrow transplantation (BMT). We evaluated 12 consecutive patients receiving HLA-matched unrelated BMT and 12 consecutive recipients of HLA-identical related BMT for the development of bone marrow transplantation-associated thrombotic microangiopathy (BMT-TM) on days 30 and 60 following BMT. A diagnosis was made in four of 12 (33.3%) unrelated compared to none of 12 (0%) HLA-identical cases. Levels of serum lactic dehydrogenase (LDH), fibrin degraded products (FDP) and de novo thrombocytopenia were elevated in eight of 12 patients (66.7%) receiving unrelated donor BMT, and none of the patients receiving related donor BMT. Our findings suggest clinical or subclinical microangiopathic changes may occur frequently in unrelated donor BMT. FDP elevation is possibly an important marker of microangiopathic changes as early complications of BMT.

ELEVATED INFLAMMATORY CYTOKINE LEVELS IN BONE MARROW GRAFT REJECTION

Graft rejection and graft failure represent major obstacles in allogeneic bone marrow transplantation (BMT). Cytokines possibly play a central role in the inflammatory and allospecific components of allograft rejection. Therefore, we evaluated inflammatory cytokine levels following BMT in 12 consecutive patients with graft rejection (GR). Seven of the patients underwent BMT from siblings (6 matched and 1 mismatched), 4 patients received bone marrow from other family members (3 mismatched and 1 matched), and 1 patient underwent HLA-matched unrelated BMT. Nine of 12 had a sex-mismatched BMT and 5/12 had an ABO-mismatched BMT. Nine of 12 underwent T cell-depleted (Campath anti-CDw52 moAb) BMT. Rejection was defined as marrow hypoplasia with a peripheral white blood cell count < 0.5 x 10(9)/L 21 days after BMT, in conjunction with the absence of donor cells by polymerase chain reaction analysis using a sex-mismatched probe and/or a tumor-specific probe (BCR/ABL). Twenty-five patients who underwent uneventful BMT with no GR served as controls. The levels of tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-1 (IL-1) were evaluated by a high sensitive RIA or an enzyme immunoassay. The levels of TNF and IL-6 were found to be higher in 10/12 and 7/7 evaluated GR patients, respectively, as compared with controls (P < 0.05). The level of IL-1 was high only in 2/12 patients. TNF elevation occurred in all patients immediately after GR. TNF and IL-6 levels were significantly higher for patients with early rejection (< 35 days after BMT) as compared with patients with late rejection (> 35 days after BMT) (P < 0.049 and P < 0.006, respectively). Eight patients engrafted after the second transplant (2 only transient). All 6 patients with stable engraftment are alive (4 with basic disease), while the 4 patients who did not engraft and the 2 patients with only transient engraftment died. In the 6 patients with no engraftment or only transient engraftment, the elevated TNF levels remained high; in the 6 patients who had stable engraftment after retransplant, TNF levels, but not IL-6 levels, decreased. In conclusion, a majority of the patients with GR displayed high levels of inflammatory cytokines (TNF and IL-6). Dysregulation of inflammatory cytokines may be involved in the pathogenesis of GR.