Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
BACKGROUND & AIMS: The IBD5 locus on chromosome 5q31 is a confirmed Crohn's disease (CD) susceptibility locus in adults. Recently, two polymorphisms in the organic cation transporter (OCTN) gene cluster within the IBD5 locus have been found to be associated with CD. Although the original report of significant linkage to IBD5 was in families with at least one case of early age at onset CD, there are no published reports on the role of OCTN genes in pediatric onset CD. We performed a comprehensive analysis of OCTN variants in an independent, exclusively pediatric onset CD cohort and examined the genotype/phenotype correlations. METHODS 264 Caucasian CD children (172 of them were trios) were genotyped along with 527 controls for OCTN1 (SLC22A4 C1672T), OCTN2 (SLC22A5 G-207C), and two haplotype-tagging SNPs (IGR2230 and IGR2198). RESULTS TDT confirmed the association of SLC22A4 and SLC22A5. Case-control analysis of the SLC22A4 1672T, SLC22A5−207C diplotype showed significant association (p = 0.04) with CD susceptibility compared with controls. Little correlation was seen with regard to clinical phenotype and the SLC22A4/SLC22A5 diplotype. There was no significant interaction between the SLC22A4/SLC22A5 diplotype and the three CD-associated CARD15 SNPs. CONCLUSIONS We confirm the association of the OCTN variants (SLC22A4 and SLC22A5) in pediatric onset CD as seen in adult CD cohorts. However, when an extended IBD5 haplotype was examined, no independent association between OCTN variants and pediatric onset CD can be demonstrated. Compared with adults, a relatively weak association of the OCTN variants was observed in our CD cohort. No definitive genotype–phenotype correlation or gene–gene interactions with CARD15 were observed. Although the IBD5 locus is associated with pediatric onset CD, no definitive conclusions can be drawn about OCTN variants as causative genes in pediatric CD at this point.
Background: Studies of bone marrow cell clonal alterations in patients with Fanconi anemia (FA), a cancer-prone inherited bone marrow failure (BMF) syndrome, have focused on their role in progression from BMF to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The role of such alterations on patient outcomes after hematopoietic cell transplantation (HCT) is unknown. Methods: Using genome-wide SNP arrays, we investigated clonal alterations in pre-HCT blood samples from 73 FA patients who received allogeneic unrelated HCT between 1991-2007. Clinical data and blood samples were available through the Center for International Blood and Marrow Transplant Research. The association of pre-HCT clonal alterations with overall survival (OS) after HCT were evaluated in univariate analysis using the Kaplan-Meier method and in multivariable analysis using Cox proportional hazard models. Results: Median age at HCT was 10.6 years (range = 2.5-28.8), 53% of the patients were males, 86% received bone marrow grafts, 64% received reduced intensity or non-myeloablative regimens, and 41% had an 8/8 HLA matched donor. Clonal alterations were detected in 16 patients (22%). The most frequent alterations were copy-loss in chromosome 7 (chr7-; N = 7, 10%), followed by copy-gain in chromosome 1 (chr1+; N = 6, 8%) and in chromosome 3 (chr3+; N = 6, 8%). No statistically significant demographic or transplant-related differences were observed in those with or without chromosomal alterations. In univariate analyses, chr1+ was statistically significantly associated with inferior survival (1-year OS of patients with and without ch1+ was 17 vs. 43%, respectively, log-rank P = .03). Similar results were observed in patients with chr3+, 1-yr OS = 0 with chr3+ vs. 45% without chr3+ (log-rank P = .003). Acute GvHD was the most common cause of death in patients with ch1+ or chr3+ (33.3% of all deaths vs. 4.4% in patients without alterations, P = .03). No statistically significant difference in OS was noted with chr7-, 1-yr OS = 29% with chr7- vs. 42%without (P = .57). Multivariable analysis adjusted for age and year of transplant showed that patients with pre-HCT copy-gain in chr1 or chr3 had a nearly three-fold excess risk of dying after HCT (hazard ratio (HR) = 2.69, 95% confidence interval [CI] = 1.22-5.91, P = .01); The HRs in non-myeloablative/reduced intensity and myeloablative conditioning were 3.84 (P = .02) and 1.47(P = .53), respectively. No association between chr7 loss and OS was seen in multivariable analyses (HR = 1.18, 95% CI = .46-3.03, P = .74). Conclusion: Pre-HCT clonal copy-gain in chr1 or chr3 was associated with worse post-transplant survival in patients with FA. The stronger association with non-myeloablative/reduced intensity conditioning suggest a possible role for mixed chimerism. Larger studies of post-HCT outcome in relation to chromosomal aberrations are warranted.
ABSTRACT In a previous study we identified the subpopulations of thymus cells that were infected by the lymphomagenic MCF13 murine leukemia virus (MLV) (F. K. Yoshimura, T. Wang, and M. Cankovic, J. Virol. 73:4890–4898, 1999) and observed an effect on thymus size by virus infection. In this report we describe our results which demonstrate that MCF13 MLV infection of thymuses reduced the number of T lymphocytes in this organ. Histological examination showed diffuse lymphocyte depletion, which was most striking in the CD4 + CD8 + lymphocyte-enriched cortical zone. Consistent with this, flow cytometric analysis showed that the lymphocytes which were depleted were predominantly the immature CD3 − CD4 + CD8 + and CD3 + CD4 + CD8 + cells. A comparison of the percentages of live, apoptotic, and dead cells of the gp70 + and gp70 − thymic lymphocytes suggested that this effect on thymus cellularity is a result of virus infection. Studies of the survival of thymic T lymphocytes in culture showed that cells from MCF13 MLV-inoculated mice underwent greater apoptosis and death than cells from control animals. Assays for apoptosis included 7-amino-actinomycin D staining, DNA fragmentation, and cleavage of caspase-3 and poly(ADP-ribose) polymerase proenzymes. Our results suggest that apoptosis of thymic lymphocytes by virus infection is an important step in the early stages of MCF13 MLV tumorigenesis.
