Search

Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.

We established and characterized a bank of 138 CMVpp65 peptide-specific T-cell (CMVpp65CTLs) lines from healthy marrow transplant donors who consented to their use for treatment of individuals other than their transplant recipient. CMVpp65CTL lines included 131 containing predominantly CD8+ T cells and 7 CD4+ T cells. CD8+ CMVpp65CTLs were specific for 1 to 3 epitopes each presented by one of only 34 of the 148 class I alleles in the bank. Similarly, the 7 predominantly CD4+ CMVpp65CTL lines were each specific for epitopes presented by 14 of 40 HLA DR alleles in the bank. Although the number of HLA alleles presenting CMV epitopes is low, their prevalence is high, permitting selection of CMVpp65CTLs restricted by an HLA allele shared by transplant recipient and hematopoietic cell transplant donor for >90% of an ethnogeographically diverse population of hematopoietic cell transplant recipients. Within individuals, responses to CMVpp65 peptides presented by different HLA alleles are hierarchical. Furthermore, within groups, epitopes presented by HLA B*07:02 and HLA A*02:01 consistently elicit immunodominant CMVpp65CTLs, irrespective of other HLA alleles inherited. All dominant CMVpp65CTLs exhibited HLA-restricted cytotoxicity against epitope loaded targets and usually cleared CMV infections. However, immunodominant CMVpp65CTLs responding to epitopes presented by certain HLA B*35 alleles were ineffective in lysing CMV-infected cells in vitro or controlling CMV infections post adoptive therapy. Analysis of the hierarchy of T-cell responses to CMVpp65, the HLA alleles presenting immunodominant CMVpp65 epitopes, and the responses they induce may lead to detailed algorithms for optimal choice of third-party CMVpp65CTLs for effective adoptive therapy.

Allogeneic stem cell transplantation is a potentially curative therapy for some malignant and non-malignant disease. There have been substantial advances since the approaches first introduced in the 1970s, and the development of approaches to transplant with HLA incompatible or alternative donors has improved access to transplant for those without a fully matched donor. However, success is still limited by morbidity and mortality from toxicity and imperfect disease control. Here we review our emerging understanding of how reconstitution of effective immunity after allogeneic transplant can protect from these events and improve outcomes. We provide perspective on milestones of immune reconstitution that are easily measured and modifiable.

Thalassemia and sickle cell disease (SCD) are the most common monogenic diseases in the world and represent a growing global health burden. Management is limited by a paucity of disease-modifying therapies; however, allogeneic hematopoietic stem cell transplantation (HSCT) and autologous HSCT after genetic modification offer patients a curative option. Allogeneic HSCT is limited by donor selection, morbidity and mortality from transplant conditioning, graft-versus-host disease and graft rejection, whereas significant concerns regarding long-term safety, efficacy and cost limit the broad applicability of gene therapy. Here the authors review current outcomes in allogeneic and autologous HSCT for transfusion-dependent thalassemia and SCD and provide our perspective on issues surrounding accessibility and costs as barriers to offering curative therapy to patients with hereditary hemoglobinopathies.

Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.

Myeloid leukemia of Down syndrome (ML-DS) in young children is associated with distinct clinical and biological features and is typically initiated with oncogenic mutations in the X-linked megakaryocytic transcription factor

Cytomegalovirus (CMV) reactivation is a significant complication following allogeneic hematopoietic stem cell transplant (HSCT) and affects upwards of 40% of pediatric HSCT patients. Pre-emptive therapy remains the only effective treatment strategy available for pediatric patients following CMV reactivation. Little is known about how the timing of induction treatment following CMV reactivation impacts outcomes in pediatric patients, especially following ex vivo T-cell-depleted (TCD) HSCT.The authors evaluated how the timing of induction treatment after CMV reactivation impacts overall survival (OS) and CMV disease in pediatric patients undergoing TCD HSCT at a single institution. The authors retrospectively analyzed patients treated on the pediatric service who received an initial ex vivo TCD HSCT at Memorial Sloan Kettering Cancer Center (MSKCC) from January 2010 to June 2018. CMV reactivation was defined as ≥1 CMV polymerase chain reaction500 copies/mL in whole blood or137 IU/mL in plasma within the first 180 days after allogeneic HSCT. To analyze the impact of the timing of induction treatment, the authors' primary study outcome was OS and secondary outcome was CMV disease.A total of 169 patients who underwent an initial allogeneic TCD HSCT on the pediatric service at MSKCC from January 2010 to June 2018 were included in the analysis. Thirty-seven (22%) patients reactivated CMV during the first 180 days following HSCT. Of those patients who reactivated CMV, CMV donor/recipient (D/R) serostatus was as follows: D+/R+ n = 28 (76%) and D-/R+ n = 9 (24%). There was no CMV reactivation observed among recipients who were CMV-seronegative irrespective of donor serostatus. In those patients who reactivated CMV, the median time from HSCT to CMV reactivation was 24 days (interquartile range, 20-31). Eleven patients ultimately developed CMV disease in addition to CMV viremia, whereas the remaining patients had only CMV viremia. The cumulative incidence of CMV reactivation at 60 days was 45.2% (95% confidence interval [CI], 32.8-57.5) in the D+/R+ subgroup and 31% (95% CI, 14.2-47.9) in the D-/R+ subgroup. For those patients who reactivated CMV, 30 (81%) received induction treatment with ganciclovir or foscarnet. To analyze the impact of the timing of induction treatment on clinical outcomes, the authors restricted the analysis to those patients who reactivated CMV and received induction treatment (n = 30). The timing of induction treatment was significantly associated with OS, with optimal timing of initiation within a week of CMV reactivation (P = 0.02). There was no significant impact on the timing of induction treatment and risk of CMV disease (P = 0.30).In ex vivo TCD HSCT in pediatric patients, early initiation of induction treatment after CMV reactivation is associated with improved OS.

Background Cord blood transplantation (CBT) is a proven therapy for high-risk hematologic malignancies. However, severe grade III-IV acute graft-versus-host disease (aGVHD) has emerged as a significant source of morbidity and mortality and most commonly targets the gastrointestinal (GI) tract after CBT. Plasma biomarkers have been found to predict aGVHD onset, aGVHD therapy response, and transplant-related mortality (TRM) after adult donor hematopoietic stem cell transplantation. However, whether plasma biomarkers are informative in CBT recipients has not been investigated. Methods Plasma biomarkers were measured 28 days after unrelated donor double-unit CBT in 113 consenting patients (median age 41 years, range 1.7-69) transplanted at a single center between 5/2006 and 5/2012 for the treatment of high-risk hematologic malignancies. Conditioning was myeloablative (n = 37), reduced intensity (n = 47), or non-myeloablative (n = 29), and CB units were 4-6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient. The median follow-up was 44 months (range 14-84). Batched samples blinded to transplant outcomes were analyzed by enzyme-linked immunosorbent assay for levels of suppressor of tumorigenicity 2 (ST2), IL-2 receptor-α (IL-2Rα), tumor necrosis factor receptor-1 (TNFR1), hepatocyte growth factor (HGF), IL-8, elafin, and regenerating islet-derived protein 3-α (REG3α). Patients were grouped according to being above or below the median day 28 value for each biomarker. The cumulative incidence of aGVHD and TRM from day 28 landmark was estimated for each biomarker and significance was assessed using Gray's test. Patients who had aGVHD onset prior to day 28 (n = 7) were excluded from aGVHD evaluation. Results We found significant associations between day 28 plasma biomarkers and grade II-IV aGVHD and/or 6-month TRM, which are shown in Table. IL2Rα, elafin, and HGF were not significant for either outcome (data not shown). ST2 was the only biomarker associated with day 100 grade II-IV aGVHD with high ST2 patients having a median aGVHD onset of 42 days (range 28-93). Notably, patients with high day 28 ST2 had significantly increased day 100 grade III-IV aGVHD of 27% (95%CI:16-40) versus 11% (95%CI:4-20) in patients with low ST2 levels, p = 0.025. High ST2 was also associated with substantially increased 6-month TRM, and GVHD was the most common cause of transplant-related death [11/19 (58%) of deaths] with a median time to GVHD death of 170 days (range 70-400). High concentrations of TNFR1, IL-8, and REG3a were also significantly associated with 6-month TRM. Notably, aGVHD and organ failure due to lung toxicity were the most common causes of TRM in patients with high TNFR1, IL8, and REG3α levels. Conclusions This is the first biomarker analysis conducted in CBT recipients. We demonstrate that a high day 28 ST2 level is associated with a subsequent increased risk of grade II-IV and III-IV aGVHD, as well as 6-month TRM. These findings are consistent with those recently reported in adult unmodified (T-replete) allograft recipients (Vander Lugt et al, NEJM, 2013). GVHD is the predominant mechanism of death in high ST2 patients and the day of onset is after day 28 in the majority which would permit time for therapeutic intervention. Thus, our findings have significant practical implications. Whether the other biomarkers offer additional prognostic information remains to be determined. They were not associated with the overall grade II-IV aGVHD incidence, but where associated with mortality from GVHD and organ failure. Overall, our promising results warrant further prospective evaluation in a large patient cohort with the ultimate aim of future interventions to ameliorate severe aGVHD and improve survival after CBT. Disclosures: No relevant conflicts of interest to declare.