Omidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase 3 trial ...to evaluate the efficacy of omidubicel compared with standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients age 13 to 65 years with hematologic malignancies were randomly assigned to omidubicel vs standard UCBT. Patients received myeloablative conditioning and prophylaxis with a calcineurin inhibitor and mycophenolate mofetil for graft-versus-host disease (GVHD). The primary end point was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% confidence interval CI, 10-14 days) for the omidubicel arm and 22 days (95% CI, 19-25 days) for the control arm (P < .001). The cumulative incidence of neutrophil engraftment was 96% for patients receiving omidubicel and 89% for patients receiving control transplants. The omidubicel arm had faster platelet recovery (55% vs 35% recovery by 42 days; P = .028), had a lower incidence of first grade 2 to 3 bacterial or invasive fungal infection (37% vs 57%; P = .027), and spent more time out of hospital during the first 100 days after transplant (median, 61 vs 48 days; P = .005) than controls. Differences in GVHD and survival between the 2 arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduces early transplant-related complications compared with standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT. The trial was registered at www.clinicaltrials.gov as #NCT02730299.
•Transplantation with omidubicel provides faster neutrophil and platelet recovery compared with a standard umbilical cord blood graft.•Transplantation with omidubicel results in fewer early bacterial and viral infections and less time in hospital.
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We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric ...patients who had first undergone myeloablative-unrelated bone marrow or peripheral blood HCT for acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome between 1999 and 2011 were included. All had high-resolution typing for HLA-A, -B, -C, and -DRB1. Of the total (n = 8003), cases were 8/8 (n = 5449), 7/8 (n = 2071), or 6/8 (n = 483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grades II to IV and III to IV acute graft vs host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared with HLA-matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, HLA-DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and HLA-DPB1 mismatch had decreased relapse. Nonpermissive HLA-DPB1 allele mismatch was associated with higher TRM compared with permissive HLA-DPB1 mismatch or HLA-DPB1 match and increased overall mortality compared with permissive HLA-DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, and -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of nonpermissive HLA-DPB1 mismatches in otherwise HLA-matched pairs is indicated.
•High-resolution matching for HLA-A, -B, -C, and -DRB1 is required for optimal survival in myeloablative-unrelated donor transplantation.•HLA-DPB1 nonpermissive mismatches should be avoided in otherwise matched transplants to minimize overall mortality.
PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by mTOR (mechanistic target of rapamycin) overactivity. Limited data suggest that mTOR inhibitors may be ...therapeutic. No placebo-controlled studies have examined mTOR inhibition on cognition and behavior in humans with PHTS with/without autism.
We conducted a 6-month phase II, randomized, double-blinded, placebo-controlled trial to examine the safety profile and efficacy of everolimus (4.5 mg/m2) in individuals (5-45 years) with PHTS. We measured several cognitive and behavioral outcomes, and electroencephalography (EEG) biomarkers. The primary endpoint was a neurocognitive composite derived from Stanford Binet-5 (SB-5) nonverbal working memory score, SB-5 verbal working memory, Conners' Continuous Performance Test hit reaction time, and Purdue Pegboard Test score.
Forty-six participants underwent 1:1 randomization: n = 24 (everolimus) and n = 22 (placebo). Gastrointestinal adverse events were more common in the everolimus group (p < 0.001). Changes in the primary endpoint between groups from baseline to month 6 were not apparent (Cohen's d = -0.10, p = 0.518). However, several measures were associated with modest effect sizes (≥0.2) in the direction of improvement, including measures of nonverbal IQ, verbal learning, autism symptoms, motor skills, adaptive behavior, and global improvement. There was a significant difference in EEG central alpha power (p = 0.049) and central beta power (p = 0.039) six months after everolimus treatment.
Everolimus is well tolerated in PHTS; adverse events were similar to previous reports. The primary efficacy endpoint did not reveal improvement. Several secondary efficacy endpoints moved in the direction of improvement. EEG measurements indicate target engagement following 6 months of daily oral everolimus. Trial Registration Information: ClinicalTrials.gov NCT02991807 Classification of Evidence: I.
Hematopoietic stem cell transplant (HCT) is used for many pediatric malignant and non-malignant diseases. However, these patients are at a high risk for emergencies post-transplant, related to prior ...comorbidities and treatments for the underlying disease, high dose chemotherapy regimen related toxicities, prolonged myelosuppression, and opportunistic infections due to their immunocompromised state. Emergencies can be during preparative regimen and hematopoietic progenitor cell (HPC) infusion, acute post-transplant (pre-engraftment) and late during post engraftment. Infectious complications are the most common cause of morbidity and mortality in the peri-transplant period. Sinusoidal obstructive syndrome is another life-threatening emergency seen in children undergoing HCT, especially in infants. Timely recognition and administration of defibrotide with/without steroids is key to the management of this complication. Another complication seen is transplant associated thrombotic microangiopathy. It can cause multiorgan failure if left untreated and demands urgent identification and management with complement blockade agents such as eculizumab. Cytokine release syndrome and cytokine storm is an important life-threatening complication seen after cellular therapy, and needs emergent intervention with ICU supportive care and tocilizumab. Other complications in acute period include but are not limited to: seizures from busulfan or other chemotherapy agents, PRES (posterior reversible encephalopathy syndrome), diffuse alveolar hemorrhage, idiopathic pulmonary syndrome and allergic reaction to infusion of stem cells. Acute graft versus host disease (GvHD) is a major toxicity of allogeneic HCT, especially with reduced intensity conditioning, that can affect the skin, liver, upper and lower gastrointestinal tract. There has been major development in new biomarkers for early identification and grading of GvHD, which enables application of treatment modalities such as post-transplant cyclophosphamide and JAK/STAT inhibitors to prevent and treat GvHD. Myelosuppression secondary to the chemotherapy increases risk for engraftment syndrome as well as coagulopathies, thus increasing the risk for clotting and bleeding in the pediatric population. The purpose of this article is to review recent literature in these complications seen with pediatric hematopoietic cell transplant (HCT) and cellular therapies and provide a comprehensive summary of the major emergencies seen with HCT.
Next generation sequencing (NGS) has become an important tool to inform disease risk for myeloid malignancies, however data remains conflicting regarding the significance of individual mutations. We ...performed targeted NGS on 112 patients with AML, and 80 with MDS, who underwent allogeneic hematopoietic cell transplantation. The most common mutations in AML were TET2 (14.7%), FLT3 (12.9%), DNMT3A (12.1%), and RUNX1 (7.8%). Complex cytogenetics (HR 2.82, P = .017) and disease status (<CR) (HR 2.58, P < .001) was significantly associated with worse RFS. No individual mutation, nor variant allelic frequency (VAF), was found to be prognostic, except mutations in the RNA-splicing pathway, (HR 2.09, P = .023). Within the MDS cohort, most common mutations were ASXL1 (12.5%), SRSF2 (12%), TET2 (8.8%), and TP53 (8.8%). Complex cytogenetics (HR 5.01, P < .001), and presence of U2AF1 (HR 3.60, P = .019), was associated with worse RFS. Analysis of VAF found that TP53 and EZH2 mutations with allelic frequencies of >33% were associated with poor RFS (HR 3.57, P = .017; and HR 6.57, P = .003; respectively). Molecular profiling is increasingly important in the care of patients with AML and MDS. Further studies are needed to understand the molecular complexities, including the significance of clonal burden, to better inform care decisions.
Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed ...or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×10
L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47;
=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.
(1) Background: EWS fusion genes are associated with Ewing sarcoma and other Ewing family tumors including desmoplastic small round tumor, DSRCT. We utilize a clinical genomics workflow to reveal ...real-world frequencies of EWS fusion events, cataloging events that are similar, or divergent at the EWS breakpoint. (2) Methods: EWS fusion events from our next-generation sequencing panel (NGS) samples were first sorted by breakpoint or fusion junctions to map out the frequency of breakpoints. Fusion results were illustrated as in-frame fusion peptides involving EWS and a partner gene. (3) Results: From 2471 patient pool samples for fusion analysis at the Cleveland Clinic Molecular Pathology Laboratory, we identified 182 fusion samples evolved with the EWS gene. They are clustered in several breakpoints: chr22:29683123 (65.9%), and chr22:29688595 (2.7%). About 3/4 of Ewing sarcoma and DSRCT tumors have an identical EWS breakpoint motif at Exon 7 (SQQSSSYGQQ-) fused to a specific part of FLI1 (NPSYDSVRRG or-SSLLAYNTSS), ERG (NLPYEPPRRS), FEV (NPVGDGLFKD) or WT1 (SEKPYQCDFK). Our method also worked with Caris transcriptome data, too. Our primary clinical utility is to use this information to identify neoantigens for therapeutic purposes. (4) Conclusions and future perspectives: our method allows interpretation of what peptides result from the in-frame translation of EWS fusion junctions. These sequences, coupled with HLA-peptide binding data, are used to identify potential sequences of cancer-specific immunogenic peptides for Ewing sarcoma or DSRCT patients. This information may also be useful for immune monitoring (e.g., circulating T-cells with fusion-peptide specificity) to detect vaccine candidates, responses, or residual disease.
Omidubicel (nicotinamide-expanded cord blood) is a potential alternative source for allogeneic hematopoietic cell transplantation (HCT) when an HLA-identical donor is lacking. A phase I/II trial with ...standalone omidubicel HCT showed rapid and robust neutrophil and platelet engraftment. In this study, we evaluated the immune reconstitution (IR) of patients receiving omidubicel grafts during the first 6 months post-transplant, as IR is critical for favorable outcomes of the procedure. Data was collected from the omidubicel phase I-II international, multicenter trial. The primary endpoint was the probability of achieving adequate CD4+ T-cell IR (CD4IR: > 50 × 10
/L within 100 days). Secondary endpoints were the recovery of T-cells, natural killer (NK)-cells, B-cells, dendritic cells (DC), and monocytes as determined with multicolor flow cytometry. LOESS-regression curves and cumulative incidence plots were used for data description. Thirty-six omidubicel recipients (median 44; 13-63 years) were included, and IR data was available from 28 recipients. Of these patients, 90% achieved adequate CD4IR. Overall, IR was complete and consisted of T-cell, monocyte, DC, and notably fast NK- and B-cell reconstitution, compared to conventional grafts. Our data show that transplantation of adolescent and adult patients with omidubicel results in full and broad IR, which is comparable with IR after HCT with conventional graft sources.
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