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•In patients with IEI, improved EFS and higher donor chimerism may be achieved by targeting a cumulative busulfan AUC of 80 mg × h/L.•The data stress the importance of uniformly using a validated population pharmacokinetic model to estimate the busulfan cumulative exposure.

•Largest single-center study of radiation-free RIC alloHCT in DC/TBD.•TBI is dispensable in RIC alloHCT for DC/TBD-associated BMF.•Optimal management of DC/TBD-associated MDS remains indeterminate.•TBI removal led to prolonged mixed-donor chimerism but faster lymphocyte recovery.•Survival fails to plateau with late deaths from non-heme DC/TBD complications.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic disease resulting from inadequate type VII collagen (C7). Although recurrent skin blisters and wounds are the most apparent disease features, the impact of C7 loss is not confined to the skin and mucous membranes. RDEB is a systemic disease marred by chronic inflammation, fibrotic changes, pain, itch, and anemia, significantly impacting QOL and survival. In this narrative review, we summarize these systemic features of RDEB and promising research avenues to address them.

•Allogeneic HCT quickly and durably resolved disease manifestations in patients with CGD, with excellent survival.•HCT should be considered early for CGD before comorbidities affect the performance status.

Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010–18.

Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.

We investigated the impact of the number of induction/consolidation cycles on outcomes of 3113 adult AML patients who received allogeneic hematopoietic cell transplantation (allo-HCT) between 2008 and 2019. Patients received allo-HCT using myeloablative (MAC) or reduced-intensity (RIC) conditioning in first complete remission (CR) or with primary induction failure (PIF). Patients who received MAC allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After RIC allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1–3 cycles.

Veno-occlusive disease (VOD) is a serious complication after hematopoietic cell transplant (HCT). Incidence of VOD in children is ∼15-20% and particular risk factors portend some patients to be very high risk (VHR). VOD is potentially fatal in up to 85% of patients who experience severe grades of VOD. Use of defibrotide for prophylaxis can be considered for those at VHR for developing VOD, but it is expensive. The cost of treating VOD is significant and the disease processes may result in long-term health effects. At our institution, for patients planned for 2ndallogeneic HCT, we limit the use of prophylactic defibrotide to VHR patients. We sought to provide justification for the use of prophylactic defibrotide in this smaller, more selective group.

Hematopoietic cell transplant (HCT) for SCID using an HLA-matched sibling donor (MSD) is associated with excellent survival and low risk of morbidity and GVHD. In the largest cohort of MSD outcomes in SCID patients to date, we examined the impact on survival and immune recovery of 1) use of a conditioning regimen and 2) GVHD prophylaxis approach.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, incurable blistering skin disease caused by biallelic mutations in type VII collagen (C7). Advancements in treatment of RDEB have come from harnessing the immunomodulatory potential of mesenchymal stem cells (MSCs). Although human bone marrow‐derived MSC (BM‐MSC) trials in RDEB demonstrate improvement in clinical severity, the mechanisms of MSC migration to and persistence in injured skin and their contributions to wound healing are not completely understood. A unique subset of MSCs expressing ATP‐binding cassette subfamily member 5 (ABCB5) resides in the reticular dermis and exhibits similar immunomodulatory characteristics to BM‐MSCs. Our work aimed to test the hypothesis that skin‐derived ABCB5+ dermal MSCs (DSCs) possess superior skin homing ability compared to BM‐MSCs in immunodeficient NOD‐scid IL2rgammanull(NSG) mice. Compared to BM‐MSCs, peripherally injected ABCB5+ DSCs demonstrated superior homing and engraftment of wounds. Furthermore, ABCB5+ DSCs vs BM‐MSCs cocultured with macrophages induced less anti‐inflammatory interleukin‐1 receptor antagonist (IL‐1RA) production. RNA sequencing of ABCB5+ DSCs compared to BM‐MSCs showed unique expression of major histocompatibility complex class II and Homeobox (Hox) genes, specifically HOXA3. Critical to inducing migration of endothelial and epithelial cells for wound repair, increased expression of HOXA3may explain superior skin homing properties of ABCB5+ DSCs. Further discernment of the immunomodulatory mechanisms among MSC populations could have broader regenerative medicine implications beyond RDEB treatment. Schema of ABCB5+ dermal mesenchymal stem cell (MSC) (DSC) characteristics compared to bone marrow (BM)‐MSCs. Potential mechanisms of superior skin homing of ABCB5+ DSCs for use in recessive dystrophic epidermolysis bullosa (RDEB) and regenerative medicine applications. Similarities in immunomodulatory capacity of ABCB5+ DSCs and BM‐MSCs are shown in the middle column including anti‐inflammatory M1 > M2 macrophage skewing.

Hematopoietic stem cell transplantation (HCT) has been increasingly used for patients with inherited metabolic disorders (IMD). Immune mediated cytopenias (IMCs) after HCT, manifesting as hemolytic anemia, thrombocytopenia, and/or neutropenia, are recognized as a significant complication in this patient population, yet our understanding of the incidence, risk factors, and pathophysiology is currently limited. Review of the published literature demonstrates a higher incidence in younger patients who undergo HCT for a nonmalignant disease indication. However, a few reports suggest that the incidence is even higher among those with IMD (incidence ranging from 10 to 56%). This review summarizes the literature, provides an approach to better understanding of the possible etiology of IMCs, and proposes a diagnostic and management plan for patients with IMD who develop single or multi-lineage cytopenias after HCT.

Immune-mediated cytopenias (IMC)—isolated or combined hemolytic anemia, thrombocytopenia, or neutropenia—are increasingly recognized as serious complications after allogeneic hematopoietic cell transplantation (HCT) for nonmalignant disorders (NMD). However, IMC incidence, duration, response to therapy, and risk factors are not well defined. This retrospective chart review identified cases of IMC with serologic confirmation among patients who underwent HCT for NMD at a single institution between 2010 and 2017. IMC after HCT for NMD in a large pediatric cohort (n = 271) was common with a cumulative incidence of 18%, identified at a median of 136 days after HCT. Treatment included prolonged immune suppression (>3 months) in 58% of all IMC cases, 91% when multiple cell lines were affected. Multiple therapeutic agents were used for the majority affected, and median time to resolution of IMC was 118 days from diagnosis. Fine-Gray competing risk multivariate regression analysis identified a combined risk factor of younger age (<3 years) and inherited metabolic disorder, as well as hemoglobinopathy (at any age) associated with 1-year incidence of IMC (P< .01). We expand these findings with the observation of declining donor T-lymphoid chimerism from day 60 to 100 and lower absolute CD4+ counts at day 100 (P< .01), before median onset of IMC, for patients with IMC compared to those without. In this cohort, 4 deaths (8%) were associated with IMC, including 2 requiring second transplantation for secondary graft failure. Although the pathogenesis of IMC post-HCT for NMD remains elusive, further research may identify approaches to prevent and better treat this HCT complication.

ABSTRACTIntroductionJunctional epidermolysis bullosa (JEB) is a rare inherited genetic disorder with limited treatments beyond palliative care. A major hallmark of JEB is skin blistering caused by functional loss or complete absence of major structural proteins of the skin. Impaired wound healing in patients with JEB gives rise to chronic cutaneous ulcers that require daily care. Wound care and infection control are the current standard of care for this patient population.Areas coveredThis review covers research and clinical implementation of emerging drug, cell, and gene therapies for JEB. Current clinical trials use topical drug delivery to manipulate the inflammation and re-epithelialization phases of wound healing or promote premature stop codon readthrough to accelerate chronic wound closure. Allogeneic cell therapies for JEB have been largely unsuccessful, with autologous skin grafting emerging as a reliable method of resolving the cutaneous manifestations of JEB. Genetic correction and transplant of autologous keratinocytes have demonstrated persistent amelioration of chronic wounds in a subset of patients.Expert OpinionEmerging therapies address the cutaneous symptoms of JEB but are unable to attend to systemic manifestations of the disease. Investigations into the molecular mechanism(s) underpinning the failure of systemic allogeneic cell therapies are necessary to expand the range of effective JEB therapies.

In the absence of cytomegalovirus (CMV) prophylaxis (ppx), CMV DNAemia occurs in up to 70% of allogeneic hematopoietic cell transplants (HCT). Post-HCT CMV infection can be life-threatening. Letermovir is routine for CMV ppx adult HCT, but not FDA approved for < 18 years nor available in a liquid formulation. With increased cost, insurance coverage barrier, and pill burden of letermovir ppx, replacement of acyclovir with letermovir for CMV ppx in pediatric HCT requires identification of patient or HCT characteristics associated with high risk for breakthrough CMV DNAemia.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severely debilitating disorder caused by mutations in COL7A1and is characterized by extreme skin fragility, chronic inflammation, and fibrosis. A majority of patients with RDEB develop squamous cell carcinoma, a highly aggressive skin cancer with limited treatment options currently available. In this study, we utilized an approach leveraging whole-genome sequencing and RNA sequencing across 3 different tissues in a single patient with RDEB to gain insight into possible mechanisms of RDEB-associated squamous cell carcinoma progression and to identify potential therapeutic options. As a result, we identified PLK-1 as a possible candidate for targeted therapy and discovered microsatellite instability and accelerated aging as factors potentially contributing to the aggressive nature and early onset of RDEB squamous cell carcinoma. By integrating multitissue genomic and transcriptomic analyses in a single patient, we demonstrate the promise of bridging the gap between genomic research and clinical applications for developing tailored therapies for patients with rare genetic disorders such as RDEB.

Severe aplastic anemia (SAA) is a life-threatening, idiopathic process involving the immune-mediated destruction of hematopoietic stem cells. Treatment involves immunosuppressive therapy (IST) and/or allogeneic hematopoietic cell transplantation (HCT). The latter has recently been optimized with use of a post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GvHD) platform, permitting successful HCT with only half-HLA-matched haploidentical donors. In pediatrics, this platform results in >90% overall survival with low rates of GvHD and graft failure. However, reports on donor chimerism and immune reconstitution are limited. We hypothesized that a PTCy platform would expedite CD3 donor engraftment and CD4 T cell recovery.

Adenosine deaminase (ADA) deficiency causes ~13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 ADA-SCID patients diagnosed between 1982-2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium (PIDTC) SCID studies. Baseline clinical, immunologic, genetic characteristics and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT) (p<0.01). Overall survival (OS) at 5-years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT) (p=0.01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs. 68% if ≥3.5 months, p=0.02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs. 68.2%, p<0.01) and OS (64.7% vs. 82.3%, p=0.02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies ADA-SCID patients soon after birth and before the onset of infections. Clinical trials: PIDTC 6901 study: ClinicalTrials.gov NCT01186913 PIDTC 6902 study: ClinicalTrials.gov NCT01346150

Recessive dystrophic epidermolysis bullosa (RDEB) is a devastating genodermatosis characterized by dysfunctional collagen VII protein resulting in epithelial blistering of the skin, mucosa, and gastrointestinal tract. There is no cure for RDEB, but improvement of clinical phenotype has been achieved with bone marrow transplant (BMT) and subsequent epidermal allografting from the BMT donor. Epidermal allografting of these patients has decreased wound surface area for up to three years post treatment. This study aimed to determine the phenotype of the epidermal allograft cells responsible for durable persistence of wound healing and skin integrity. We found that epidermal allografts provide basal keratinocytes co-expressing collagen VII and basal stem cell marker keratin 15. Characterization of RDEB full-thickness skin biopsies with single-cell RNA sequencing uncovered pro-inflammatory immune and fibroblast phenotypes potentially driven by the local environment of RDEB skin. This is further highlighted by the presence of a myofibroblast population, which has not been described in healthy control human skin. Finally, we found inflammatory fibroblasts expressing pro-fibrotic gene periostin (POSTN), which may have implications in development of squamous cell carcinoma, a common, lethal complication of RDEB that lacks curative treatment. In conclusion, this study provides insights and targets for future RDEB studies and treatments.

No relevant conflicts of interest to declare.

Introduction

Arora: Kadmom: Research Funding; Pharmacyclics: Research Funding; Syndax: Research Funding. Janakiram: Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria; FATE, Nektar Therapeutics: Research Funding. Smith: Astellas Gene Therapies: Current Employment. Bachanova: Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brunstein: BlueRock: Research Funding; AlloVir: Consultancy; FATE: Research Funding; NANT: Research Funding; GamidaCell: Research Funding. MacMillan: Equilium: Other: DSMB member; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Miller: Sanofi: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vycellix: Consultancy; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; Wugen: Membership on an entity's Board of Directors or advisory committees. Betts: Patent Disclosures: Patents & Royalties: B.C.B. holds a patent (WO2015120436A2) related to CD4+ T cell pSTAT3 as a marker and therapeutic target of acute GVHD. B.C.B. additionally holds a provisional patent (WO2017058950A1) related to the use of JAK inhibitors for rejection and GVHD prevention. . Vercellotti: Mitobridge, an Astellas Company: Consultancy, Research Funding; CSL Behring: Research Funding. Weisdorf: Fate Therapeutics: Research Funding; Incyte: Research Funding. Holtan: Generon: Consultancy; Incyte: Consultancy, Research Funding.

Prolonged neutropenia increases risk for lethal invasive fungal infection (IFI) such as Rhizopus.Isavuconazonium sulfate is a new triazole that lacks pediatric dosing recommendations. Clinical courses of 4 pediatric patients with IFI in the peri-allogeneic hematopoietic cell transplantation (alloHCT) period between 2015 and 2017 were reviewed, including previously unreported pharmacokinetic and safety data. IFI included Rhizopusand presumed fungal meningitis. Isavuconazonium sulfate was initiated with a loading dose followed by daily dosing, adjusted to a goal trough >3 ug/mL based on adult literature. This target was achieved at a median of 7 days, demonstrating varying rates of metabolism. Renal insufficiency, electrolyte disturbances, and transaminitis were noted, though attribution was confounded by other alloHCT complications. 1 patient survived infection-free to hospital discharge and 1 of 3 deceased patients had evidence of unresolved IFI (Case 2). Case 2 was subtherapeutic for 39% of the duration of treatment, compared to others at an average of 29%, suggesting this target trough to be clinically relevant. We recommend initiation of isavuconazonium sulfate at 10 mg/kg with a max dose of 372 mg. A loading dose of 10 mg/kg is utilized every 8 hours for 6 doses followed by 10 mg/kg dosing every 24 hours. Monitoring must continue beyond steady state. If early monitoring is not possible, we recommend a first drug level at week 3. If dose increases are required, a partial reload has been more successful instead of increasing daily doses. Further larger studies are needed to demonstrate optimum dosing in pediatric patients.

No relevant conflicts of interest to declare.

Wagner: Magenta Therapeutics: Consultancy, Research Funding; Novartis: Research Funding.

Introduction:Recessive dystrophic epidermolysis bullosa (RDEB) is a severe, life-limiting systemic genodermatosis, characterized by COL7A1mutation(s) yielding inadequate type VII collagen to maintain the integrity of the cutaneous basement and mucosal membranes. The mainstay of therapy for RDEB is supportive care to minimize the daily morbidity of blistering/scarring, pain/pruritis, systemic inflammation, and high metabolic demand. Leveraging the pluripotency of bone marrow cells, investigations of BMT as a systemic therapy for RDEB showed promise in pre-clinical murine (Tolar J, et al., Blood 2009, 113(5): 1167-74) as well as early phase human clinical trials utilizing fully myeloablative conditioning (Wagner J, et al., NEJM 2010, 363(7): 629-39). However, regimen-rated toxicity limited dampened enthusiasm for the clinical approach.