Current Concepts and Advances in Graft-Versus-Host Disease Immunology.

Worldwide, each year over 30,000 patients undergo an allogeneic hema-topoietic stem cell transplantation with the intent to cure high-risk hematologic malignancy, immunodeficiency, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances in donor selection and conditioning regimens and greater availability of allograft sources, transplant recipients still endure the morbidity and mortality of graft-versus-host disease (GVHD). Herein, we identify key aspects of acute and chronic GVHD pathophysiology, including host/donor cell effectors, gut dysbiosis, immune system and cytokine imbalance, and the interface between inflammation and tissue fibrosis. In particular, we also summarize the translational application of this heightened understanding of immune dysregulation in the design of novel therapies to prevent and treat GVHD.

Epitope editing enables targeted immunotherapy of acute myeloid leukaemia.

Despite the considerable efficacy observed when targeting a dispensable lineage antigen, such as CD19 in B cell acute lymphoblastic leukaemia1,2, the broader applicability of adoptive immunotherapies is hampered by the absence of tumour-restricted antigens3-5. Acute myeloid leukaemia immunotherapies target genes expressed by haematopoietic stem/progenitor cells (HSPCs) or differentiated myeloid cells, resulting in intolerable on-target/off-tumour toxicity. Here we show that epitope engineering of donor HSPCs used for bone marrow transplantation endows haematopoietic lineages with selective resistance to chimeric antigen receptor (CAR) T cells or monoclonal antibodies, without affecting protein function or regulation. This strategy enables the targeting of genes that are essential for leukaemia survival regardless of shared expression on HSPCs, reducing the risk of tumour immune escape. By performing epitope mapping and library screenings, we identified amino acid changes that abrogate the binding of therapeutic monoclonal antibodies targeting FLT3, CD123 and KIT, and optimized a base-editing approach to introduce them into CD34+ HSPCs, which retain long-term engraftment and multilineage differentiation ability. After CAR T cell treatment, we confirmed resistance of epitope-edited haematopoiesis and concomitant eradication of patient-derived acute myeloid leukaemia xenografts. Furthermore, we show that multiplex epitope engineering of HSPCs is feasible and enables more effective immunotherapies against multiple targets without incurring overlapping off-tumour toxicities. We envision that this approach will provide opportunities to treat relapsed/refractory acute myeloid leukaemia and enable safer non-genotoxic conditioning.

Exagamglogene Autotemcel for Transfusion-Dependent ß-Thalassemia.

BACKGROUND: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis through ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of the erythroid-specific enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs). METHODS: We conducted an open-label, single-group, phase 3 study of exa-cel in patients 12 to 35 years of age with transfusion-dependent ß-thalassemia and a ß0/ß0, ß0/ß0-like, or non-ß0/ß0-like genotype. CD34+ HSPCs were edited by means of CRISPR-Cas9 with a guide mRNA. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was transfusion independence, defined as a weighted average hemoglobin level of 9 g per deciliter or higher without red-cell transfusion for at least 12 consecutive months. Total and fetal hemoglobin concentrations and safety were also assessed. RESULTS: A total of 52 patients with transfusion-dependent ß-thalassemia received exa-cel and were included in this prespecified interim analysis; the median follow-up was 20.4 months (range, 2.1 to 48.1). Neutrophils and platelets engrafted in each patient. Among the 35 patients with sufficient follow-up data for evaluation, transfusion independence occurred in 32 (91%; 95% confidence interval, 77 to 98; P<0.001 against the null hypothesis of a 50% response). During transfusion independence, the mean total hemoglobin level was 13.1 g per deciliter and the mean fetal hemoglobin level was 11.9 g per deciliter, and fetal hemoglobin had a pancellular distribution (≥94% of red cells). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No deaths or cancers occurred. CONCLUSIONS: Treatment with exa-cel, preceded by myeloablation, resulted in transfusion independence in 91% of patients with transfusion-dependent ß-thalassemia. (Supported by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-111 ClinicalTrials.gov number, NCT03655678.).

Exagamglogene Autotemcel for Severe Sickle Cell Disease.

BACKGROUND: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A. METHODS: We conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed. RESULTS: A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred. CONCLUSIONS: Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.).

TCRαß/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: updated final analysis.

ABSTRACT: TCRαß/CD19 cell depletion is a promising graft manipulation technique frequently used in the context of human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (HSCT). We previously reported the results of a phase I-II clinical trial (NCT01810120) to assess the safety and the efficacy of this type of exvivo T-cell depletion in 80 children with acute leukemia, showing promising survival outcomes. We now report an updated analysis on a cohort of 213 children with a longer follow-up (median, 47.6 months for surviving patients). With a 5-year cumulative incidence of nonrelapse mortality of 5.2% (95% confidence interval [CI], 2.8%-8.8%) and a cumulative incidence of relapse of 22.7% (95% CI, 16.9%-29.2%), projected 10-year overall and disease-free survival (DFS) were 75.4% (95% CI, 68.6%-80.9%) and 71.6% (95% CI, 64.4%-77.6%), respectively. Cumulative incidence of both grade II-IV acute and chronic graft-versus-host disease were low (14.7% and 8.1%, respectively). In a multivariable analysis for DFS including type of disease, use of total body irradiation in the conditioning regimen (hazard ratio [HR], 0.5; 95% CI, 0.26-0.98; P = .04), disease status at HSCT (complete remission [CR] ≥3 vs CR 1/2; HR, 2.23; 95% CI, 1.20-4.16; P = .01), and high levels of pre-HSCT minimal residual disease (HR, 2.09; 95% CI, 1.01-4.33; P = .04) were independently associated with outcome. In summary, besides confirming the good outcome results already reported (which are almost superimposable on those of transplant from HLA-matched donors), this clinical update allows the identification of patients at higher risk of treatment failure for whom personalized approaches, aimed at reducing the risk of relapse, are warranted.

A phase 2 trial of CD24Fc for prevention of graft-versus-host disease.

ABSTRACT: Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622.

How I reduce and treat posttransplant relapse of MDS.

ABSTRACT: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative option for patients with high-risk myelodysplastic syndromes (MDS). Advances in conditioning regimens and supportive measures have reduced treatment-related mortality and increased the role of transplantation, leading to more patients undergoing HSCT. However, posttransplant relapse of MDS remains a leading cause of morbidity and mortality for this procedure, necessitating expert management and ongoing results analysis. In this article, we review treatment options and our institutional approaches to managing MDS relapse after HSCT, using illustrative clinical cases that exemplify different clinical manifestations and management of relapse. We address areas of controversy relating to conditioning regimen intensity, chemotherapeutic bridging, and donor selection. In addition, we discuss future directions for advancing the field, including (1) the need for prospective clinical trials separating MDS from acute myeloid leukemia and focusing on posttransplant relapse, as well as (2) the validation of measurable residual disease methodologies to guide timely interventions.

An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease.

ABSTRACT: In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Outcomes of HLA-mismatched HSCT with TCRαß/CD19 depletion or post-HSCT cyclophosphamide for inborn errors of immunity.

ABSTRACT: HLA-mismatched transplants with either in vitro depletion of CD3+ T-cell receptor (TCR)αß/CD19 (TCRαß) cells or in vivo T-cell depletion using posttransplant cyclophosphamide (PTCY) have been increasingly used for patients with inborn errors of immunity (IEIs). We performed a retrospective multicenter study via the EBMT registry on 306 children with IEIs undergoing their first transplant between 2010 and 2019 from an HLA-mismatched donor using TCRαß (n = 167) or PTCY (n = 139). The median age for hematopoietic stem cell transplantation (HSCT) was 1.2 years (range, 0.03-19.6 years). The 3-year overall survival (OS) was 78% (95% confidence interval (CI), 71-84) after TCRαß and 66% (57-74) after PTCY (P = .013). Pre-HSCT morbidity score (hazard ratio [HR], 2.27; 1.07-4.80, P = .032) and non-busulfan/treosulfan conditioning (HR, 3.12; 1.98-4.92, P < .001) were the only independent predictors of unfavorable OS. The 3-year event-free survival (EFS) was 58% (50%-66%) after TCRαß and 57% (48%-66%) after PTCY (P = .804). The cumulative incidence of severe acute graft-versus-host disease (GvHD) was higher after PTCY (15%, 9%-21%) than TCRαß (6%, 2%-9%, P = .007), with no difference in chronic GvHD (PTCY, 11%, 6%-17%; TCRαß, 7%, 3%-11%, P = .173). The 3-year GvHD-free EFS was 53% (44%-61%) after TCRαß and 41% (32%-50%) after PTCY (P = .080). PTCY had significantly higher rates of veno-occlusive disease (14.4% vs TCRαß 4.9%, P = .009), acute kidney injury (12.7% vs 4.6%, P = .032), and pulmonary complications (38.2% vs 24.1%, P = .017). Adenoviremia (18.3% vs PTCY 8.0%, P = .015), primary graft failure (10% vs 5%, P = .048), and second HSCT (17.4% vs 7.9%, P = .023) were significantly higher in TCRαß. In conclusion, this study demonstrates that both approaches are suitable options in patients with IEIs, although they are characterized by different advantages and outcomes.

Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate-conditioned Fanconi anemia mice.

ABSTRACT: Fanconi anemia (FA) is an inherited DNA repair disorder characterized by bone marrow (BM) failure, developmental abnormalities, myelodysplasia, leukemia, and solid tumor predisposition. Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a mainstay treatment, is limited by conditioning regimen-related toxicity and graft-versus-host disease (GVHD). Antibody-drug conjugates (ADCs) targeting hematopoietic stem cells (HSCs) can open marrow niches permitting donor stem cell alloengraftment. Here, we report that single dose anti-mouse CD45-targeted ADC (CD45-ADC) facilitated stable, multilineage chimerism in 3 distinct FA mouse models representing 90% of FA complementation groups. CD45-ADC profoundly depleted host stem cell enriched Lineage-Sca1+cKit+ cells within 48 hours. Fanca-/- recipients of minor-mismatched BM and single dose CD45-ADC had peripheral blood (PB) mean donor chimerism >90%; donor HSCs alloengraftment was verified in secondary recipients. In Fancc-/- and Fancg-/- recipients of fully allogeneic grafts, PB mean donor chimerism was 60% to 80% and 70% to 80%, respectively. The mean percent donor chimerism in BM and spleen mirrored PB results. CD45-ADC-conditioned mice did not have clinical toxicity. A transient <2.5-fold increase in hepatocellular enzymes and mild-to-moderate histopathological changes were seen. Under GVHD allo-HSCT conditions, wild-type and Fanca-/- recipients of CD45-ADC had markedly reduced GVHD lethality compared with lethal irradiation. Moreover, single dose anti-human CD45-ADC given to rhesus macaque nonhuman primates on days -6 or -10 was at least as myeloablative as lethal irradiation. These data suggest that CD45-ADC can potently promote donor alloengraftment and hematopoiesis without significant toxicity or severe GVHD, as seen with lethal irradiation, providing strong support for clinical trial considerations in highly vulnerable patients with FA.

Cardiovascular Management of Patients Undergoing Hematopoietic Stem Cell Transplantation: From Pretransplantation to Survivorship: A Scientific Statement From the American Heart Association.

Hematopoietic stem cell transplantation can cure various disorders but poses cardiovascular risks, especially for elderly patients and those with cardiovascular diseases. Cardiovascular evaluations are crucial in pretransplantation assessments, but guidelines are lacking. This American Heart Association scientific statement summarizes the data on transplantation-related complications and provides guidance for the cardiovascular management throughout transplantation. Hematopoietic stem cell transplantation consists of 4 phases: pretransplantation workup, conditioning therapy and infusion, immediate posttransplantation period, and long-term survivorship. Complications can occur during each phase, with long-term survivors facing increased risks for late effects such as cardiovascular disease, secondary malignancies, and endocrinopathies. In adults, arrhythmias such as atrial fibrillation and flutter are the most frequent acute cardiovascular complication. Acute heart failure has an incidence ranging from 0.4% to 2.2%. In pediatric patients, left ventricular systolic dysfunction and pericardial effusion are the most common cardiovascular complications. Factors influencing the incidence and risk of complications include pretransplantation therapies, transplantation type (autologous versus allogeneic), conditioning regimen, comorbid conditions, and patient age. The pretransplantation cardiovascular evaluation consists of 4 steps: (1) initial risk stratification, (2) exclusion of high-risk cardiovascular disease, (3) assessment of cardiac reserve, and (4) optimization of cardiovascular reserve. Clinical risk scores could be useful tools for the risk stratification of adult patients. Long-term cardiovascular management of hematopoietic stem cell transplantation survivors includes optimizing risk factors, monitoring, and maintaining a low threshold for evaluating cardiovascular causes of symptoms. Future research should prioritize refining risk stratification and creating evidence-based guidelines and strategies to optimize outcomes in this growing patient population.

Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia.

Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αß T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.).

High sensitivity of host Helios+/Neuropilin-1+ Treg to pretransplant conditioning hampers development of OX40bright/integrin-ß7+ regulatory cells in acute gastrointestinal GvHD.

This study sought to compare the behavior of Treg subsets displaying different coexpression patterns of Neuropilin-1 (Nrp1) and Helios, under the influence of gut stress unrelated to hematopoietic stem cell transplantation, pretransplantation conditioning, and posttransplant gastrointestinal acute graft versus host disease (GI-aGvHD). Host CD4+/CD25hi/Foxp3+ Treg cells, identified by flow cytometry, were isolated from various tissues of mice affected by these stressors. Expression of CD25, CTLA-4, CD39, OX40, integrin-ß7, LAG3, TGFß/LAP, granzyme-A, -B, and interleukin-10 was compared in four Treg subsets displaying Helios or Nrp1 only, both or none. Fluorescence-activated cell sorter-sorted Treg subsets, displaying markers affected in a conditioning- and GI-aGVHD-restricted manner, were further investigated by transcriptome profiling and T-cell suppression assays. We found that conditioning by irradiation greatly diminished the relative frequency of Helios+/Nrp1+ Treg, shifting the balance toward Helios-/Nrp1- Treg in the host. Upregulation of integrin-ß7 and OX40 occurred in GI-aGvHD-dependent manner in Helios+/Nrp1+ cells but not in Helios-/Nrp1- Treg. Sorted Treg subsets, confirmed to overexpress Nrp1, Helios, OX40, or integrin-ß7, displayed superior immunosuppressive activity and enrichment in activation-related messenger RNA transcripts. Our data suggest that conditioning-induced shrinkage of the Nrp1+/Helios+ Treg subset may contribute to the development of GI-GvHD by impairing gut homing and decreasing the efficiency of Treg-mediated immunosuppression.

The use of prognostic models in allogeneic transplants: a perspective guide for clinicians and investigators.

Allogeneic hematopoietic cell transplant (HCT) can cure many hematologic diseases, but it carries the potential risk of increased morbidity and mortality rates. Prognostic evaluation is a scientific entity at the core of care for potential recipients of HCT. It can improve the decision-making process of transplant vs no transplant, help choose the best transplant strategy and allows for future trials targeting patients' intolerances to transplant; hence, it ultimately improves transplant outcomes. Prognostic models are key for appropriate actuarial outcome estimates, which have frequently been shown to be better than physicians' subjective estimates. To make the most accurate prognostic evaluation for HCT, one should rely on >1 prognostic model. For relapse and relapse-related mortality risks, the refined disease risk index is currently the most informative model. It can be supplemented with disease-specific models that consider genetic mutations as predictors in addition to information on measurable residual disease. For nonrelapse mortality and HCT-related morbidity risks, the HCT-comorbidity index and Karnofsky performance status have proven to be the most reliable and most accepted by physicians. These can be supplemented with gait speed as a measure of frailty. Some other global prognostic models might add additional prognostic information. Physicians' educated perceptions can then put this information into context, taking into consideration conditioning regimen and donor choices. The future of transplant mandates (1) clinical investigators specifically trained in prognostication, (2) increased reliance on geriatric assessment, (3) the use of novel biomarkers such as genetic variants, and (4) the successful application of novel statistical methods such as machine learning.

Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Allogeneic stem cell transplantation compared to conservative management in adults with inborn errors of immunity.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative for severe inborn errors of immunity (IEIs), with recent data suggesting alloSCT in adulthood is safe and effective in selected patients. However, questions remain regarding the indications for and optimal timing of transplant. We retrospectively compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Seventy-nine patients (aged ≥ 15 years) underwent alloSCT between 2008 and 2018 for IEIs such as chronic granulomatous disease (n = 20) and various combined immune deficiencies (n = 59). A cohort of nontransplanted patients from the French Centre de Référence Déficits Immunitaires Héréditaires registry was identified blindly for case-control analysis, with ≤3 matched controls per index patient, without replacement. The nontransplanted patients were matched for birth decade, age at last review greater than index patient age at alloSCT, chronic granulomatous disease or combined immune deficiencies, and autoimmune/lymphoproliferative complications. A total of 281 patients were included (79 transplanted, 202 nontransplanted). Median age at transplant was 21 years. Transplant indications were mainly lymphoproliferative disease (n = 23) or colitis (n = 15). Median follow-up was 4.8 years (interquartile range, 2.5-7.2). One-year transplant-related mortality rate was 13%. Estimated disease-free survival at 5 years was higher in transplanted patients (58% vs 33%; P = .007). Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. Sensitivity analyses removing patients with common variable immune deficiency and their matched transplanted patients confirm these results. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality.

Genotype, oxidase status, and preceding infection or autoinflammation do not affect allogeneic HCT outcomes for CGD.

Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by life-threatening infections and inflammatory conditions. Hematopoietic cell transplantation (HCT) is the definitive treatment for CGD, but questions remain regarding patient selection and impact of active disease on transplant outcomes. We performed a multi-institutional retrospective and prospective study of 391 patients with CGD treated either conventionally (non-HCT) enrolled from 2004 to 2018 or with HCT from 1996 to 2018. Median follow-up after HCT was 3.7 years with a 3-year overall survival of 82% and event-free survival of 69%. In a multivariate analysis, a Lansky/Karnofsky score <90 and use of HLA-mismatched donors negatively affected survival. Age, genotype, and oxidase status did not affect outcomes. Before HCT, patients had higher infection density, higher frequency of noninfectious lung and liver diseases, and more steroid use than conventionally treated patients; however, these issues did not adversely affect HCT survival. Presence of pre-HCT inflammatory conditions was associated with chronic graft-versus-host disease. Graft failure or receipt of a second HCT occurred in 17.6% of the patients and was associated with melphalan-based conditioning and/or early mixed chimerism. At 3 to 5 years after HCT, patients had improved growth and nutrition, resolved infections and inflammatory disease, and lower rates of antimicrobial prophylaxis or corticosteroid use compared with both their baseline and those of conventionally treated patients. HCT leads to durable resolution of CGD symptoms and lowers the burden of the disease. Patients with active infection or inflammation are candidates for transplants; HCT should be considered before the development of comorbidities that could affect performance status. This trial was registered at www.clinicaltrials.gov as #NCT02082353.

How I prevent GVHD in high-risk patients: posttransplant cyclophosphamide and beyond.

Advances in conditioning, graft-versus-host disease (GVHD) prophylaxis and antimicrobial prophylaxis have improved the safety of allogeneic hematopoietic cell transplantation (HCT), leading to a substantial increase in the number of patients transplanted each year. This influx of patients along with progress in remission-inducing and posttransplant maintenance strategies for hematologic malignancies has led to new GVHD risk factors and high-risk groups: HLA-mismatched related (haplo) and unrelated (MMUD) donors; older recipient age; posttransplant maintenance; prior checkpoint inhibitor and autologous HCT exposure; and patients with benign hematologic disorders. Along with the changing transplant population, the field of HCT has dramatically shifted in the past decade because of the widespread adoption of posttransplantation cyclophosphamide (PTCy), which has increased the use of HLA-mismatched related donors to levels comparable to HLA-matched related donors. Its success has led investigators to explore PTCy's utility for HLA-matched HCT, where we predict it will be embraced as well. Additionally, combinations of promising new agents for GVHD prophylaxis such as abatacept and JAK inhibitors with PTCy inspire hope for an even safer transplant platform. Using 3 illustrative cases, we review our current approach to transplantation of patients at high risk of GVHD using our modern armamentarium.

Impact of TP53 on outcome of patients with myelofibrosis undergoing hematopoietic stem cell transplantation.

TP53 mutations (TP53MTs) have been associated with poor outcomes in various hematologic malignancies, but no data exist regarding its role in patients with myelofibrosis undergoing hematopoietic stem cell transplantation (HSCT). Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53MT in this setting. Among 349 included patients, 49 (13%) had detectable TP53MT, of whom 30 showed a multihit configuration. Median variant allele frequency was 20.3%. Cytogenetic risk was favorable (71%), unfavorable (23%), and very high (6%), with complex karyotype present in 36 patients (10%). Median survival of patients with TP53MT was 1.5 vs 13.5 years for those with wild-type TP53 (TP53WT; P < .001). Outcome was driven by multihit TP53MT constellation (P < .001), showing 6-year survival of 56% for individuals with single-hit vs 25% for those with multihit TP53MT vs 64% for those with TP53WT. Outcome was independent of current transplantation-specific risk factors and conditioning intensity. Similarly, cumulative incidence of relapse was 17% for single-hit vs 52% for multihit vs 21% for TP53WT. Ten patients with TP53MT (20%) presented as leukemic transformation vs only 7 (2%) in the TP53WT group (P < .001). Out of the 10 patients with TP53MT, 8 showed multihit constellation. Median time to leukemic transformation was shorter for multihit and single-hit TP53MT (0.7 and 0.5 years, respectively) vs 2.5 years for TP53WT. In summary, multihit TP53MT represents a very high-risk group in patients with myelofibrosis who are undergoing HSCT, whereas single-hit TP53MT alone showed similar outcome to patients with nonmutated TP53, informing prognostication for survival and relapse together with current transplantation-specific tools.

Allogeneic hematopoietic stem cell transplantation: lessons learned by a molecular immunologist/transplant patient.

Much has been learned about the genes and pathways that contribute to a diverse array of hematopoietic malignancies and other hematopoietic diseases. However, for many of these diseases, an allogeneic hematopoietic stem cell (HSC) transplant remains the preferred treatment option. This opinion article provides the perspective of a molecular immunologist who became a transplant patient after many years studying basic mechanisms of blood cell development. Among many lessons learned were the magnitude of racial and ethnic disparities in donor registries, the substantial improvement in outcomes over time that were due to the collective impact of numerous advances, the benefits and limitations of genetic and clinical data, and the remarkably intricate balance between promoting graft-versus-disease activity of donor cells while suppressing graft-versus-host disease (GVHD).