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Curative allogeneic hematopoietic stem cell transplantation following reduced toxicity conditioning in adults with primary immunodeficiency.

ABSTRACT: Primary immunodeficiencies (PID) are heterogeneous inborn errors of the immune system. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative and safe at the pediatric age but remains underperformed in adults. We report our experience on 32 consecutive adult patients with various PID including 17 (53%) with a combined immune deficiency, six (19%) with a disease of immune dysregulation and nine (28%) with a chronic granulomatous disease (CGD) who underwent an allo-HSCT between 2011 and 2020. The median age at transplant was 27 years (17-41). All assessable patients engrafted. The majority of patients received a fludarabine-Busulfan (FB) based regimen (FB2-3 in 16, FB4 in 12). Overall survival (OS) was 80.4% (100% for CGD and 74% for other PID patients) at 9 months and beyond (median follow-up 51.6 months). Six patients died, all in the first-year post-transplant. Cumulative incidences of grade II-IV acute GVHD/chronic GVHD were 18%/22%. Stem cell source, GVHD prophylaxis and conditioning intensity had no impact on OS. All surviving patients had over 90% donor chimerism, immune reconstitution, no sign of active PID related complications and were clinically improved. Allo-HSCT is effective in young adults PID patients with an acceptable toxicity and should be discussed in case of life-threatening PID.

SUBMITTER: Marcais A

PROVIDER: S-EPMC9258769 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Curative allogeneic hematopoietic stem cell transplantation following reduced toxicity conditioning in adults with primary immunodeficiency.

Marçais Ambroise A Mahlaoui Nizar N Neven Bénédicte B Lanternier Fanny F Catherinot Émilie É Salvator Hélène H Cheminant Morgane M Jeljeli Maxime M Asnafi Vahid V van Endert Peter P Couderc Louis-Jean LJ Lortholary Olivier O Picard Capucine C Moshous Despina D Hermine Olivier O Fischer Alain A Suarez Felipe F

Bone marrow transplantation 20220706 10

Primary immunodeficiencies (PID) are heterogeneous inborn errors of the immune system. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative and safe at the pediatric age but remains underperformed in adults. We report our experience on 32 consecutive adult patients with various PID including 17 (53%) with a combined immune deficiency, six (19%) with a disease of immune dysregulation and nine (28%) with a chronic granulomatous disease (CGD) who underwent an allo-HSCT between ...[more]

PMID: 35794259

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Project description:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapeutic option for many patients with hematological malignancies and nonmalignant hematopoietic disorders. To achieve stable engraftment of donor hematopoietic stem cells (HSCs), recipient HSC deletion is needed to create space for incoming donor HSCs and donor HSCs must escape immune rejection by the recipient. Conventional allo-HSCT requires high dose of irradiation and/or chemotherapy to produce sufficient host stem cell and immune system ablation to permit donor HSC engraftment. However, these procedures also result in nonspecific tissue injury that can cause short- and long-term adverse effects as well as incite and amplify graft-versus-host-disease (GVHD). The delivery of targeted radiotherapy to hematopoietic tissues with the use of a radioimmunoconjugate (ROIC) as a part of transplant preparative regimen has shown clinical benefits. ROIC clinical data provide evidence for decreased relapse without increased transplant-related mortality by delivering higher targeted radiation to sites of malignancy than when given in a nontargeted fashion. An alternative approach to allo-HSCT has been developed and tested in preclinical mouse models in which nonmyeloablative preconditioning with low dose of the alkylating agent (busulfan) or lower systemic dose of irradiation combined with co-stimulatory pathway blockade (CTLA4-Ig, anti-CD40L monoclonal antibody) and/or immunosuppressive drugs have been used. Under these conditions, mixed chimerism and transplantation tolerance to fully MHC mismatched donor marrow was observed. Recently, several novel proof-of-concept antibody-mediated preconditioning methods have been developed that can selectively target hematopoietic stem and immune cells with minimal overall toxicity. Antibody-drug-conjugate (ADC) combined with reduced intensity conditioning or high dose ADC as single dose monotherapy have shown promise for allo-HSCT in preclinical models. The purpose of the current review is to discuss the literature exploring antibody-based conditioning that includes native antibody, radiolabeled antibody conjugates, and ADC for allo-HSCT.

Project description:Noninfectious pulmonary toxicity (NPT), a significant complication of allogeneic hematopoietic cell transplantation (alloHCT), includes idiopathic pneumonia syndrome (IPS), diffuse alveolar hemorrhage (DAH), and cryptogenic organizing pneumonia (COP), with an overall incidence ranging from 1% to 15% in different case series and a variable mortality rate. A registry study of the epidemiology and outcomes of NPT after alloHCT has not been conducted to date. The primary objective of the present study was to assess the incidence of and risk factors for IPS, DAH, and COP; the secondary objective was to assess overall survival (OS) in patients developing NPT. This retrospective study included adult patients who underwent alloHCT between 2008 and 2017 and reported to the Center for International Blood and Marrow Transplant Research. Multivariable Cox proportional hazards regression models were developed to identify the risk factors for development of NPT and for OS, by including pretransplantation clinical variables and time-dependent variables of neutrophil and platelet recovery, and acute graft-versus-host disease (GVHD) post-transplantation. This study included 21,574 adult patients, with a median age of 55 years. According to the HCT Comorbidity Index (HCT-CI), 24% of the patients had moderate pulmonary comorbidity and 15% had severe pulmonary comorbidity. The cumulative incidence of NPT at 1 year was 8.1% (95% confidence interval [CI], 7.7% to 8.5%). Individually, the 1-year cumulative incidences of IPS, DAH, and COP were 4.9% (95% CI, 4.7% to 5.2%), 2.1% (95% CI, 1.9% to 2.3%), and .7% (95% CI, .6% to .8%), respectively. Multivariable analysis showed that severe pulmonary comorbidity, grade II-IV acute GVHD, mismatched unrelated donor and cord blood transplantation, and HCT-CI score ≥1 significantly increased the risk of NPT. In contrast, alloHCT performed in 2014 or later, non-total body irradiation (TBI)- and TBI-based nonmyeloablative conditioning and platelet recovery were associated with a decreased risk. In a landmark analysis at day+100 post-transplantation, the risk of DAH was significantly lower in patients who had platelet recovery by day +100. Multivariable analysis for OS demonstrated that NPT significantly increased the mortality risk (hazard ratio, 4.2; P < .0001).

Dataset Information

Curative allogeneic hematopoietic stem cell transplantation following reduced toxicity conditioning in adults with primary immunodeficiency.

Publications

Curative allogeneic hematopoietic stem cell transplantation following reduced toxicity conditioning in adults with primary immunodeficiency.

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