Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency

doi:10.1016/j.jaci.2014.11.029

Journal of Allergy and Clinical Immunology

Volume 135, Issue 4, April 2015, Pages 988-997.e6

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https://doi.org/10.1016/j.jaci.2014.11.029 Get rights and content

Background

Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted.

Objective

We sought to define the outcomes of HSCT for patients with CVID.

Methods

Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012.

Results

Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved.

Conclusion

This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.

Section snippets

Inclusion criteria

The study was approved by the Ethics committee of the Freiburg University Medical Center (no. 275/12), and all patients or their parents signed informed consent forms for data collection. Patients with a diagnosis of CVID who underwent transplantation for any indication were recruited through the SCETIDE database of the Inborn Errors Working Party of the European Society for Blood and Marrow Transplantation, European Society for Immunodeficiencies (ESID), and personal communication. Inclusion

Indication for transplantation, conditioning, and stem cell source

We examined demographic data and variables related to HSCT to understand the characteristics of this cohort. The indication for HSCT was PID related in 24 (96%) of 25 patients. PID-related indications included lymphoma in 6 (24%) of 25, severe infections despite standard treatment in 3 (12%) of 25, and complex immunologic dysregulation in 15 (60%) of 25 patients (Fig 1, A). In patient 007 the indication for HSCT was not PID related (acute myeloid leukemia, Table I). The immune dysregulation

Discussion

In a subgroup of patients with CVID, the disease can take a severe course and is associated with an increased mortality rate compared with that of the general population.8, 13 Recently, HSCT has been reported in a few CVID cases to be a potentially curative treatment.¹⁸ This multicenter study was performed to provide clinicians caring for patients with CVID more robust information regarding outcome after HSCT.

In our cohort the indications for HSCT were complications secondary to CVID, such as

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Individualized high-dose ATG with TDM is feasible and safe for patients with hyperinflammation in a CBT setting. We observe high target ATG exposure attainment, good immune reconstitution (despite very high doses of ATG) and acceptable rates of GvHD and rejection.
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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.
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Citation Excerpt :
Consequently, adults with IEI have recently been added to the list of indications for HSCT by the European Society for Blood and Marrow Transplantation (EBMT) and American Society for Transplantation and Cellular Therapy (ASTCT).14-16 To date, all published retrospective4,10-12 and prospective13,17 studies on HSCT outcomes in adults with IEI taken together report on <150 patients. In children with genetically confirmed IEI known to have a poor prognosis with conservative therapy alone, the role of HSCT is usually well defined and supported by clear evidence for transplant efficacy.4
Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.
Morbidity, Mortality, and Therapeutics in Combined Immunodeficiency: Data From the USIDNET Registry
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Optimal management of patients with combined immunodeficiency, especially pertaining to hematopoietic stem cell transplantation (HSCT), remains unclear.
To identify factors influencing HSCT and mortality in the population with combined immunodeficiency in North America.
We identified 337 participants in the United States Immunodeficiency Network database with diverse forms of combined immunodeficiency and their characteristics, including demographic characteristics, laboratory values, infectious history, comorbidities, and treatment strategies. Univariate analysis was performed using logistic regression, whereas multivariate analysis was performed using multiple Cox proportional hazards.
On univariate analysis, disseminated invasive viral infections and variants in STAT3, GATA2, and, DOCK8 were associated with increased odds of HSCT. Mucocutaneous fungal infections and variants in STAT3 were associated with increased odds of survival, whereas disseminated/invasive fungal infections, disseminated/invasive viral infections, and parasitic infections were associated with decreased odds of survival. On multiple variable Cox proportional hazards analysis, variants in ZAP70, nonspecific bacterial, and disseminated/invasive viral infections were associated with increased hazards of transplantation, whereas variants in multiple genes (RMRP, NEMO, DOCK8, CD40L, and CARD9), disseminated/invasive viral infections, autoimmune disease, and higher absolute lymphocyte count were associated with increased hazards of death. Importantly, demographic characteristics, basic lymphocyte subset counts, and absence of genetic diagnosis were not associated with HSCT or mortality.
We determined that specific genetic diagnoses and infection burden impacts the decision to undergo HSCT in this cohort. In addition, certain genetic diagnoses and invasive viral infections carry an increased risk of mortality.

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: Supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803). C.L. is supported by a clinical fellowship from the Dutch Cancer Society (2013-5883).

: Disclosure of potential conflict of interest: C. Wehr has received research and travel support from the German Federal Ministry of Education and Research. C. Lindemans has received research support from the Dutch Cancer Society (2013-5883). A. Schulz is employed by Medical Center Ulm. M. Recher has received research support from a Swiss National Science Foundation Professorship Grant (PP00P3_144863). U. Baumann has received research support from EURO-PADnet (FP7/2007-2011). K.-W. Sykora has received travel support from EUSA Pharma. S. Goldacker has received research support from Octapharma. A. Fielding has received consultancy fees from Amgen. S. Seneviratne is employed by the Royal Free Hospital, London. K. E. Sullivan has received consultancy fees from the Immune Deficiency Foundation, is employed by UpToDate, and has received research support from Baxter. B. Grimbacher has received research support from BMBF (01E01303 and 012X1306F) and the European Union (EU); is employed by UCL and UKL-FR; has received research support from BMBF (01E01303 and 012X1306F), the EU, and Helmholtz (DZIF 8000805-3); and has received lecture fees from CSL, Baxter, and Biotest. H.-H. Peter has provided expert testimony for Pfizer and has received lecture fees. K. Warnatz has received lecture fees from Baxter, GlaxoSmithKline, CSL Behring, Pfizer, Biotest, Novartis Pharma, Stallergenes AG, Roche, Meridian HealthComms, Octapharma, and the American Academy of Allergy, Asthma & Immunology; has received payment for manuscript preparation from UCB Pharma; and has received payment for development of educational presentations from European Society for Immunodeficiency. M. Rizzi has received research support from Pfizer (Europe Aspire Award [10/2013-09/2014]) and Novartis (Stiftung für Klinische Forschung Grant [11/2014-10-2016]). The rest of the authors declare that they have no relevant conflicts of interest.

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Immune deficiencies, infection, and systemic immune disordersMulticenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency

Background

Objective

Methods

Results

Conclusion

Section snippets

Inclusion criteria

Indication for transplantation, conditioning, and stem cell source

Discussion

Blood

Clin Immunol

Blood

J Allergy Clin Immunol

Blood

J Allergy Clin Immunol

Blood

Blood

Blood

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Blood

Blood

Biol Blood Marrow Transplant

Biol Blood Marrow Transplant

Blood

Blood

Blood

Ann Allergy Asthma Immunol

Curr Opin Immunol

Immune deficiencies, infection, and systemic immune disorders
Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency