Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

Fox, Thomas A.; Chakraverty, Ronjon; Burns, Siobhan O.; Carpenter, Benjamin; Thomson, Kirsty; Lowe, David M.; Fielding, Adele K.; Peggs, Karl S.; Kottaridis, Panagiotis D.; Uttenthal, Ben; Bigley, Venetia; Buckland, Matthew; Grandage, Victoria; Denovan, Shari; Grace, Sarah; Dahlstrom, Julia; Workman, Sarita; Symes, Andrew; Mackinnon, Stephen; Hough, Rachael; Morris, Emma

doi:10.1182/blood-2017-09-807487

Cited by 68 publications

(76 citation statements)

References 38 publications

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“…The outcomes presented here, coupled with recently reported impressive BMT outcomes by others [23,36,55], support the safety and efficacy of RIC-BMT for patients across a broad range of PIDs, even those with significant comorbidities, older age, active infection/malignancy, only alternative donor options, and immune-dysregulation phenotypes. The spectrum of PIDs continues to expand, and the present era is one far different from when BMT for PID was used pre-emptively in very young children with diseases uniformly associated with early mortality.…”

Section: Discussionsupporting

confidence: 77%

“…comorbidities, particularly lung and/or liver dysfunction. Half had HCT-CI scores of 3; similar rates of high-risk patients requiring BMT for PID have been published by others [36]. In a registry analysis of HCT-CI in nonmalignant diseases, HCT-CI scores 3 were associated with a significant decrease in survival [43] and, because severe combined immunodeficiency represented nearly half of PID patients in that study, the extent of comorbidities seen in older patients with PIDs requiring BMT was almost certainly underrepresented.…”

Section: Discussionsupporting

confidence: 70%

“…The low incidence of severe acute and chronic GVHD may be partly related to the gradual increase in donor T cells noted in most patients, allowing for early mixed chimerism, which may be tolerogenic. Even so, our GVHD outcomes stand in contrast to non-PTCy-based approaches to RIC-BMT for PID, even ones that result in potentially protective mixed chimerism [27,28,36]. Notably, the low incidence of GVHD did not compromise control of malignancy and LPD, with all patients with pre-BMT malignancy/LPD remaining in remission, or of pre-BMT immune cytopenias, which also resolved.…”

Section: Discussionmentioning

confidence: 84%

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Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases

Dimitrova

Gea‐Banacloche

Steinberg

et al. 2020

Biology of Blood and Marrow Transplantation

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Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients. Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 84%

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Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases

Dimitrova

Gea‐Banacloche

Steinberg

et al. 2020

Biology of Blood and Marrow Transplantation

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“…Detailed recommendations on allogeneic HSCT for each particular PID and other inherited conditions fall beyond the scope of this manuscript and guidelines are regularly reviewed by the EBMT Inborn Errors Working Party (https://www.ebmt.org/working-parties/ inborn-errors-working-party-iewp). Beyond the main indication in children and adolescents, allogeneic HSCT is also a clinical option in young adults with PID (see Table 1) [219,220].…”

Section: Inherited Diseasesmentioning

confidence: 99%

Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019

Duarte

Labopin

Bader

et al. 2019

Bone Marrow Transplant

268

186

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This is the seventh special EBMT report on the indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders. Our aim is to provide general guidance on transplant indications according to prevailing clinical practice in EBMT countries and centres. In order to inform patient decisions, these recommendations must be considered together with the risk of the disease, the risk of the transplant procedure and the results of non-transplant strategies. In over two decades since the first report, the EBMT indications manuscripts have incorporated changes in transplant practice coming from scientific and technical developments in the field. In this same period, the establishment of JACIE accreditation has promoted high quality and led to improved outcomes of patient and donor care and laboratory performance in transplantation and cellular therapy. An updated report with operating definitions, revised indications and an additional set of data with overall survival at 1 year and non-relapse mortality at day 100 after transplant in the commonest standard-of-care indications is presented. Additional efforts are currently underway to enable EBMT member centres to benchmark their risk-adapted outcomes as part of the Registry upgrade Project 2020 against national and/or international outcome data.

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“…In practice, few patients with uncorrected classical WAS reach adulthood and HSCT is rarely offered in adult primary immunodeficiencies (PID) as outcomes were historically poor. However, we recently published excellent outcomes (85% long‐term survival at 10 years post‐HSCT) for a cohort of adults with different types of PID, making this a viable treatment option for carefully selected patients in specialist centres (Davila Saldana, ; Fox et al , ). We have also successfully treated one classical WAS adult with GT, which has achieved substantial clinical improvement and provided proof‐of‐principle that GT is a viable option even for adults (Kohn, ; Morris et al , ).…”

Section: How We Manage Wasmentioning

confidence: 99%

How I manage patients with Wiskott Aldrich syndrome

et al. 2019

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Summary Wiskott Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form, significant combined immune deficiency, autoimmune complications and risk of haematological malignancy necessitate early correction with stem cell transplantation or gene therapy. A milder form, X‐linked thrombocytopaenia (XLT), shares similar bleeding risk from thrombocytopaenia but is not associated with other significant clinical features and is generally managed conservatively. Here, we detail our approach to the diagnosis and treatment of classical WAS and XLT.

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Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

Abstract: Key Points Allo-HSCT with RIC is safe and effective in younger adults with severe PID. Referral triggers should include severe infections, autoimmunity, malignancy, and disease progression despite conservative management.

Cited by 68 publications

References 38 publications

Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases

Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases

Indications for haematopoietic stem cell transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe, 2019

How I manage patients with Wiskott Aldrich syndrome

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