Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial

Cutler, Corey; Kim, Haesook T.; Bindra, Bhavjot; Sarantopoulos, Stefanie; Ho, Vincent T.; Chen, Yi Bin; Rosenblatt, Jacalyn; McDonough, Sean M.; Watanaboonyongcharoen, Phandee; Armand, Philippe; Koreth, John; Glotzbecker, Brett; Alyea, Edwin P.; Blazar, Bruce R.; Soiffer, Robert J.; Ritz, Jérôme; Antin, Joseph H.

doi:10.1182/blood-2013-04-495895

Cited by 108 publications

(92 citation statements)

References 48 publications

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“…The correlative biological analysis of HY-Abs supports the allogeneic B-cell pathogenic role in independent prospective trials for cGVHD prophylaxis and treatment. 9,24,29,30 HY-Abs would serve as a prognostic biomarker for cGVHD and an immunologic indicator.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans

Nakasone¹,

Tian

Sahaf³

et al. 2015

Blood

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Key Points• Detection of multiple HY-Abs at 3 months post-F→M HCT predicts cGVHD incidence, severity, and nonrelapse mortality.• Patients with a high HY score may be good candidates for cGVHD prevention trials, especially those targeting allogeneic B cells.Allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome (HY-Abs) develop after hematopoietic cell transplant (HCT) of male recipients with female donors (F→M). However, the temporal association between HY-Ab development and chronic graft-versus-host disease (cGVHD) has yet to be elucidated. We studied 136 adult F→M HCT patients, with plasma prospectively collected through 3 years posttransplant, and measured immunoglobulin G against 6 H-Y antigens. Multiple HY-Abs were frequently detected beginning at 3 months posttransplant: 78 (57%) of F→M patients were seropositive for at least 1 of the 6 HY-Abs, and 3-month seropositivity for each HYAb was associated with a persistent seropositive response throughout the posttransplant follow-up period (P < .001 in each). There were no associations between pretransplant features and 3-month overall HY-Ab development. Detection of multiple HY-Abs at 3 months (represented by HY score) was significantly associated with an increased risk of cGVHD (P < .0001) and nonrelapse mortality (P < .01). Compared to clinical factors alone, the addition of HY score to clinical factors improved the predictive potential of cGVHD (P < .01). Monitoring HY-Ab development thus stratifies cGVHD risk in F→M HCT patients and may support preemptive prophylaxis therapy for cGVHD beginning at 3 months posttransplant. (Blood. 2015;125(20):3193-3201)

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Section: Discussionmentioning

confidence: 99%

Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans

Nakasone¹,

Tian

Sahaf³

et al. 2015

Blood

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“…GVHD are still unclear (14)(15)(16). The major experience derived from the pivotal studies of Khouri (14) that showed a 40 rather good disease control with the unexpected finding of a limited incidence of acute and chronic extensive GVHD.…”

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confidence: 99%

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen

Dodero

Milone

Sarina

et al. 2017

Biology of Blood and Marrow Transplantation

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The graft versus host disease free, relapse free survival is 34% after transplantation in 2 lymphomas; 3Reduced extensive chronic GVHD with a combination of ATG and Rituximab in recipients of 4 unrelated graft 5One Rituximab Infusion prevents EBV-related lymphoproliferative disorders 6 Abstract 7The treatment of patients with refractory/relapsed B-Cell non-Hodgkin lymphoma (NHL) is evolving due to the 8 availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and 9 mortality remain a matter of concern. We conducted a multicentre prospective phase II trial to evaluate the benefit of 10 including only one dose of Rituximab (R) in the conditioning regimen before alloSCT. The primary end-point was 11 progression-free survival. The study enrolled 121 patients with relapsed/refractory B-cell lymphomas. The conditioning 12 regimen consisted of thiotepa, cyclophosphamide, fludarabine and R (500 mg/ms). Rabbit anti-thymocyte globulin 13(ATG) was administered only in case of unrelated donors. Sixty-seven (55%) and fifty-four (45%) patients received 14 grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of non-relapse mortality 15(NRM) was 21% at 3-years. The CCI of chronic GVHD at 3-years was 54% and 31% in recipients of matched sibling 16 and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-years progression-free and 17 overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite end-point 18 of graft-versus-host disease-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a 19 prospective trial of lymphomas patients: the 1 and 3-years GRFS were 40% and 34%, respectively. AlloSCT can cure a 20 fraction of patients with rather low NRM and an encouraging PFS and GRFS.

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“…11 B-cell depletion with rituximab prevented cGVHD in humans. 19 Patients with cGVHD frequently have circulating antibodies reactive to recipient cells. 1,9,20 Besides their functions in antibody secretion, cytokine and chemokine production, and antigen presentation, B cells exhibit regulatory properties in several human autoimmune diseases including systemic lupus erythematosus, 21 rheumatoid arthritis, 22 primary Sjögren syndrome, 7 and immune thrombocytopenia, 23 all of which share certain clinical features with human cGVHD.…”

Section: Introductionmentioning

confidence: 99%

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Masson

Bouaziz

Buanec

et al. 2015

Blood

146

119

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Key Points• Chronic graft-versus-host disease is associated with a global Breg defect.• This defect is particularly accentuated in the CD24 hi CD27 1 Breg compartment.Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24 hi CD27 1 and CD27 hi CD38 hi plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24 hi CD27 1 B cells and IL-10-producing CD24 hi CD27 1 B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24 hi CD27 1 B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. (Blood. 2015;125(11):1830-1839 IntroductionChronic graft-versus-host disease (cGVHD) is the leading cause of morbi-mortality after allogeneic hematopoietic stem cell transplantation (AHSCT). 1 GVHD prevention by means of adoptive transfer of regulatory T cells (Tregs) 2,3 and cGVHD treatment by in vivo induction of Tregs by low-dose interleukin 2 (IL-2) 4,5 may be effective. The exact role of IL-10-producing regulatory B cells (Bregs) in cGVHD is yet to be understood. Bregs have been shown to downmodulate adaptive 6 or innate immune responses 7 in mice and humans. In cGVHD, B cells are essentially recognized as positive regulators of inflammation. 1,8,9 Increased B-cell receptor responsiveness was found in cGVHD patients. 10 B-cell homeostatic defects were described in cGVHD, including elevated B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF)/B-cell ratios, 11-15 expansion of CD21 lo B cells, 16 reduced CD5 1 B1-like cell numbers, 17 decreased CD27 1 memory B cells, and hypogammaglobulinemia. 18 BAFF concentrations correlated with increased circulating pre-germinal center (GC) B-cell and post-GC plasmablast cell counts in patients with cGVHD. 11 B-cell depletion with rituximab prevented cGVHD in humans. 19 Patients with cGVHD frequently have circulating antibodies reactive to recipient cells. 1,9,20 Besides their functions in antibody secretion, cytokine and chemokine production, and antigen presentation, B cells exhibit regulatory properties in several human autoimmune diseases including systemic lupus erythemat...

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Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial

Cited by 108 publications

References 48 publications

Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans

Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

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