Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence

Arai, Sally; Sahaf, Bita; Narasimhan, Balasubramanian; Chen, George L.; Jones, Carol D.; Lowsky, Robert; Shizuru, Judith A.; Johnston, Laura; Laport, Ginna G.; Weng, Wen‐Kai; Benjamin, Jonathan; Schaenman, Joanna; Brown, Janice; Ramirez, Jessica; Zehnder, James L.; Negrin, Robert S.; Miklos, David B.

doi:10.1182/blood-2011-12-395970

Cited by 109 publications

(90 citation statements)

References 44 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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“…Rituximab has potential role in reducing the irreversible damage associated with cGVHD. Rituximab therapy may have a potential role in prophylaxis for cGVHD as well [125,126]. Various trials testing it in firstline setting are underway.…”

Section: Rituximabmentioning

confidence: 99%

State-of-the-art acute and chronic GVHD treatment

Jamil

Mineishi

2015

Int J Hematol

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owing to the advancement in reduced intensity conditioning (RIC) and in patients without HLA-matched donors due to the use of cord blood and haploidentical HSCT [4][5][6]. Although marked improvement has been made in supportive care, immunosuppressive therapy and DNA-based Human Leukocyte Antigen (HLA) typing, graft vs host disease (GVHD) remains a major cause of morbidity and non-relapse mortality among allogeneic HSCT recipients. It was first described by Billingham in 1966 as a syndrome where immunocompetent T cells from the donor recognize and damage the host tissue in an immunocompromised recipient. It presents with heterogeneous symptoms involving multiple organ systems including gastrointestinal tract, skin, mucosa, liver and lungs [7]. In the past clinical features occurring within 100 days after HSCT was called acute GVHD (aGVHD) and those happening after 100 days were labeled chronic GVHD (cGVHD) [8,9]. This definition was rather unsatisfactory thus National Institute of Health (NIH) consensus criteria were developed and have been revised. The criteria have added new categories such as late-onset aGVHD (acute GVHD occurring after 100 days) and overlap syndrome which includes features of both acute and chronic GVHD to the classification, and also have introduced new definitions for organ system involvement [10][11][12]. The categorization of acute vs chronic GVHD is based on the combination of clinical symptoms rather than the time of onset. Depending upon a number of variables associated with patients, donors, and types of transplant, the incidence of aGVHD varies with incidence of grade II-IV GVHD at 40 % in matched related donor (MRD) transplant to 50 % in MUD transplant. The main risk factors for aGVHD include degree of HLA mismatch, age of the patient, previous all immunization of the donor and the kind of GVHD prophylaxis used. About 30-70 % of allogeneic HSCT recipients alive after 100 days will Abstract Graft-versus-host disease (GVHD) remains as the major obstacle for successful hematopoietic stem cell transplant (HSCT). Roughly half of the patients undergoing HSCT develop GVHD which requires treatment, and above 10 % of the patient may die because of it. However, GVHD presents with anti-tumor activity, called graft-versus-tumor (GVT) effect, and it carries significant anti-tumor activity, thus suppressing GVHD completely may increase the relapse of original disease. Thus, it is important to control GVHD to the appropriate level.

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“…However, chronic graft vs. host disease (cGVHD) remains a significant cause of late morbidity and mortality (1)(2)(3)(4).…”

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confidence: 99%

“…In support of a B-cell role (4)(5)(6)(7)(8)(9), the presence of circulating autoantibody (10) and alloantibody (11,12) have been associated with development of cGVHD. Specifically, predominant B-cell subsets have been demonstrated in patients with cGVHD and identified in different studies as naïve (6) and postgerminal center B cells (7,8,10).…”

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confidence: 99%

H–Y antigen-binding B cells develop in male recipients of female hematopoietic cells and associate with chronic graft vs. host disease

Sahaf¹,

Yang

Arai³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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B cells are known to play an important role in pathogenesis of human chronic graft vs. host disease (cGVHD). Our group has previously shown that IgG allo-antibodies recognize Y chromosomeencoded proteins (H-Y) and a dominant H-Y epitope, DEAD box protein (DBY-2) detectable 6-12 mo after transplant in male patients who receive grafts from female donors (F→M) hematopoietic cell transplantation (HCT). Here we present FACS studies of peripheral blood mononuclear cells collected 6 mo after transplant showing that 16 of 28 (57%) F→M HCT patients have circulating donor B cells that express B-cell receptor (mainly IgM and Igλ) specific for DBY-2. The detection of these DBY-2 B cells 6 mo after HCT are associated with cGVHD development (P = 0.004). Specifically, 15 of 16 F→M with DBY-2 B cells developed cGVHD. In contrast, cGVHD developed in only 5 of the 12 who did not have DBY-2 B cells detected. This demonstrates circulating human B cells binding an alloantigen (DBY-2) and that these DBY-2-specific B cells appear before development of cGVHD in roughly half of the F→M patients. Our study suggests that detection of anti-DBY-2 B cells may predict cGVHD and that this prediction may have clinical utility. Validation of this hypothesis will require larger prospective studies.allogeneic | antigen-specific B cells | transplantation | DDX3Y

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Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence

Cited by 109 publications

References 44 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

State-of-the-art acute and chronic GVHD treatment

H–Y antigen-binding B cells develop in male recipients of female hematopoietic cells and associate with chronic graft vs. host disease

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