CBF
  1. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, Defor T, Levine BL, June CH, Rubinstein P, McGlave PB, Blazar BR, Wagner JE. Blood First Edition Paper, prepublished online October 15, 2010;DOI 10.1182/blood-2010-07-293795.

The authors emphasize that acute graft-versus-host disease (aGVHD) is associated with high risk of morbidity and mortality and is a common complication after double umbilical cord blood (UCB) transplantation. Regulatory T cells (Tregs) represent a novel cell-based approach for potentially reducing the risk of severe aGVHD. Tregs are a subset of CD4+ T cells that co-express CD25 (IL-2Rα chain) and high levels of Foxp3 and are dependent on IL-2. Experiments in murine models have shown that lethal aGVHD can be prevented by Tregs leading to enhanced survival. Further, Tregs inhibited the development of chronic GVHD and facilitated engraftment in murine models of allogeneic transplantation. In this study, the authors established a method of D4+CD25+FoxP3+ T regulatory cell (Treg) enrichment from cryopreserved UCB followed by a 18 + 1 day expansion culture including anti-CD3/anti-CD28 antibody coated beads and recombinant human interleukin-2. They evaluated the safety profile of UCB Treg in 23 patients. Patients received a dose of 0.1 to 30 X 105UCB Treg/ kg after double UCB transplantation. The targeted Treg dose was achieved in 74% of cultures with all products being suppressive in vitro (median 86% suppression at a 1:4 ratio). No infusional toxicities were observed. After infusion, UCB Treg could be detected for 14 days with the highest proportion of circulating CD4+CD127-FoxP3+ cells observed on day +2. Compared to identically treated 108 historical controls without Treg, there was a reduced incidence of grade II-IV aGVHD (43% versus 61%, p=.05) with no deleterious effect on risks of infection, relapse or early mortality. The authors suggest that their results serve the basis for a definitive study of UCB Treg to determine its potency in preventing allogeneic aGVHD.

  1. Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Margaret L. MacMillan, Daniel J. Weisdorf, Claudio G. Brunstein, Qing Cao, Todd E. DeFor, Michael R. Verneris, Bruce R. Blazar, and John E. Wagner. Blood, 2009;113:2410-2415.

[Note: Dr. MacMillan discussed GVHD after Cord Blood Transplantation at the 7th Annual International Umbilical Cord Blood Transplantation Symposium in June 2009 in Los Angeles: www.cordbloodsymposium.org ]

The authors sought to identify potential risk factors for acute GVHD in 265 consecutive recipients of UCB treated at a single institution. They also sought to determine the impact on the incidence of GVHD of double UCBT which is a strategy that is used to overcome the limited number of cells available in a single unit, particularly for adults and adolescents. Patients received a double UCB graft if they lacked a suitable single UCB, as determined by cell-dose criteria. 86% of single CBT recipients (n = 80) had a hematologic malignancy as did 92% of double CBT recipients (n = 185).

Patients and donors were typed for HLA-A and HLA-B at antigen level and for DRB1 at allele level. HLA-C, HLA-DQ, and HLA-DP were not considered in donor unit selection. The majority (76%) of the single UCBT recipients received myeloablative conditioning compared with only 42% of the double UCBT recipients. In addition, a greater proportion of the single UCBT recipients received equine antithymocyte globulin (ATG) as part of their conditioning therapy, and cyclosporine A (CsA) and short-course methylprednisolone as GVHD immunoprophylaxis (98% vs 57%, P < .01). The total nucleated, CD34 and CD3 cell doses infused were significantly lower in recipients of a single unit.

For the entire cohort of patients, the cumulative incidence of grade II-IV and grade III-IV acute GVHD at day 100 after UCBT was 52% and 19%, respectively.

For double UCB graft recipients, the incidence of grade II-IV acute GVHD was 58% compared with 39% in single UCB unit recipients (P < .01). Recipients of 2 UCB units had a higher incidence of grade II disease only, manifest by a higher incidence of stage III skin GVHD only (44 vs 23%, P = .02).

For the entire cohort of patients, the cumulative incidence of chronic GVHD after UCBT was 17%.

TRM at 1 year was 39% and 24% (P = .02) after a single and double UCBT, respectively. Among patients who developed grade II-IV acute GVHD, TRM at 1 year following the onset of acute GVHD was lower in recipients of double UCBT (20%) versus single UCBT (39%), P = .05) Based on this analysis, 3 findings emerge: (1) acute GVHD occurs more often, and at an earlier time point after transplantation of 2 partially HLA-matched UCB units compared with a single unit; (2) when acute GVHD occurs after a double UCBT, it is more likely grade II in severity with involvement principally of the skin; and (3) TRM is significantly lower in patients with acute GVHD when receiving transplants with 2 UCB units.

  1. Chronic graft-versus-host disease (cGVHD) following unrelated donor hematopoietic stem cell transplantation (HSCT): higher response rate in recipients of unrelated donor (URD) umbilical cord blood (UCB). Arora M, Nagaraj S, Wagner JE, Barker JN, Brunstein CG, Burns LJ, Defor TE, McMillan ML, Miller JS, Weisdorf DJ. Biol Blood Marrow Transplant. 2007;13:1145-52.

Patients who underwent HLA matched or mismatched volunteer adult unrelated donor (URD) or unrelated UCB HSCT were evaluated; all consecutive patients who developed cGVHD were included. Adult URD transplants were performed in 123 patients and results were compared to those of 47 unrelated UCB transplants. The URD transplant recipients were significantly younger (median age 25 versus 39 years, P = .002), and the URD grafts were mostly HLA matched whereas the UCB transplants were not (67% versus 10%, P < .0001).

UCB recipients had\ more frequent responses to therapy (complete remission [CR] + partial remission [PR]) to treatment (URD 48% versus UCB 74% at 2 months [P = .005]; 49% versus 78% at 6 months [P = .001] and 51% versus 72% at 1 year [P = .03] in the URD and UCB groups, respectively). Nonrelapse mortality (NRM) after diagnosis of cGVHD was worse after URD grafts (1 year NRM 27% [19%-35%] URD versus 11% [2%-20%] UCB, P = .055). Separate multivariate analyses were performed in each cohort. In both, thrombocytopenia and no CR or PR at 2 months were independently associated with increased mortality. In addition, progressive onset of cGVHD was a significant predictor of increased mortality in URD cohort.

These data suggest that cGVHD following UCB transplant may be more responsive to therapy and also lead to a lower NRM.
  1. Chronic graft-versus-host disease following umbilical cord blood transplantation: retrospective survey involving 1,072 patients in Japan. Narimatsu H, Miyakoshi S, Yamaguchi T, Kami M, Matsumura T, Yuji K, Murashige N, Kusumi E, Kodama Y, Komatsu T, Sakamaki H, Kouzai Y, Okada M, Osugi Y, Kobayashi R, Inoue M, Takahashi S, Kai S, Kato K, Inoue-Nagamura T, Taniguchi S, Kato S. Blood. Prepublished on line June 16, 2008; DOI 10.1182/blood-2007-11-118893.

This is a review of the clinical features in 1,072 Japanese patients with hematologic malignancies transplanted through the Japan Cord Blood Bank Network. All recipients received a single cord blood unit. Patients with a history of any type of allogeneic HSCT prior to CBT were excluded. CMV positive cord blood units were not provided to transplantation centers.

The median age was 33 years (range, 0-79 years) and the median patient body weight was 50.0 kg (range, 4.0-96.1 kg). 46% of the patients developed grade II-IV acute GVHD within 100 days of transplantation. The cumulative incidence of chronic GVHD 2 years after transplantation was 28% (95% CI, 25-31%). Of the 299 patients for whom the information on types of chronic GVHD was available, 184 developed limited disease and 115 developed extensive disease. Of the 224 patients for whom information on both the treatment of chronic GVHD and its response were available, 93 patients (42%) received systemic immunosuppressive agents including corticosteroids (n=63), calcineurin inhibitors (n=15), both (n=13) and others (n=2). Of those 93 patients 64 (68%) responded to treatment. Chronic GVHD was refractory in the remaining 29, and fatal in 5.

The incidence of chronic GVHD was comparable to the previous smaller reports on CBT in Western countries and lower than that reported after unrelated BMT in Japanese patients.

The present study suggests a higher response rate and lower mortality in chronic GVHD patients after CBT than after unrelated BMT and PBSCT. Additional findings were that chronic GVHD after CBT improved EFS and reduced the risk of disease progression. Chronic GVHD following CBT probably has clinically significant graft-versus-malignancy effects. Interestingly, chronic GVHD after CBT improved OS as well, in contrast to the unclear effects of chronic GVHD on OS improvement in conventional allogeneic HSCT.

The low overall incidence despite HLA mismatches, relatively low need for systemic immunosuppression and positive survival impact indicate milder nature of chronic GVHD after CBT.

  1. Clinical characteristics of chronic graft-versus-host disease following umbilical cord blood transplantation for adults. Sugimoto K, Narimatsu H, Kawase T, Iida H, Watanabe M, Kohno A, Kuwatsuka Y, Uchida T, Hamaguchi M, Terakura S, Naoe T, Matsuo K, Murata M, Sawa M, Miyamura K, Morishita Y; Nagoya Blood and Marrow Transplantation Group (NBMTG). Bone Marrow Transplant. 2008;41:729-36.

The clinical characteristics of chronic GVHD following cord blood transplantation (CBT) in adults have not been well described. This is a report of the outcomes of 77 patients underwent CBT at eight transplantation centers of the Nagoya Blood and Marrow Transplantation Group. Of the 77 patients, 29 survived without graft failure or progression of underlying diseases for at least 100 days after transplantation. The median age of the 29 patients was 42 years (range, 18-67 years).

Seven patients developed chronic GVHD (extensive, n=4; limited, n=3) disease. The cumulative incidence of chronic GVHD 1 year after day 100 was 24% (95% confidence interval (CI), 11-41%), and the organs involved were the skin (n=6), oral cavity (n=4), liver (n=1) and gastrointestinal tract (n=1). In three patients, chronic GVHD was resolved with supportive care. The remaining four were successfully treated with additional immunosuppressive therapy.

Chronic GVHD after CBT improved OS and EFS, which suggests that it has a graft-versus-malignancy effect. Event-free survival rates of the 29 patients with and without chronic GVHD 3 years after day 100 were 83 (95% CI, 27-97%) and 36% (95% CI, 17-56%), respectively (P=0.047).

The authors point out that the incidence of chronic GVHD after CBT (24%) was lower than after HLA-matched BMT in Japanese patients (approximately 45%). Also, chronic GVHD had a 100% favorable response rate to immunosuppressants and was not fatal. This is in sharp contrast to the chronic GVHD that develops in BMT or PBSCT, since 20-40% of chronic GVHD is fatal in such patients. Further, chronic GVHD after CBT infrequently involves vital organs, such as the liver and the lung; instead, the skin and oral cavity are involved. The chronic GVHD did not impair transplant recipients’ quality of life; all of the patients who developed chronic GVHD without disease progression maintained Karnofsky performance status of at least 90%.

The authors concluded that although chronic GVHD is a significant complication in CBT, its characteristics are different from those of GVHD following BMT and PBSCT; it is mild and infrequent.

Limitations of the present multicenter study included the small, retrospective nature and the various preparative regimens and GVHD prophylaxes in the patients. Also, most of the patients were classified as belonging to the favorable risk group.

  1. Rituximab reduces the incidence of acute graft-versus-host disease. Christopeit M, Schütte V, Theurich S, Weber T, Grothe W, Behre G. Blood. 2009;26;113:3130-1.

The authors present data from a retrospective study on 34 patients transplanted consecutively with an allogeneic stem cell graft. Seventeen patients received rituximab (375 mg/m2) once. Of these, 13 received rituximab as a means of conditioning against CD20-positive non-Hodgkin’s lymphoma (NHL) 8 days before transplantation. Four patients received rituximab prophylactically against posttransplantation lymphoma on days +31, +49, +49 and +89, respectively, after transplantation but before the advent of aGVHD. Seventeen patients did not receive rituximab, 2 of whom were diagnosed with NHL.

Seventeen patients were diagnosed with aGVHD. Only 3 of 17 patients receiving rituximab (17.6%) developed aGVHD. Without rituximab, 14 of 17 patients (82.3%) developed aGVHD of any grade (P<.001) and 9 of 17 patients (52.9%) developed aGVHD grade II-IV (P=0.031). Patients receiving both ATG and rituximab did not develop aGVHD of any grade (0/10) compared with 10 of 17 (58.8%) receiving only ATG (P=<0.001). All 3 patients receiving rituximab and not ATG experienced aGVHD.

The authors concluded that the data, although from a retrospective study on a limited number of patients, point toward a prophylactic role of rituximab against aGVHD.

  1. Cutaneous manifestations of chronic graft-versus-host disease. Hymes SR, Turner ML, Champlin RE, Couriel DR. Biol Blood Marrow Transplant. 2006; 12:1101-13.

This is an article that, among other things, displays the cutaneous manifestations of cGVHD in 14 excellent color photographs. It is very informative and should be seen in the original. The authors use the lesional morphology of cGVHD to develop a classification system that may prove useful in early diagnosis. In addition, this approach may help to facilitate the correlation of different morphologic entities with outcome and response to therapy.

Traditionally, cGVHD has been defined as developing >100 days post-transplant. However, since the availability of new, less intensive preparative regimens and the use of donor lymphocyte infusions, it is not uncommon to see a delayed or late aGVHD (i. e., aGVHD >100 days) and, in some cases, overlapping aGVHD and cGVHD, or other “atypical” forms of cGVHD. Acute GVHD and cGVHD in the skin are more accurately diagnosed by clinical and, less frequently, histopathologic features. The authors describe, illustrate and summarize the diversity of cutaneous manifestations of cGVHD.

Cutaneous chronic graft versus host disease has traditionally been classified into lichenoid and scleroderma-like forms. However, the initial presentation is sometimes subtle and a variety of less common cutaneous manifestations may be prevalent. This clinical review lists 16 Clinical Patterns of cGVHD, such as xerotic, lichen planus-like, lichen sclerosus-like, papulosquamous/psoriasiform, poikiloderma, etc.

  1. Umbilical cord blood transplantation: where do we stand? Wadlow RC, Porter DL. Biol Blood Marrow Transplant 2002; 8:637-647.Abstract

In both related and unrelated umbilical cord blood transplantation, as well as in cases of HLA-matched and –mismatched grafts, the incidence and severity of acute and chronic GVHD appear to be less than in conventional hematopoietic stem cell transplants. There are a number of studies that suggest that cord blood transplantation results in less GVHD compared to transplantation of cells from other sources, and no trial results have suggested that cord blood transplants increase the risk of GVHD.

  1. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Grewal SS, Barker JN, Davies SM, Wagner JE. Blood 2003; 101:4233-4244.

Various reports of unrelated cord blood transplants indicate an incidence of grades II-IV acute GVHD of 33%-44%, and an incidence of grades III-IV acute GVHD of 11%-22%. The incidence of chronic GVHD has ranged from 0% to 25%. These results are particularly notable since the majority of unrelated umbilical cord blood transplants were performed using 1 to 2 HLA-mismatched grafts. Although a majority of patients were young in these reports, the incidence of severe GVHD in adults receiving mismatched umbilical cord blood grafts has also been low.

HLA mismatch has been the strongest risk factor for GVHD in recipients of marrow transplants. This association is less clear in cord blood transplants. Many series have failed to observe an influence of 0- to 3- antigen mismatch on the risk of acute or chronic GVHD. However, some authors have reported higher rates of acute GVHD with mismatched grafts, although not with chronic GVHD.

  1. Hematopoietic stem-cell transplantation using umbilical-cord blood. Cohen Y, Nagler A. Leukemia & Lymphoma 2003; 44:1287-1299.Abstract

In pediatric patients, despite the frequent use of HLA mismatched grafts, incidence of grade III-IV acute GVHD (11-24% in the groups reviewed) was comparable to that reported for (well-matched) unrelated donor BMT. The influence of HLA disparity on incidence and severity of acute GVHD was controversial. In the Japanese and New York Blood Center (NYBC) studies, a higher degree of HLA-disparity was associated with an increased incidence of severe GVHD. These results conflict with other studies in which no correlation between GVHD and HLA disparity was apparent. Chronic GVHD rates varied between 9 (University of MN) and 31% (NYBC), compared to 42% at two years in unrelated donor BMT, and it was limited in extent in most cord blood transplants.

In adults, the probability of grade III-IV GVHD using cord bloods (ranging between 9 and 38%) was comparable to that reported in HLA-matched unrelated donor BMT despite the extensive use of HLA disparate grafts with cord bloods, There was no association between incidence of acute GVHD and the degree of HLA disparity. Chronic GVHD developed in about 30% of patients at risk in two large series.

  1. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. Rocha V, Wagner JE, Jr., Sobocinski KA, Klein JP , Zhang MJ, Horowitz MM et al. N Engl J Med 2000; 342:1846-1854.Abstract

The authors studied the records of 113 recipients of cord blood from HLA-identical siblings and compared them with the records of 2052 recipients of bone marrow from HLA-identical siblings during the same period. The study population consisted of children 15 years of age or younger. They compared the rates of GVHD, hematopoietic recovery, and survival using Cox proportional-hazards regression to adjust for potentially confounding factors. Multivariate analysis demonstrated a lower risk of acute GVHD (relative risk, 0.41; P=0.001) and chronic GVHD (relative risk, 0.35; P=0.02) among recipients of cord-blood transplants. As compared with recovery after bone marrow transplantation, the likelihood of recovery of the neutrophil count and the platelet count was significantly lower in the first month after cord-blood transplantation (relative risk, 0.40 (P<0.001), and relative risk, 0.20 (P<0.001)), respectively. Mortality was similar in the two groups (relative risk of death in the recipients of cord blood, 1.15; P=0.43). The conclusion reached was that recipients of cord-blood transplants from HLA-identical siblings have a lower incidence of acute and chronic GVHD than recipients of bone marrow transplants from HLA-identical siblings.

i. GVHD IN BMT AND PBSC HEMATOPOIETIC CELL TRANSPLANTS

  1. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Schrezenmeier H, Passweg JR, Marsh JC, Bacigalupo A, Bredeson CN, Bullorsky E, Camitta BM, Champlin RE, Gale RP, Fuhrer M, Klein JP, Locasciulli A, Oneto R, Schattenberg AV, Socie G, Eapen M. Blood. 2007;110:1397-400. Abstract

We analyzed the outcome of 692 patients with severe aplastic anemia (SAA) receiving transplants from HLA-matched siblings. A total of 134 grafts were peripheral blood progenitor cell (PBPC) grafts, and 558 were bone marrow (BM) grafts. Rates of hematopoietic recovery and grades 2 to 4 chronic graft-versus-host disease (GVHD) were similar after PBPC and BM transplantations regardless of age at transplantation. In patients older than 20 years, chronic GVHD and overall mortality rates were similar after PBPC and BM transplantations. In patients younger than 20 years, rates of chronic GVHD (relative risk [RR] 2.82; P = .002) and overall mortality (RR 2.04; P = .024) were higher after transplantation of PBPCs than after transplantation of BM. In younger patients, the 5-year probabilities of overall survival were 73% and 85% after PBPC and BM transplantations, respectively. Corresponding probabilities for older patients were 52% and 64%. These data indicate that BM grafts are preferred to PBPC grafts in young patients undergoing HLA-matched sibling donor transplantation for SAA.

  1. Management of acute graft-versus-host disease. Bacigalupo A. Br J Haematol. 2007;137:87-98. Abstract

This is an authoritative and well-referenced review of acute GVHD. It includes discussion of pathogenesis and grading. A detailed review of preventative approaches includes discussion of HLA matching, T-cell depletion ex-vivo, T-cell depletion in vivo, expanding regulatory T cells, post-transplant immunosuppressive therapy, mesenchymal stem cells, inactivation of antigen presenting cells, reduced-intensity conditioning regimens, and anti-IL2 anti-TNF antibodies), Aspects of treatment that are reviewed include first-line treatment, second-line treatment, interleukin 2 receptor antibodies, anti-CD147 monoclonal antibody, RNF antibodies, pre-emptive treatment, cellular therapy of GVHD, and extracorporeal photopheresis.

The authors conclude that treatment of established GVHD is complex and has not made major advances in the last decade. It is possible that patients are treated too late, when tissue damage has already taken place and cytokine production by activated donor T cells and autologous macrophages can proceed undisturbed. It would seem that acute GVHD is, to a certain extent, self-programmed, since very early treatment with high dose corticosteroids and/pr ATG does not modify the natural course of the disease. Over the last three decades the risk of acute GVHD has been considerably reduced and by modifying the transplant program and the stem cell source. Now the need is to improve our ability to predict GVHD and develop new strategies of early treatment.

  1. The management and outcome of chronic graft-versus-host disease. Fraser CJ, Scott Baker K. Br J Haematol. 2007;138:131-45. Abstract

This review focuses on therapeutic options for prevention, primary treatment, salvage therapy and supportive care. Issues pertaining to relevant outcome measures including impact on transplant-related mortality, relapse rates, quality of life, functional impairment and complications related to therapy are also reviewed. Numerous reference citations are included.

The authors point out that chronic GVHD is the leading cause of non-relapse mortality in transplant survivors and has a significant impact upon their functional status and quality of life. Despite significant advances being made in the field of HCT over the past 25 years, there has been little change in the incidence, morbidity and mortality of cGVHD. This is partly because of a lack of understanding about the pathogenesis of the disorder but also because a lack of well validated grading systems and outcome measures has hindered clinical research.

Standard primary treatment remains a combination of corticosteroids and calcineurin inhibitors. There is no standard therapy for those who fail to respond to corticosteroids. Many agents have been studied but there is an urgent need for systematic research to compare the efficacy of different approaches. Infection is the leading cause of death among patients with cGVHD so antimicrobial prophylaxis is mandatory. A multidisciplinary approach to the care of patients with cGVHD is essential to adequately address its effects on both physical and psychological functioning.

  1. Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Couriel DR, Hosing C, Saliba R, Shpall EJ, Anderlini P, Rhodes B, Smith V, Khouri I, Giralt S, de Lima M, Hsu Y, Ghosh S, Neumann J, Andersson B, Qazilbash M, Hymes S, Kim S, Champlin R, Donato M. Blood. 2006;107:3074-80. Abstract

Extracorporeal photochemotherapy (ECP) has been tested extensively in small cohorts of patients with chronic GVHD. This is a report of a retrospective study of 71 patients with severe chronic GVHD treated with ECP.

Response rate was 61% (n = 43), and 14 patients had complete responses (CRs). The best responses were observed in skin, liver, oral mucosa, and eye. Factors affecting outcomes were assessed in the less heavily pretreated subgroup (n = 63). Thrombocytopenia was associated with a lower response rate (P = .04), and there was a trend toward a higher response rate in de novo chronic GVHD.

At 6 months, a total of 27 (69%) of 39 patients who were alive continued to have a sustained response (CR 4 [10%] of 39, and partial response [PR] 23 [59%] of 39). The cumulative incidence of steroid discontinuation at 1 year was 22%. The overall survival since initiation of therapy was 53% at 1 year.

Response to ECP and platelet count at initiation of therapy were the strongest predictors of nonrelapse mortality (NRM) on univariate analysis. Objective responses were observed in a substantial number of patients with both skin and visceral chronic GVHD failing corticosteroids and other immunosuppression.

The authors also discuss previous reports of successful use of extracorporeal photochemotherapy in the treatment of severe acute and chronic graft-versus-host disease (Greinix HT, et al., Blood 1998;92:3098-3104; Apisarnthanarax N, et al., Bone Marrow Transplant. 2003;31:459-65.)

  1. Rituximab for steroid-refractory chronic graft-versus-host disease. Cutler C, Miklos D, Kim HT, Treister N, Woo SB, Bienfang D, Klickstein LB, Levin J, Miller K, Reynolds C, Macdonell R, Pasek M, Lee SJ, Ho V, Soiffer R, Antin JH, Ritz J, Alyea E. Blood 2006;108:756-62. Abstract

This is a report of a phase 1/2 study of anti-B-cell therapy with rituximab in steroid-refractory chronic GVHD. Twenty-one patients were treated with 38 cycles of rituximab. Rituximab was tolerated well, and toxicity was limited to infectious events.

The clinical response rate was 70%, including 2 patients with complete responses. Responses were limited to patients with cutaneous and musculoskeletal manifestations of chronic GVHD and were durable through 1 year after therapy. The median dose of prednisone among treated subjects fell from 40 mg/day to 10 mg/day, 1 year after rituximab therapy (P < .001). A chronic GVHD symptom score improved in the majority of treated patients. Antibody titers against Y chromosome-encoded minor HLA antigens fell and remained low, whereas titers against infectious antigens (EBV, tetanus) remained stable or rose during the treatment period.

The authors concludec that specific anti-B-cell therapy with rituximab may be beneficial for patients with steroid-refractory chronic GVHD.

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