Biology of Blood and Marrow Transplantation
Volume 15, Issue 9 , Pages 1005-1013, September 2009

Efficacy of Rituximab in the Setting of Steroid-Refractory Chronic Graft-versus-Host Disease: A Systematic Review and Meta-Analysis

  • Mohamed A. Kharfan-Dabaja

      Affiliations

    • Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, Florida
    • Department of Hematology, Moffitt Cancer Center, Tampa, Florida
    • ,
  • Asmita R. Mhaskar

      Affiliations

    • Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida
    • ,
  • Benjamin Djulbegovic

      Affiliations

    • Department of Hematology, Moffitt Cancer Center, Tampa, Florida
    • Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida
    • Center for Evidence-Based Medicine, University of South Florida, College of Medicine, Tampa, Florida
    • ,
  • Corey Cutler

      Affiliations

    • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
    • ,
  • Mohamad Mohty

      Affiliations

    • Hematology Clinic, Hospital Center of the University of Nantes, Nantes, France
    • ,
  • Ambuj Kumar

      Affiliations

    • Department of Health Outcomes and Behavior, Moffitt Cancer Center, Tampa, Florida
    • Center for Evidence-Based Medicine, University of South Florida, College of Medicine, Tampa, Florida
    • Corresponding Author InformationCorrespondence and reprint requests: Ambuj Kumar, MD, MPH, Moffitt Cancer Center & Research Institute, College of Medicine, University of South Florida, 12902 Magnolia Drive, MRC 232A, Tampa, FL 33612.

Received 25 February 2009; accepted 6 April 2009. published online 11 June 2009.

Article Outline

Increased insight into the role of B lymphocytes in the pathophysiology of graft-versus-host disease has led to a number of studies assessing the efficacy of the anti-CD20 monoclonal antibody (mAb) rituximab in treating steroid-refractory chronic graft-versus-host disease (cGVHD). Findings vary greatly among these studies, however. We conducted a systematic review to summarize the totality of evidence on the efficacy of rituximab in steroid-refractory cGVHD. We performed a PubMed search and contacted experts in the field to identify relevant studies. Endpoints included overall response rate (including organ-specific) and ability of rituximab to allow dosage reduction of immunosuppressive therapies. Data were pooled under a random-effects model. Seven studies (3 prospective and 4 retrospective, with a total of 111 patients) met the inclusion criteria. The pooled proportion of overall response was 0.66 (95% confidence interval=0.57 to 0.74). There was no heterogeneity among the pooled studies. Response rates were 13% to 100% for cGVHD of the skin, 0 to 83% for cGVHD of the oral mucosa, 0 to 66% for cGVHD of the liver, and 0 to 38% for cGVHD of the lung. Common adverse events were related to infusion reactions or infectious complications. The relatively small number of patients and the varying criteria for reporting organ response and dosage reduction of steroids, among other limitations, hinders our ability to reach definitive conclusions on the overall efficacy of rituximab for cGVHD involving other organs.

Key Words: Rituximab, Chronic graft-versus-host disease, Systematic review, Meta-analysis

 

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Introduction 

Chronic graft-versus-host disease (cGVHD) represents one of the most challenging sequelae of allogeneic hematopoietic cell transplantation (allo-HCT), resulting in significant long-term morbidity and mortality. The continuous growth in the number of allo-HCTs using alternate donors, particularly HLA-mismatched donors, is further increasing the incidence of cGVHD 1, 2. The increasing use of mobilized peripheral blood stem cells (PBSC) as the graft source also is contributing to the increasing prevalence of cGVHD 1, 2, 3.

A recently released National Institutes of Health (NIH) working group report on criteria for clinical trials in cGVHD provides standardized criteria for diagnosis of cGVHD and an improved scoring system that better describes the extent and severity of cGVHD for each organ, taking into account the importance of preserving function [4]. Similarly, expert consensus opinion has resulted in the establishment of more practical criteria aimed at assessing the therapeutic response in patients with cGVHD more objectively [5]. Unfortunately, however, treatment outcomes for cGVHD remain disappointing. Systemic corticosteroid therapy is the most commonly used first-line treatment for patients with established cGVHD, but long-term corticosteroid use is limited by the increased risk of infection, which remains the leading cause of death in cGVHD [6]. There is no consensus regarding the best treatment option for patients with cGVHD who do not respond to or progress after corticosteroid therapy. Encouraging responses have been reported using extracorporeal photopheresis 7, 8, mycophenolate mofetil (MMF) 9, 10, and low-dose methotrexate (MTX), among other modalities [11].

Advances in the understanding of cGVHD have implicated B lymphocytes in the pathophysiology of cGVHD. Miklos et al. [12] demonstrated a correlation between cGHVD and development of antibody responses to H-Y minor histocompatibility antigens in cases of sex-mismatched (male recipients with female donors) allo-HCT. These findings provided the scientific rationale for a number of studies exploring rituximab to treat patients with steroid-refractory cGVHD. These studies yielded varying findings regarding organ-specific responses, however. Consequently, we performed a systematic review to evaluate the totality of evidence regarding the efficacy of rituximab in treating steroid-refractory cGVHD.

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Methods 

Literature Search 

We searched the Medline (Pubmed) database using a broad search strategy to identify prospective or retrospective studies evaluating the efficacy of rituximab in patients with steroid-refractory cGVHD. The search was conducted using following terms: “Rituximab”[Substance Name] AND “Graft vs. Host Disease”[MeSH]. Relevant references in each obtained article were scanned to identify other relevant studies. In addition, experts in the field were approached for unpublished data or to identify additional studies in the subject area. No search limits were applied.

Inclusion Criteria 

All prospective studies evaluating the efficacy of rituximab in cGVHD were included regardless of the number of patients enrolled. Retrospective studies were included if they evaluated the efficacy of rituximab in cGVHD in a minimum of 5 patients. Single case reports were excluded.

Study Selection, Quality Assessment, and Data Extraction 

Two reviewers (A.M. and A.K.) appraised the list of references and selected the studies in consultation with other reviewers (M.K.D. and C.C.). Disagreements were resolved by consensus. Two reviewers (A.M. and A.K.) independently extracted the data from selected articles. Data were extracted on specific clinical outcomes (benefits and harms), as well as on the methodological quality of the studies.

Data Analysis and Statistical Methods 

For the purpose of meta-analysis, the proportions were first transformed into a quantity according to the Freeman-Tukey variant of the arcsine square root transformed proportion [13]. The pooled proportion was calculated as the back-transform of the weighted mean of the transformed proportions, using a random-effects model [14].

A formal statistical test for heterogeneity using an I2 test was performed [15]. The heterogeneity and robustness of the findings also were evaluated through additional sensitivity analyses. The possibility of publication bias was assessed using the Begg and Egger funnel plot method [16]; although this method has some limitations, it is widely used to assess publication bias [17]. The meta-analysis was performed using StatsDirect software (StatsDirect Ltd, Altrincham, Cheshire, UK). The work was performed ion accordance with the guidelines promulgated at the Quality of Reporting of Meta-Analyses conference [15].

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Results 

Identification of Studies 

Figure 1 summarizes the process used to identify and select the studies for the systematic review. The initial search yielded 37 articles, of which 31 were excluded for the reasons shown in Figure 1. Of the 6 studies that met the inclusion criteria, 3 were categorized as prospective studies and 3 were retrospective analyses. One retrospective case series was identified through expert contact [18]. We found no randomized controlled trials evaluating the efficacy of rituximab versus other therapeutic alternatives for treating steroid-refractory cGVHD.

Methodological Quality of Studies 

We conducted a critical appraisal of the methodological quality of all studies.

Prospective Studies 

Unclear reporting of sampling procedures makes it difficult to determine whether the study sample consisted of consecutive series of patients or a convenient sampling method was used, possibly introducing a selection or an ascertainment bias that could potentially plague observational studies.

Retrospective Studies 

Whether an analysis addressed a priori hypothesis or was a result of some post hoc observation was unclear. In addition, the relatively small sample sizes (range, 8 to 38 patients) limited our ability to draw definitive conclusions from these studies.

Publication Bias 

A Begg and Egger funnel plot showed a symmetric distribution, indicating the absence of a publication bias for all of the outcomes assessed here (results not shown).

Outcomes 

Mortality 

Mortality data were extractable from all 7 studies 18, 19, 20, 21, 22, 23, 24. The pooled proportion of mortality from 7 studies involving 111 patients was 0.158 (95% confidence interval [CI]=0.083 to 0.253) (Fig 2A). There was no statistically significant heterogeneity among the studies (I2=32.7%; P=.178). The pooled proportion of mortality was 0.122 (95% CI=0.034 to 0.253) in 3 prospective studies involving 37 patients 19, 20, 22 and 0.158 (95% CI=0.08 to 0.252) in 4 retrospective studies evaluating 74 patients 18, 21, 23, 24.

  • View full-size image.
  • Figure 2 

    Forest plot for the outcomes of survival, overall response and organ specific response (skin and liver). The summary effect estimate (proportion) for individual studies are indicated by black rectangles (the size of the rectangle is proportional to the study weight), with the lines representing 95% confidence intervals (CIs). The overall summary effect estimate (proportion) and 95% CI are indicated by the diamond.

Overall Response Rate 

Overall response rate (ORR) data were extractable from 6 studies involving a total of 108 patients (Fig 2B) 18, 19, 20, 21, 23, 24. The pooled proportion of ORR was 0.66 (95% CI=0.57 to 0.74), and there was no statistically significant heterogeneity among the studies (I2=0%; P=.90). The pooled proportion of ORR was 0.70 (95% CI=0.54 to 0.83) in 2 prospective studies evaluating 34 patients 19, 20 and 0.64 (95% CI=0.53 to 0.74) in 4 retrospective studies involving 74 patients 18, 21, 23, 24.

Organ-Specific Response 

Skin cGVHD 

Data on cutaneous cGVHD were extractable from 6 studies involving a total of 67 patients 18, 19, 21, 22, 23, 24. The pooled proportion ORR was 0.60 (95% CI=0.41 to 0.78) (Fig 2C). There was a statistically significant heterogeneity among the pooled studies (I2=60%; P=.03). The pooled proportion ORR was 0.85 (95% CI=0.59 to 0.98) in 2 prospective studies enrolling 9 patients 19, 22 and 0.51 (95% CI=0.308 to 0.717) in 4 retrospective studies involving 58 patients 18, 21, 23, 24.

Mucosa (Oral) cGVHD 

Data on cGVHD of the oral mucosa were extractable from 5 studies involving a total of 46 patients 18, 19, 20, 22, 24. The pooled proportion of ORR was 0.36 (95% CI=0.12 to 0.65). There was a statistically significant heterogeneity among the included studies for this outcome (I2=73%; P=.0046). The pooled proportion of oral cGVHD response was 0.26 (95% CI=0.007 to 0.84) in 3 prospective studies involving 15 patients 19, 20, 22 and 0.45 (95% CI=0.29 to 0.62) in 2 retrospective studies involving 31 patients 18, 24.

Liver cGVHD 

ORR data for the outcome of liver cGVHD were extractable from 6 studies involving a total of 34 patients 18, 19, 21, 22, 23, 24. The pooled proportion of ORR was 0.29 (95% CI=0.12 to 0.51) (Fig 2D). There was no statistically significant heterogeneity among the pooled studies for this outcome (I2=41.8%; P=.126). The pooled proportion ORR was 0.28 (95% CI=0.03 to 0.64) in 2 prospective studies enrolling 7 patients 19, 22 and 0.29 (95% CI=0.06 to 0.59) from 4 retrospective studies involving 27 patients 18, 21, 23, 24.

Gastrointestinal cGVHD 

Data on response rate for gastrointestinal (GI) cGVHD were reported in 4 studies (1 prospective and 3 retrospective) involving a total of 12 patients 18, 21, 22, 24. The pooled proportion ORR was 0.31 (95% CI=0.07 to 0.62). There was no statistically significant heterogeneity among the pooled studies (I2=35.7%; P=.19). One prospective study showed no response to rituximab treatment in 1 patient with steroid-refractory gastrointestinal cGVHD [22]. The pooled proportion ORR in 3 retrospective studies involving 11 patients was 0.346 (95% CI=0.05 to 0.72) 18, 21, 24.

Lung cGVHD 

Data on response rates in cases of steroid-refractory cGVHD involving the lung were extractable from 4 studies involving a total of 15 patients 18, 22, 23, 24. In 1 prospective study, rituximab produced no response [22]. The pooled proportion of lung cGVHD response in 3 retrospective studies involving 14 patients was 0.30 (95% CI=0.11 to 0.53) 18, 23, 24. There was no significant heterogeneity among the pooled studies (I2=0%; P=.58).

Other Organs with cGVHD 

Reponses to rituximab also were reported in patients with steroid-refractory ocular cGVHD, with rates ranging from 13% (1/8) to 38% (6/16) 23, 24, and in patients with steroid-refractory cGVHD of the musculoskeletal system, with response rates of 100% (1/1) and 75% (3/4) 18, 23.

Does Administration of Rituximab Allow Reduction (or Discontinuation) of Immunosuppressive Therapies, Including Corticosteroids? 

Administration of rituximab facilitates dosage reduction of previous immunosuppressive therapies in patients with refractory cGVHD. Zaja et al. [24] reported a median dosage reduction of immunosuppressive therapy (including corticosteroids) of 82% (range, 0 to 100%), mostly in cases of steroid-refractory cGVHD involving the skin and oral mucosa.

Two studies specifically addressed the glucocorticoid-sparing effect of rituximab in patients with steroid-refractory cGVHD. Mohty et al. [21] reported a median glucocorticoid dosage reduction of 86% (range, 0 to 100%) in 11 of 15 patients (73%) treated with rituximab; this steroid sparing-effect also was more pronounced in skin and oral mucosal cGVHD, consistent with a previous report [24]. Similarly, Cutler et al. [20] reported a 75% median dosage reduction of prednisone (from 40mg to 10mg) in more than two-thirds of their patients. These and other studies are summarized in Table 1.

Table 1. Dose Reduction of Immunosuppressive or Corticosteroid Therapy after Initiation of Rituximab
Author, YearMedian Dose Reduction(Range)Proportion of Patients Discontinuing Immunosuppressive Therapy(n/N)
Von Bonin et al., 2008 [18]NR23% (3/13)∗
Mohty et al., 2008 [21]86% (33%-100%)NR
Zaja et al., 2007 [24]82% (0-100%)†NE
Okamoto et al., 2006 [22]NE‡NA
Cutler et al., 2006 [20]75% (NE)11% (3/28)∗
Canninga-Van Dijk et al., 2004 [19]NE67% (4/6)
Ratanatharathorn et al., 2003 [23]NR (68.75%-87.5%)§NR

NR indicates not reported; NE, not extractable; NA, not available.

∗Updated data were provided by the authors (Cutler et al., CS).

†Zaja et al. reported organ-specific dose reduction; the numbers given here are for median % dose reduction of CS for 10 patients evaluable for skin response.

‡Okamoto et al. reported no change in the dose of immunosuppressive drugs during rituximab therapy.

§Ratanatharathorn et al. reported data for dose reduction of CS extractable for 2 of the 4 patients who showed a response to rituximab; the values for % CS dose reduction are 68.75% for one patient and 87.5% for the other patient.

Treatment-Related Morbidity and Mortality (TRM) 

Rituximab appears to be relatively well tolerated, with side effects related mainly to infusion reactions (5% to 11%) and infectious complications, including sepsis (3% to 33%), pneumonia (8% to 33%), viral conjunctivitis (5%), diarrhea (14%), and herpes zoster reactivation (33%; 1/3), among others 18, 19, 20, 21, 22, 23, 24. Long-term toxicities related to treatment were not reported 18, 19, 20, 21, 22, 23, 24.

None of the studies, prospective or retrospective, reported mortality attributable to rituximab treatment.

Sensitivity Analyses 

Because of the limited number of prospective studies available, as well as the relatively small number of patients for each cGVHD manifestation, we could not perform a sensitivity analysis to explore the reasons behind the heterogeneity in the outcomes of organ-specific responses related to cGVHD of the skin and mucosa. This heterogeneity can be attributed to several clinical factors, however. The patients enrolled in these studies had a wide range of diseases and previous interventions (eg, differing conditioning regimens, number of treatments for cGVHD before rituximab therapy, concomitant treatment with corticosteroids or other immunosuppressive treatments), as well as differing criteria for assessing response rates. All of these factors may possibly contribute to the heterogeneity for some of the outcomes.

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Discussion 

The totality of the evidence on the efficacy of rituximab for treating steroid-refractory cGVHD demonstrates that the skin is the most responsive organ (Table 2) 19, 20, 21, 22, 24. Responses were impressive in cases of sclerodermatous or lichenoid cutaneous cGVHD 20, 22. In the prospective study of Okamoto et al. [22], 3 patients (100%) with sclerodermatous cGVHD had responses occurring between 60 and 90 days from initiation of therapy. Similarly, Cutler et al. [20] reported a decrease in median body surface area (BSA) involved with sclerodermatous cGVHD from 35% to 25% after 2 cycles of therapy, followed by a further decrease to 20% at 1 year after the initiation of rituximab. Cases of lichenoid cutaneous cGVHD also responded to rituximab therapy, showing a decrease in median BSA involvement from 20% to 5% after 2 cycles and a further decrease to 3% after 1 year [20]. It is important to keep in mind that clinical responses may continue to improve several months after the start of rituximab. In summary, these findings suggest that rituximab is effective in treating cutaneous cGVHD.

Table 2. Clinical Studies Evaluating the Efficacy of Rituximab in the Setting of Steroid-Refractory cGVHD
Author, YearStudy DesignNumber of Patients EnrolledMedian Age, Years (Range)ORR, %Morbidity, %Mortality, % (n/N)Dose (Median Number of Doses) (Cycles)Criteria for Response Assessment
By Organ (Responders/Total)TTR Days, Median
Von Bonin et al., 2008 [18]Retrospective1360 (40-67)
ORR, 69%

Skin, 56% (5/9)

Eyes, 0% (0/4)

Liver, 0% (0/3)

Gut, 0% (0/2)

Lungs, 0% (0/2)

Oral mucosa, 50% (4/8)

Muscles, 75% (3/4)

NRInfectious complications, 28% (1/13)50mg/m2 (weekly intervals for 3 weeks) (3)∗National Institutes of Health consensus criteria†
Mohty et al., 2008 [21]Retrospective1550 (20-67)
ORR, 66%

Skin, 69%

Eyes, NR

Liver, 66%

Gut, 20%

Lungs, 0% (0/2)

Oral mucosa, NA

NRNegligible33% (5/15)375mg/m2 (weekly intervals for 4 weeks) (1)CR, PR. and organ-specific objective responses
Zaja et al., 2007 [24]Retrospective3848 (22-61)
ORR, 65%

Skin, 63%

Eyes, 43%

Liver, 25%

Gut, 75%

Lungs, 38%

Oral mucosa, 30%

Musculoskeletal, 80%


57.days

138.days

49.days

NR

60.days

46.days

78.days


Infusion reaction, 11%

Pneumonia, 8%

Renal failure, 3%

Central nervous system, 3%

Sepsis, 3%

21% (8/38)375mg/m2(weekly intervals for 4 weeks) (1)Differed by organ
Okamoto et al., 2006 [22]
Prospective

(noncontrolled)

335 (33-42)
ORR, NE

Skin, 100%

Eyes, 0% (0/3)

Liver, 0% (0/2)

Gut, NR

Lungs, 0% (0/1)

Oral mucosa, 0% (0/2)


60-90days


Pneumonia, 33%

Sepsis, 33%

Herpes zoster, 33%

33% (1/3)375mg/m2 (weekly intervals for 4 weeks) (1)Subjective; individual patient- based
Cutler et al., 2006 [20]
Prospective

(noncontrolled)

28‡42 (21-62)
ORR, 68%

Skin, (§/17)

Eyes, 0% (0/8)

Liver, NR (NR/1)

Gut, NA

Lungs, NA

Oral mucosa, 0% (0/7)


NR


Infant diarrhea, 14%

Viral conjunctivitis, 5%

Hepatitis B reactivation, 5%

Septic arthritis, 5%

GI hemorrhage, 5%

Nephrolithiasis, 5%

Infusion reaction, 5%

11% (3/28)375mg/m2 (weekly intervals for 4 weeks) (1)Differed by organ; aggregate responses for each organ provided
Canninga-Van Dijk, et al., 2004 [19]
Prospective

(noncontrolled)

636.5 (17-50)
ORR, 83%

Skin, 83 % (5/6)

Eyes, NA

Liver, 40% (2/5)

Gut, NA

Lungs, NA

Oral mucosa, 83% (5/6)

NRNR0%375mg/m2 (weekly intervals for 4 weeks) (1)Score-based reporting for each organ
Ratanatharathorn et al., 2003 [23]Retrospective case studies846 (28-58)
ORR, 50%

Skin, 13% (1/8)

Eyes, 13%(1/8)

Liver, 0% (0/1)

Gut, NR

Lungs, 33% (1/3)

Oral mucosa, NA

NRNR0%375mg/m2 (weekly intervals for 4 weeks) (1)OR and subjective organ-specific response

TTR indicates time to clinical response; NR, not reported; NE, not extractable; NA, not applicable; CR, complete response; PR, partial response; ORR, overall response rate.

∗In the von Bonin et al. study, once a week rituximab treatment, 1 cycle (communication with authors).

†Filipovich et al., 2005 [4]; Pavletic et al., 2006 [5].

‡The Cutler et al. [20] study enrolled 30 patients, but only 28 were evaluable.

§NE: Reporting is cumulative and not per patient.

Updated data on deaths and total patients obtained from the authors (Cutler et al., CS).

The response to rituximab appears to be less pronounced in other organs. Cases of steroid-refractory cGVHD of the oral mucosa showed ORRs ranging from 0 20, 22 to 83% [19]. Similarly, clinical responses to rituximab in cases of hepatic cGVHD ranged from 0 18, 22, 23 to 66% [21]. Note that these differing hepatic cGVHD response rates might be explained by intrinsic differences in the degree of severity of hepatic damage resulting from cGVHD before the initiation of rituximab, differing durations of therapy, or the use of different criteria to measure responses to treatment, among other factors. The time to achieve clinical response in hepatic cGVHD was 49 days in 1 study [24]. The responses to rituximab in patients with lung cGVHD were even less impressive, ranging from 0% 21, 22 to 38% 23, 24. It is unclear whether the limited efficacy of rituximab in organs other than skin is due to the treatment per se, or whether those organs are more susceptible to irreversible cGVHD-immune mediated damage. The underuse of more aggressive diagnostic tools to assess organ damage before initiation of treatment, coupled with the lack of more objective clinical tools to better quantitate clinical improvement in certain organs, limit clinicians' ability to assess the true efficacy of rituximab, or lack thereof, in those organs.

The bona fide corticosteroid-sparing effect of rituximab treatment in cGVHD resulted in a shortened duration, or sometimes even discontination, of corticosteroid treatment. It is possible that this effect ultimately may translate into improved quality of life for these patients. Quality of life assessment tools should be incorporated into prospective clinical trials to objectively address this issue.

There are several limitations to the evidence presented herein, including (1) the absence of randomized trials; (2) the inclusion of only 3 prospective studies that enrolled a very small number of patients (n=37), with none of the prospective studies clearly reporting either the design or phase of these prospective studies; (3) the poor methodological quality of the prospective studies (eg, none of these studies provided details on patient enrollment, limiting our ability to ascertain whether the study subjects were derived through convenient sampling or consecutive enrollment, to avoid selection bias); and (4) the lack of a homogeneous response criteria among studies, which limits the ability to assess responses as a composite or to compare responses among studies. In addition, the retrospective studies also were limited by the relatively small sample size, and none of the reports included in this systematic review indicated whether the analysis was intended to address an a priori hypothesis or to generate a hypothesis. Several questions remain unanswered: What is the relationship between response rates (and time to maximum response) and depletion of B cell levels in relation to the number of doses of rituximab administered? Is there an additional benefit to using higher doses of rituximab? Future clinical trials should evaluate response rates at different times in the course of cGVHD to provide a better understanding of the pathophysiologic evolution of cGVHD over time.

Limited understanding of the complex pathophysiology of GVHD remains the main barrier to development of universally effective prophylaxis against acute GVHD (aGVHD) and successful treatment of both aGVHD and cGVHD. Development of antibody responses, such as allogeneic H-Y, in association with cGVHD implicates B lymphocytes as important players in the pathogenesis of cGVHD [20]. B lymphocytes play an essential role in antigen presentation to T cells and allogeneic antibody induction, among other mechanisms [25]. Several studies already have incorporated rituximab into the conditioning regimen for patients with CD20+-expressing malignancies undergoing allo-HCT with encouraging results 26, 27. A BMT Clinical Trials Network is currently evaluating a multicenter phase II clinical trial (BMT CTN protocol 0701) that combines rituximab with fludarabine (Flu) plus cyclophosphamide (Cy) as a nonmyeloablative regimen for patients with relapsed follicular non-Hodgkin lymphoma (NHL).

Earlier intervention with anti B cell therapy could potentially reduce cGVHD-mediated irreversible organ damage. Investigators at Stanford University are currently evaluating a strategy of adding rituximab to prednisone as front-line therapy for newly diagnosed cGVHD, aiming to improve response while allowing more rapid tapering of corticosteroid dosage (ClinicalTrials.gov; identifier NCT00350545); similar studies are underway in Europe.

It is important to understand that the totality of the evidence generated through this systematic review demonstrates the gaps in the existing evidence base related to the efficacy of rituximab in treating patients with steroid-refractory cGVHD. This systematic review underscores the need for well-designed and adequately powered prospective studies to conclusively address this issue.

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Acknowledgements 

Financial disclosure: The authors have nothing to disclose.

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References 

  1. Karanes C, Nelson GO, Chitphakdithai P, et al. Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant. 2008;14:8–15
  2. MacMillan ML, Davies SM, Nelson GO, et al. Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biol Blood Marrow Transplant. 2008;14:16–22
  3. Stem Cell Trialists' Collaborative Group Allogeneic peripheral blood stem cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol. 2005;23:5074–5087
  4. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease, I: Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. 2005;11:945–956
  5. Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease, IV: Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006;12:252–266
  6. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215–233
  7. Couriel D, Hosing C, Saliba R, et al. Extracorporeal photopheresis for acute and chronic graft-versus-host disease: does it work?. Biol Blood Marrow Transplant. 2006;12:37–40
  8. Foss FM, DiVenuti GM, Chin K, et al. Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors. Bone Marrow Transplant. 2005;35:1187–1193
  9. Kim JG, Sohn SK, Kim DH, et al. Different efficacy of mycophenolate mofetil as salvage treatment for acute and chronic GVHD after allogeneic stem cell transplant. Eur J Haematol. 2004;73:56–61
  10. Takami A, Mochizuki K, Okumura H, et al. Mycophenolate mofetil is effective and well tolerated in the treatment of refractory acute and chronic graft-versus-host disease. Int J Hematol. 2006;83:80–85
  11. Giaccone L, Martin P, Carpenter P, et al. Safety and potential efficacy of low-dose methotrexate for treatment of chronic graft-versus-host disease. Bone Marrow Transplant. 2005;36:337–341
  12. Miklos DB, Kim HT, Miller KH, et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood. 2005;105:2973–2978
  13. Stuart A, Ord J. Kendall's Advanced Theory of Statistics. London: Edward Arnold; 1994;
  14. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188
  15. Higgins J, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions, version 5.0.0 [updated February 2008]. Available from: www.cochrane-handbook.org.
  16. Egger M, Smith DG, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634
  17. Peters JL, Sutton AJ, Jones DR, et al. Performance of the trim and fill method in the presence of publication bias and between-study heterogeneity. Stat Med. 2007;26:4544–4562
  18. von Bonin M, Oelschlagel U, Radke J, et al. Treatment of chronic steroid-refractory graft-versus-host disease with low-dose rituximab. Transplantation. 2008;86:875–879
  19. Canninga-van Dijk MR, van der Straaten HM, Fijnheer R, et al. Anti-CD20 monoclonal antibody treatment in 6 patients with therapy-refractory chronic graft-versus-host disease. Blood. 2004;104:2603–2606
  20. Cutler C, Miklos D, Kim HT, et al. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood. 2006;108:756–762
  21. Mohty M, Marchetti N, El-Cheikh J, et al. Rituximab as salvage therapy for refractory chronic GVHD. Bone Marrow Transplant. 2008;41:909–911
  22. Okamoto M, Okano A, Akamatsu S, et al. Rituximab is effective for steroid-refractory sclerodermatous chronic graft-versus-host disease. Leukemia. 2006;20:172–173
  23. Ratanatharathorn V, Ayash L, Reynolds C, et al. Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant. 2003;9:505–511
  24. Zaja F, Bacigalupo A, Patriarca F, et al. Treatment of refractory chronic GVHD with rituximab: a GITMO study. Bone Marrow Transplant. 2007;40:273–277
  25. Eisenberg R, Looney RJ. The therapeutic potential of anti-CD20: “what do B-cells do?”. Clin Immunol. 2005;117:207–213
  26. Kharfan-Dabaja MA, Tate C, Perkins J, et al. Rituximab is feasible to administer to allograft recipients with advanced CD20+ malignancies and does not affect timely hematopoietic engraftment. Biol Blood Marrow Transplant. 2008;14:121–122
  27. Khouri IF, McLaughlin P, Saliba RM, et al. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008;111:5530–5536

 Financial disclosure: See Acknowledgments on page 1012.

PII: S1083-8791(09)00187-6

doi:10.1016/j.bbmt.2009.04.003

Biology of Blood and Marrow Transplantation
Volume 15, Issue 9 , Pages 1005-1013, September 2009

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