`
`Evaluation of mycophenolate mofetil for initial treatment of chronic
`graft-versus-host disease
`Paul J. Martin,1,2 Barry E. Storer,1,3 Scott D. Rowley,4 Mary E. D. Flowers,1,2 Stephanie J. Lee,1,2 Paul A. Carpenter,1,5
`John R. Wingard,6 Paul J. Shaughnessy,7 Marcel P. DeVetten,8 Madan Jagasia,9 Joseph W. Fay,10 Koen van Besien,11
`Vikas Gupta,12 Carrie Kitko,13 Laura J. Johnston,14 Richard T. Maziarz,15 Mukta Arora,16 Pamala A. Jacobson,16 and
`Daniel Weisdorf16
`
`1Fred Hutchinson Cancer Research Center, Seattle, WA; Departments of 2Medicine and 3Biostatistics, University of Washington, Seattle; 4Hackensack
`University Medical Center, NJ; 5Department of Pediatrics, University of Washington, Seattle; 6University of Florida, Gainesville; 7Texas Transplant Institute,
`San Antonio; 8University of Nebraska, Omaha; 9Vanderbilt University, Nashville, TN; 10Baylor University Medical Center at Dallas, TX; 11University of Chicago, IL;
`12Princess Margaret Hospital, Toronto, ON; 13University of Michigan, Ann Arbor; 14Stanford University, CA; 15Oregon Health & Science University, Portland; and
`16University of Minnesota, Minneapolis
`
`We conducted a double-blind, random-
`ized multicenter trial to determine whether
`the addition of mycophenolate mofetil
`(MMF) improves the efficacy of initial sys-
`temic treatment of chronic graft-versus-
`host disease (GVHD). The primary end-
`point was resolution of chronic GVHD
`and withdrawal of all systemic treatment
`within 2 years, without secondary treat-
`ment. Enrollment of 230 patients was
`planned, providing 90% power to observe
`a 20% difference in success rates be-
`Introduction
`
`tween the 2 arms. The study was closed
`after 4 years because the interim esti-
`mated cumulative incidence of success
`for the primary endpoint was 23% among
`74 patients in the MMF arm and 18%
`among 77 patients in the control arm,
`indicating a low probability of positive
`results for the primary endpoint after com-
`pleting the study as originally planned.
`Analysis of secondary endpoints showed
`no evidence of benefit from adding MMF
`to the systemic regimen first used for
`
`treatment of chronic GVHD. The esti-
`mated hazard ratio of death was 1.99
`(95% confidence interval, 0.9-4.3) among
`patients in the MMF arm compared with
`the control arm. MMF should not be
`added to the initial systemic treatment
`regimen for chronic GVHD. This trial
`was registered at www.clinicaltrials.gov
`as #NCT00089141 on August 4, 2004.
`(Blood. 2009;113:5074-5082)
`
`Chronic graft-versus-host disease (GVHD) causes considerable
`morbidity and mortality after allogeneic hematopoietic cell trans-
`plantation (HCT).1 High-dose glucocorticoids and continued admin-
`istration of a calcineurin inhibitor have long served as the mainstay
`of treatment for chronic GVHD.2 In most patients, systemic
`treatment must be continued for at least 2 years.3 Long-term
`glucocorticoid treatment causes numerous complications, includ-
`ing infections, myopathy, avascular necrosis, osteoporosis, glucose
`intolerance, hypertension, growth retardation in children, weight
`gain, changes in body habitus, cutaneous atrophy and striae,
`cataracts, emotional lability, and interference with sleep.4 Develop-
`ment of less toxic treatments that could reduce the dose or duration
`of glucocorticoid administration or improve disease control would
`be of enormous benefit for patients with chronic GVHD.
`Mycophenolate mofetil (MMF) is the 2-(4-morpholino) ethyl
`ester of mycophenolic acid (MPA).5 After oral administration,
`MMF is rapidly absorbed and hydrolyzed to MPA, which selec-
`tively and reversibly inhibits inosine monophosphate dehydroge-
`nase, thereby blocking the de novo pathway of purine synthesis in
`lymphocytes and depleting the intracellular pool of guanosine
`triphosphate. Case-series reports and phase 2 studies have sug-
`gested that MMF might be effective for treatment of steroid-
`refractory chronic GVHD both in adults and in children.6-15 In
`
`2 large surveys, respondents endorsed MMF more frequently than
`other agents for treatment of high-risk or steroid-refractory chronic
`GVHD.16,17
`These results suggested that outcomes among patients with
`chronic GVHD might be improved by adding MMF to the initial
`systemic treatment regimen. The principal objective of the current
`clinical trial was to determine whether the addition of MMF
`improves the efficacy of initial systemic treatment for chronic
`GVHD. In addition to increasing the response rate and allowing
`earlier discontinuation of immunosuppressive therapy, more effec-
`tive primary treatment for chronic GVHD would be expected to
`decrease the incidence of complications related to glucocorticoid
`treatment, reduce the probability of secondary therapy, and de-
`crease the risk of death from causes other than recurrent malignancy.
`
`Methods
`
`Eligibility and enrollment
`
`Patients were enrolled within 14 days after beginning systemic immunosup-
`pressive treatment for chronic GVHD with at least one symptom or sign that
`is not characteristic of acute GVHD.1 Exclusion criteria included uncon-
`trolled fungal, cytomegalovirus, or varicella zoster virus infection; inability
`
`Submitted February 1, 2009; accepted February 28, 2009. Prepublished online
`as Blood First Edition paper, March 6, 2009; DOI 10.1182/blood-2009-
`02-202937.
`
`The publication costs of this article were defrayed in part by page charge
`payment. Therefore, and solely to indicate this fact, this article is hereby
`marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
`
`The online version of this article contains a data supplement.
`
`© 2009 by The American Society of Hematology
`
`5074
`
`BLOOD, 21 MAY 2009 䡠 VOLUME 113, NUMBER 21
`
`
`
`BLOOD, 21 MAY 2009 䡠 VOLUME 113, NUMBER 21
`
`MMF FOR INITIAL TREATMENT OF CHRONIC GVHD
`
`5075
`
`Figure 1. Flow diagram summarizing results of the random-
`ization, administration of the study drug, and analysis of
`results at the end of the study.
`
`I
`Randomization
`
`I
`
`~ ~
`
`Allocated to MMF (n = 77)
`Received allocated intervention (n = 74)
`Did not receive allocated intervention (n = 3)
`Reasons: concern about relapse
`
`too many pills
`
`non-compliance
`
`
`
`Allocated to placebo (n = 80)
`Received allocated intervention (n = 77)
`Did not receive allocated intervention (n = 3)
`Reasons: concern about thrombocytopenia
`
`patient felt overwhelmed
`
`new medical condition
`
`l
`
`Continued intervention (n = 61)
`Discontinued intervention (n = 13)
`Reasons: adverse events (n = 3)
`
`burden of participation (n = 3)
`
`concern about side effects (n = 2)
`
`treatment considered excessive (n = 1)
`
`new medical condition (n = 1)
`
`insurance limitations (n = 1)
`
`noncompliance (n = 2)
`
`l
`
`Continued intervention (n = 64)
`Discontinued intervention (n = 13)
`Reasons: adverse events (n = 4)
`
`burden of participation (n = 1)
`
`concern about side effects (n = 5)
`
`treatment considered excessive (n = 1)
`
`new medical condition (n = 1)
`
`incarceration (n = 1)
`
`l
`
`Analyzed (n = 74)
`Primary endpoint reached (n = 56)
`Primary endpoint pending at study closure (n = 18)
`
`l
`
`Analyzed (n = 77)
`Primary endpoint reached (n = 53)
`Primary endpoint pending at study closure (n = 24)
`
`to tolerate oral administration of medications; known hypersensitivity to
`MMF; melena, frank gastrointestinal hemorrhage, or ulceration; absolute
`neutrophil count less than 1500/L; administration of immunosuppressive
`medications other than steroids, cyclosporine, tacrolimus, or sirolimus;
`onset of chronic GVHD during treatment with more than 1.0 mg/kg per day
`prednisone or equivalent; any prior systemic immunosuppressive treatment
`for chronic GVHD; bronchiolitis obliterans as a manifestation of chronic
`GVHD; any evidence at the time of enrollment indicating a high probability
`of subsequent recurrent or progressive malignancy; pregnancy or breastfeed-
`ing; or hospitalization for reasons other than rehabilitation at the time of
`enrollment. Women of childbearing potential were required to use effective
`contraception during administration of the study drug. Informed consent
`was documented with the use of forms approved by the Institutional Review
`Board of the Fred Hutchinson Cancer Research Center and the respective
`participating transplantation centers, in accordance with the Declaration
`of Helsinki.
`From May 6, 2004 to June 11, 2008, 157 patients from 15 transplanta-
`tion centers enrolled in the study. Six patients (3 in the MMF arm and 3 in
`the placebo arm) withdrew after randomization but before taking any study
`drug (Figure 1). Follow-up information could not be obtained for these
`patients. Results are reported for the remaining 151 patients.
`
`Treatment plan
`
`Patients continued treatment with a calcineurin inhibitor or sirolimus,
`according to the regimen administered when the diagnosis of chronic
`GVHD was made. Most patients were also treated with prednisone, initially
`at a dose of 1.0 mg/kg per day, at the discretion of the physician. The study
`drug was provided by Roche Laboratories (Nutley, NJ) and was dispensed
`under investigator-initiated US IND 64390 and Canadian CTA 115111.
`Participants were given capsules containing either MMF or placebo
`according to randomization by an independent registrar. Identity of the
`study drug was not disclosed to participants, physicians, or study staff until
`after the study was closed.
`In kidney transplantation recipients, concurrent treatment with cyclospor-
`ine decreases the area under the curve (AUC) of plasma MPA concentra-
`tions across time between doses of MMF.18-22 This effect is proportional to
`the concentration of cyclosporine in the blood23 and does not occur with
`tacrolimus21 or sirolimus.24 The MPA AUC after a 750-mg dose of MMF in
`the absence of cyclosporine approximates the MPA AUC after a 1000-mg
`dose of MMF in the presence of cyclosporine at therapeutic concentrations
`in the blood.20,21 Because similar drug interactions were expected in
`patients with chronic GVHD, the study drug was administered at 1000 mg
`orally twice daily among patients with trough cyclosporine concentrations
`
`more than or equal to 100 ng/mL in the blood, and at 750 mg orally twice
`daily for all other patients. Doses were reduced or withheld temporarily in
`patients who had neutropenia or gastrointestinal side effects.
`Topical therapy, including glucocorticoid creams, topical tacrolimus,
`oral beclomethasone, topical azathioprine, and ophthalmic glucocorticoids,
`and other supportive measures were managed at the discretion of the
`physician.25,26 Medications to prevent Pneumocystis pneumonia and infec-
`tion with cytomegalovirus, herpes simplex virus, varicella zoster virus,
`encapsulated bacteria, and fungal organisms were administered according
`to institutional practice.26
`Decisions regarding the administration of immunosuppressive medica-
`tions were made by the treating physician. The protocol provided guidelines
`for tapering the doses of immunosuppressive medications, together with
`recommendations for order in which immunosuppressive medications
`should be withdrawn. The recommended sequence was withdrawal of
`prednisone, followed by withdrawal of the calcineurin inhibitor or siroli-
`mus, followed by withdrawal of the study drug, as allowed by resolution of
`chronic GVHD.
`
`Plasma trough concentrations of MPA
`
`Consenting patients had a blood sample drawn to measure the trough
`concentrations of MPA in the plasma. Testing was done at 3 months after
`enrollment because the MPA AUC increases during the first 3 months after
`beginning treatment with MMF.27-29 Total MPA and free MPA (ie, not bound
`to protein) concentrations were measured in the laboratory of Dr Pamala
`Jacobson at the University of Minnesota, using methods described previ-
`ously.30 Free MPA has biologic activity, whereas protein-bound MPA does
`not. Unblinded results were not disclosed until after the study was closed.
`
`Definition of endpoints
`
`Treatment success was defined as withdrawal of all systemic treatment,
`including the study drug, after resolution of all reversible manifestations of
`chronic GVHD with no secondary systemic therapy. Ocular and oral sicca
`and joint contractures, and any sequelae of scleroderma present at the onset
`of systemic treatment were not considered to be reversible for purposes of
`defining treatment success. Discontinuation of immunosuppressive medica-
`tions for the purpose of improving donor chimerism after HCT with
`nonmyeloablative conditioning or for inducing an antitumor response after
`the development of recurrent or secondary malignancy was not considered
`as treatment success.
`Treatment failure was defined as the initiation of secondary systemic
`therapy or as development of bronchiolitis obliterans, recurrent malignancy,
`
`
`
`5076
`
`MARTIN et al
`
`BLOOD, 21 MAY 2009 䡠 VOLUME 113, NUMBER 21
`
`or death from causes other than recurrent malignancy during primary
`treatment for chronic GVHD, each indicating that treatment success did not
`occur or could not be attained. Discontinuation of treatment with study drug
`because of toxicity was not considered as treatment failure.
`Secondary systemic therapy included any intervention intended to
`control chronic GVHD through any systemic treatment
`that was not
`included in the primary treatment regimen. Administration of systemic
`glucocorticoids to patients who were not treated initially with glucocorti-
`coids was considered as secondary systemic therapy. Topical therapy was
`not considered as secondary systemic therapy. An increase in the dose of
`prednisone and any resumption of treatment with prednisone or study drug
`after previous discontinuation for any reason was not considered as
`secondary systemic therapy. Any increase in the dose of cyclosporine or
`tacrolimus or resumption of treatment with cyclosporine or tacrolimus after
`previous discontinuation for any reason was not considered as secondary
`systemic treatment if the drug in question was included as part of the
`primary treatment regimen. A change in treatment from cyclosporine to
`tacrolimus or vice versa resulting from drug toxicity was not considered as
`secondary treatment, but any such change made because of uncontrolled
`chronic GVHD was considered as secondary treatment.
`Recurrent malignancy was defined as clinical or histopathologic
`evidence demonstrating the reappearance or progression of any malignancy
`considered as an indication for the transplantation. Recurrent malignancy
`was also defined as any posttransplantation intervention not routinely used
`to prevent the development of overt recurrence, prompted by any evidence
`of persisting malignant cells.
`
`Stratification and statistical analysis
`
`Randomization was stratified according to involvement of a single organ
`versus multiple organs and by the use of a myeloablative or nonmyeloabla-
`tive pretransplantation conditioning regimen. Randomization was also
`stratified by transplantation center for purposes of ensuring balance
`between the arms but not for analysis.
`Based on historical experience of patients comparable with those who
`were eligible for this study, the 2-year success rate for the placebo arm was
`expected to be approximately 22%. The study was designed to test whether
`treatment with MMF could increase the success rate from 22% to 42%. The
`original plan was to enroll a total of 230 patients assigned to the MMF and
`placebo arms at a 1:1 ratio to have 90% power to observe a statistically
`significant difference with a 2-sided type 1 error of 0.05. The primary
`endpoint was to have been analyzed as a binomial outcome by comparing
`the proportion of treatment successes at 2 years between arms, according to
`randomized assignment, using a 2 test. Because the study was stopped
`before this endpoint could be determined in all patients, the current analysis
`is based on the estimated cumulative incidence at 2 years.31 Stratified Cox
`regression was used for hazard ratio analysis, with P values based on
`associated likelihood ratio statistics. All P values are 2-sided. Adverse event
`data were analyzed as the proportion of patients in each arm who developed
`a given complication during administration of the study drug or within
`30 days after discontinuation, using 2 tests and Fisher exact tests, as
`appropriate.
`
`Data and safety monitoring
`
`A data and safety monitoring board (DSMB) reviewed interim study
`progress and safety data at 3-month intervals according to a written charter.
`No interim analyses of efficacy were planned when the study was designed.
`Follow-up for up to 2 years was required to ascertain the primary endpoint,
`and it was anticipated that enrollment could be completed within 2 years.
`The DSMB reviewed the interim efficacy results after 151 patients had been
`enrolled during a period of 4 years, when it became apparent that the
`rationale for not reviewing interim efficacy results was no longer valid. On
`June 11, 2008, the DSMB recommended closure of the study because the
`estimated conditional probability of positive results after enrollment of all
`230 patients was 0.27 under the most optimistic assumptions.
`
`Table 1. Patient and transplantation characteristics
`MMF (n ⴝ 74)
`Characteristic, n (%)
`
`Placebo (n ⴝ 77)
`
`42 (55)
`40 (52)
`
`52 (68)
`25 (32)
`15 (19)
`26 (34)
`
`63 (82)
`10 (13)
`4 (5)
`
`41 (53)
`25 (32)
`11 (14)
`
`Age 50 y or older
`Male patient
`Risk of recurrent malignancy*
`Low
`High
`Female donor for male patient
`Nonmyeloablative conditioning
`Source of stem cells
`Mobilized blood
`Marrow
`Cord blood
`Donor
`HLA-matched relative
`HLA-matched unrelated donor
`HLA-mismatched unrelated donor
`
`40 (54)
`41 (55)
`
`50 (68)
`24 (32)
`18 (24)
`21 (28)
`
`64 (86)
`6 (8)
`4 (5)
`
`36 (49)
`23 (31)
`15 (20)
`
`*Table S1 contains definitions of risk categories.
`
`Results
`
`Patient characteristics
`
`Demographic and transplantation characteristics were well bal-
`anced between the 2 arms (Table 1). GVHD-associated risk
`factors,1 including patient age, use of female donors for male
`patients, use of mobilized blood cells, donor-recipient relationship,
`and human leukocyte antigen matching, showed no differences that
`would be expected to bias outcomes of the study. The disease
`categories associated with risk of recurrent malignancy32 and the
`proportions of patients who had nonmyeloablative conditioning
`regimens were well balanced between the 2 arms (Table 1 and
`Table S1, available on the Blood website; see the Supplemental
`Materials link at the top of the online article). GVHD characteris-
`tics at baseline (Table 2)33 were also well balanced between the
`2 arms. Other risk factors potentially associated with prolonged
`duration of immunosuppression or increased risk of nonrelapse
`mortality,1,3 including progressive onset from acute GVHD, mul-
`tiple sites involved with chronic GVHD, and hyperbilirubinemia or
`thrombocytopenia at the onset of chronic GVHD, showed no
`differences that would be expected to bias outcomes of the study.
`
`Study drug administration and trough plasma concentrations
`of MPA
`
`Ten patients (14%) in the MMF arm and 9 (12%) in the control arm
`stopped taking the study drug earlier than prescribed by the
`protocol for reasons other than adverse events, as summarized in
`Figure 1. The median interval from registration in the study to
`premature discontinuation of study drug administration was
`4.6 months (range, 0.3-19 months) among patients in the MMF
`arm, compared with 4.0 months (range, 0.9-16 months) in the
`control arm. Follow-up information was obtained for all but one of
`the patients who stopped taking the study drug prematurely.
`Follow-up information could not be obtained in one case because
`the patient was incarcerated. Based on counts of study drug
`capsules, patients in the MMF arm took a median 98% (90% range,
`82.0%-100%) of the prescribed amount of study drug, compared
`with 95.7% (90% range, 74.7%-100%) in the control arm.
`Six patients taking MMF at 1000 mg twice daily and 35 patients
`taking MMF at 750 mg twice daily had plasma samples drawn
`3 months after enrolling in the study. One patient in each group had
`no MPA detectable in the sample. The median total MPA trough
`
`
`
`BLOOD, 21 MAY 2009 䡠 VOLUME 113, NUMBER 21
`
`MMF FOR INITIAL TREATMENT OF CHRONIC GVHD
`
`5077
`
`Table 2. GVHD characteristics at baseline
`MMF (n ⴝ 74)
`Characteristic
`
`Placebo (n ⴝ 77)
`
`Table 3. Outcomes of primary therapy
`Outcome
`
`MMF (n ⴝ 74)
`
`Placebo (n ⴝ 77)
`
`29 (39)
`38 (51)
`7 (9)
`
`11 (15)
`48 (65)
`15 (20)
`0 (0)
`17 (23)
`4 (5)
`
`24 (32)
`10 (14)
`25 (34)
`15 (20)
`
`Onset type, n (%)
`De novo
`Quiescent
`Progressive
`Karnofsky score, n (%)
`100
`80-90
`60-70
`⬍ 60
`Platelet count ⬍ 100 000/L, n (%)
`Bilirubin ⬎ 2 mg/dL, n (%)
`Skin severity, n (%)*
`None
`Mild
`Moderate
`Severe
`Mouth, n (%)
`None
`Mild
`Moderate
`Severe
`Eyes, n (%)
`None
`Mild
`Moderate
`Severe
`Gastrointestinal tract, n (%)
`None
`Mild
`Moderate
`Severe
`Liver, n (%)
`None
`Mild
`Moderate
`Severe
`Joints/fascia, n (%)
`None
`Mild
`Moderate
`Severe
`Female genital tract, n (%)†
`None
`Mild
`Moderate
`Severe
`Eosinophilia, n (%)
`Myositis, n (%)
`Esophageal stricture, n (%)
`No. of involved sites, n (%)
`4 (5)
`1
`18 (24)
`2
`16 (22)
`3
`20 (27)
`4
`16 (22)
`5-7
`Overall severity according to NIH algorithm, n (%)*
`Mild
`7 (9)
`Moderate
`60 (81)
`Severe
`7 (9)
`Initial treatment of chronic GVHD, n (%)
`Prednisone
`Cyclosporine
`Tacrolimus
`Sirolimus
`
`8 (11)
`56 (76)
`9 (12)
`1 (1)
`
`40 (54)
`17 (23)
`17 (23)
`0 (0)
`
`46 (62)
`23 (31)
`0 (0)
`5 (7)
`
`39 (53)
`22 (30)
`10 (14)
`3 (4)
`
`62 (84)
`7 (9)
`5 (7)
`0 (0)
`
`27 (82)
`2 (6)
`4 (12)
`0 (0)
`18 (24)
`2 (3)
`1 (1)
`
`70 (95)
`22 (30)
`39 (53)
`1 (1)
`
`30 (39)
`38 (49)
`9 (12)
`
`16 (21)
`44 (57)
`14 (18)
`3 (4)
`17 (22)
`5 (6)
`
`11 (14)
`28 (36)
`25 (32)
`13 (17)
`
`20 (26)
`49 (64)
`7 (9)
`1 (1)
`
`41 (53)
`22 (29)
`14 (18)
`0 (0)
`
`49 (64)
`25 (32)
`2 (3)
`1 (1)
`
`34 (44)
`27 (35)
`15 (19)
`1 (1)
`
`64 (83)
`13 (17)
`0 (0)
`0 (0)
`
`29 (78)
`7 (19)
`1 (3)
`0 (0)
`17 (22)
`4 (5)
`0 (0)
`
`5 (6)
`15 (19)
`19 (25)
`19 (25)
`19 (25)
`
`9 (12)
`65 (84)
`3 (4)
`
`73 (95)
`23 (30)
`39 (51)
`1 (1)
`
`Treatment success within 2 y, n (%)
`Treatment success after 2 y, n (%)
`Treatment failure, n (%)
`Secondary systemic therapy, n (%)
`Development of bronchiolitis obliterans,
`n (%)
`Recurrent malignancy, n (%)*
`Death, n (%)*
`Continuing primary therapy for ⬎ 2 y,
`n (%)†
`Continuing primary therapy for ⬍ 2 y,
`(%)†
`
`11 (15)
`0 (0)
`43 (58)
`24 (32)
`
`5 (7)
`13 (18)
`1 (1)
`
`2 (3)
`
`18 (24)
`
`10 (13)
`3 (4)
`38 (49)
`25 (32)
`
`4 (5)
`8 (10)
`1 (1)
`
`2 (3)
`
`24 (31)
`
`*Events occurring after the end of primary therapy are not included.
`†At the time of study closure.
`
`concentration was 2.18 g/mL (range, 0.79-4.11 g/mL) among
`the 5 remaining patients taking MMF at 1000 mg twice daily, compared
`with 1.12 g/mL (range, 0.08-10.1 g/mL) among the 34 remaining
`patients taking MMF at 750 mg twice daily (P ⫽ .09, Wilcoxon
`rank-sum test). The median free MPA trough concentration was
`31.2 g/mL (range, 16.1-73.9 ng/mL) among patients taking MMF
`at 1000 mg twice daily, compared with 14.3 g/mL (range,
`0-249 ng/mL) among those taking MMF at 750 mg twice daily
`(P ⫽ .02, Wilcoxon rank-sum test). Two of the 34 patients taking
`MMF at 750 mg twice daily had MPA detectable in whole plasma
`but not in the protein-free fraction.
`
`Outcomes related to treatment of chronic GVHD
`
`In the MMF arm, 11 of the 74 patients (15%) had treatment
`success, compared with 13 of the 77 patients (17%) in the control
`arm (Table 3), although 3 of the successes in the control arm
`occurred after the 2-year limit used to define the primary endpoint.
`The estimated cumulative incidence of treatment success at 2 years
`was 22.6% in the MMF arm, compared with 18.3% in the control
`arm. The estimated difference in the cumulative incidence of
`
`100
`
`80
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`""---------
`-_, ------
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`Months from Randomization
`Figure 2. Cumulative incidence of treatment success and treatment failure. The
`lower black curves and left scale represent the cumulative incidence of discontinued
`systemic treatment for chronic GVHD without secondary therapy for chronic GVHD,
`development of bronchiolitis obliterans, recurrent malignancy during primary treat-
`ment for chronic GVHD, or death during primary treatment for chronic GVHD; upper
`gray curves and right scale, cumulative incidence of treatment failure, including
`secondary therapy for chronic GVHD, development of bronchiolitis obliterans,
`recurrent malignancy during primary treatment for chronic GVHD, or death during
`primary treatment for chronic GVHD. The gap between the lower and upper curves
`indicates the proportion of patients continuing primary treatment for chronic GVHD
`without recurrent malignancy or development of bronchiolitis obliterans. Vertical line
`at 2 years represents the prespecified interval time designated for assessment of the
`primary endpoint; —, MMF group; and 哹, control group.
`
`*Severity scores for individual organs are based on degree of disability, and
`overall severity of chronic GVHD is based on number of affected organs and the
`highest severity score for any individual organ, as described by Filipovich et al.32
`†Percentages based on the number of women in the study.
`
`
`
`5078
`
`MARTIN et al
`
`Table 4. GVHD-related outcomes
`
`BLOOD, 21 MAY 2009 䡠 VOLUME 113, NUMBER 21
`
`Endpoint
`
`No. of events
`
`Treatment success
`Treatment failure
`Secondary systemic treatment†
`Bronchiolitis obliterans†
`Withdrawal of prednisone†
`End of systemic treatment†
`
`11
`43
`24
`5
`30
`15
`
`MMF
`
`Placebo
`
`Cumulative incidence
`at 2 y
`
`No. of events
`
`Cumulative incidence
`at 2 y
`
`0.23
`0.70
`0.38
`0.09
`0.44
`0.23
`
`13
`38
`25
`4
`33
`15
`
`0.18
`0.64
`0.44
`0.07
`0.41
`0.18
`
`HR (95% CI)*
`
`1.66 (0.7-3.7)
`1.65 (1.1-2.6)
`1.19 (0.7-2.1)
`1.61 (0.4-6.0)
`1.28 (0.8-2.1)
`1.51 (0.7-3.2)
`
`P
`
`.22
`.03
`.55
`.48
`.34
`.28
`
`*Hazard ratio for MMF arm relative to placebo arm; stratified on the number of sites affected by chronic GVHD at onset (1 vs ⬎ 1) and the type of conditioning regimen
`(myeloablative vs nonmyeloablative).
`†Competing risks are limited to recurrent malignancy and death.
`
`success between the 2 arms was 4.3% (95% confidence interval
`[CI], ⫺11.4%-20.0%) in favor of the MMF arm, clearly failing to
`reject the null hypothesis and inconsistent with the alternative
`hypothesis. When the study was closed, 20 patients (27%) in the
`MMF arm were continuing primary therapy, compared with 26 (34%)
`in the control arm. In the MMF arm, 43 patients (58%) had
`treatment failure, compared with 38 (49%) in the control arm.
`Recurrent malignancy accounted for most of the difference in
`treatment failures between the 2 arms.
`As shown in Figure 2, the cumulative incidence of treatment
`failure appeared to be higher in the MMF arm than in the
`placebo arm, with little apparent difference in the cumulative
`incidence of treatment success between the 2 arms. A hazard
`ratio analysis suggests that a possibly higher underlying rate of
`treatment success in the MMF arm was negated by an increased
`rate of treatment failure (Table 4). The hazards of secondary
`systemic treatment, development of bronchiolitis obliterans,
`withdrawal of prednisone, and withdrawal of all systemic
`treatment after resolution of GVHD showed no statistically
`significant differences between the 2 arms. Further analysis
`showed that prednisone doses and the prevalence of complete
`response were similar across time in the 2 arms (Figure 3).
`
`Adverse events
`
`Three of the 74 patients (4%) in the MMF arm stopped taking the
`study drug permanently because of side effects: one resulting from
`gastrointestinal intolerance, one resulting from recurrent neutrope-
`nia, and one resulting from tinnitus and muscle cramping (Table 5).
`Four of the 77 patients (5%) in the control arm stopped taking the
`study drug because of side effects: one resulting from pruritis and
`urticaria and 3 resulting from recurrent neutropenia.
`The proportion of patients who had infection associated with
`administration of the study drug was lower among patients in the
`MMF arm than in the control arm (P ⫽ .05), but the proportion of
`patients given antibiotics for empiric treatment of documented
`infection was possibly higher among patients in the MMF arm than
`in the control arm (Table 5). Among patients in the MMF arm, the
`median number of infections per quarterly observation interval was
`0.38 (range, 0-2.5), compared with 0.38 (range, 0-2.25) in the
`control arm (P ⫽ .81, Wilcoxon rank-sum test).
`Results showed no statistically significant differences in the
`proportions of patients who developed neutropenia in the 2 arms.
`The proportion of all patients with thrombocytopenia (platelet
`count ⬍ 100 000/L) was possibly higher in the MMF arm than in
`the control arm. Among 58 patients with a platelet count more than
`100 000/L at enrollment in the MMF arm, 17 (29%) developed
`thrombocytopenia during administration of the study drug. Among
`61 patients with a platelet count more than 100 000/L at
`
`enrollment in the placebo arm, 7 (11%) developed thrombocytope-
`nia during administration of the study drug (P ⫽ .015).
`Results showed no statistically significant difference in the
`numbers of patients with diabetes between the 2 arms. No
`
`A
`
`to
`
`a,~ 0.8
`
`s! 0.7
`1~ 0.6
`.. ~ 0.5
`u5t
`c! 0.4
`~ ill 0.3
`::.~
`.§. 0.2
`
`0.1
`
`0.0
`
`0
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`Months from Randomization
`
`B 3.0
`2.8
`I!
`0 2.6
`!I,
`2.4
`.. >
`-€
`2.2
`3,
`:i: z
`.. ::.
`1.6
`" 1.4
`1.2
`1.0
`
`C:
`
`0
`
`6
`
`24
`18
`12
`Months from Randomization
`
`30
`
`36
`
`C 100 ~-.,.,I
`-. ____ _ ., _________ _
`-- ---.. ,_ ----------
`
`80
`
`60
`
`40
`
`20
`
`01;===---,-----..-----.-----,------,------,J
`36
`24
`30
`0
`6
`12
`18
`Months from Randomization
`Figure 3. Mean steroid doses, mean GVHD severity scores, and percentages of
`patients with complete response after randomization show no benefit of MMF
`for initial treatment of chronic GVHD. (A) Prednisone doses. (B) Mean National
`Institutes of Health severity scores and (C) prevalence of complete response (CR)
`across time among surviving patients without recurrent malignancy. (A,B) Bars
`represent ⫾ SD. (C) The upper black curves represent relapse-free survival for
`reference. Changes in prevalence of CR (gray lines) can occur either with the onset
`or end of CR or with death or recurrent malignancy in the presence or absence of CR.
`In all panels: —, MMF group; and 哹, control group.
`
`
`
`BLOOD, 21 MAY 2009 䡠 VOLUME 113, NUMBER 21
`
`MMF FOR INITIAL TREATMENT OF CHRONIC GVHD
`
`5079
`
`Table 5. Adverse events during administration of study drug
`Event, n (%)
`
`MMF (n ⴝ 74)
`
`Placebo (n ⴝ 77)
`
`Permanent withdrawal of study drug because of toxicity
`Temporary withdrawal of study drug
`Any infection
`Any bacterial infection
`Any viral infection
`Any fungal infection
`Pneumonia
`Conjunctivitis
`Empiric antibiotic treatment
`Hospitalization for treatment of infection
`Neutropenia episode
`Thrombocytopenia
`New skin cancer
`Other new malignancy
`Avascular necrosis
`Diabetes mellitus
`Osteoporosis
`Thyroid disease
`
`3 (4)
`23 (31)
`55 (74)
`18 (24)
`27 (36)
`18 (24)
`17 (23)
`4 (5)
`23 (31)
`20 (27)
`13 (18)
`32 (43)
`6 (8)
`0 (0)
`4 (5)
`17 (23)
`14 (19)
`8 (11)
`
`4 (5)
`22 (29)
`67 (87)
`16 (21)
`27 (35)
`24 (31)
`10 (13)
`11 (14)
`14 (18)
`16 (21)
`12 (16)
`23 (30)
`9 (12)
`3 (4)
`3 (4)
`15 (19)
`13 (17)
`16 (21)
`
`P
`
`.99
`.73
`.05
`.60
`.86
`.35
`.11
`.07
`.06
`.37
`.74
`.09
`.46
`.25
`.72
`.60
`.74
`.09
`
`Includes events occurring within 30 days after administration of study drug was discontinued.
`
`statistically significant differences were observed in the propor-
`tions of patients with avascular necrosis or osteoporosis between
`the 2 arms. Six patients (8%) in the MMF arm and 9 (12%) in the
`control arm developed skin cancer after enrollment in the study. In
`addition, 3 patients in the control arm developed other secondary
`malignancies (one adenocarcinoma of the lung, one renal cell
`carcinoma, and one prostate cancer).
`
`Survival, nonrelapse mortality, recurrent malignancy, and
`survival without recurrent malignancy
`
`At closure of the study, 19 of 74 patients (26%) in the MMF arm
`had died, compared with 10 of 77 (13%) in the control arm.
`Infections and recurrent malignancy appear to account for most of
`the excess deaths in the MMF arm (Table 6). The estimated hazard
`ratio of death was 1.99 (95% CI, 0.9-4.3) among patients in the
`MMF arm compared with the control arm (P ⫽ .10; Figure 4). The
`estimated hazard ratio of death without recurrent malignancy was
`1.62 (95% CI, 0.5-5.0, P ⫽ .41). The estimated hazard ratio of
`recurrent malignancy was 1.72 (95% CI, 0.8-3.8, P ⫽ .18), and
`with adjustment for risk category, the hazard ratio was 1.74 (95%
`CI, 0.8-3.9, P ⫽ .17). With adjustment for risk category,
`the
`estimated hazard ratios of recurrent malignancy were 2.48 (95%
`CI, 0.9-7.0, P ⫽ .09) for patients taking MMF at 1000 mg twice
`daily compared with placebo, 1.49 (95% CI, 0.6-3.6, P ⫽ .38) for
`patients taking MMF at 750 mg twice daily compared with
`placebo, and 1.67 (95% CI, 0.6-4.7, P ⫽ .33) for patients taking
`MMF a