TRANSPLANTATION
`
`A phase 2/3 multicenter randomized clinical trial of ABX-CBL versus ATG as
`secondary therapy for steroid-resistant acute graft-versus-host disease
`Margaret L. MacMillan,1 Daniel Couriel,2 Daniel J. Weisdorf,1 Gisela Schwab,3 Nancy Havrilla,3 Thomas R. Fleming,4
`Saling Huang,3 Lorin Roskos,3 Shimon Slavin,5 Richard K. Shadduck,6 John DiPersio,7 Mary Territo,8 Steve Pavletic,9
`Charles Linker,10 Helen E. Heslop,11 H. Joachim Deeg,12 and Bruce R. Blazar1
`
`1Blood and Marrow Transplant Program, University of Minnesota, Minneapolis; 2M. D. Anderson Cancer Center, Houston, TX; 3Abgenix, Fremont, CA;
`4University of Washington, Seattle; 5Hadassah Hebrew University Hospital, Jerusalem, Israel; 6Western Pennsylvania Hospital, Pittsburgh; 7Washington
`University School of Medicine, St Louis, MO; 8University of California, Los Angeles (UCLA) Medical Center; 9University of Nebraska Medical Center, Omaha;
`10University of California, San Francisco (UCSF) Stanford Healthcare; 11Baylor College of Medicine, Houston, TX; 12Fred Hutchinson Cancer Research Center,
`Seattle, WA
`
`Treatment for steroid-resistant acute graft-
`versus-host disease (GVHD) has had lim-
`ited success. ABX-CBL is a hybridoma-
`generated murine
`IgM monoclonal
`antibody against
`the CD147 antigen,
`weakly expressed on human leukocytes
`and up-regulated on activated lympho-
`cytes. A prospective, multicenter, open-
`label, randomized clinical trial comparing
`ABX-CBL to antithymocyte globulin (ATG)
`for treatment of steroid-resistant acute
`GVHD was conducted in 95 patients at 21
`Introduction
`
`centers. Forty-eight patients received
`ABX-CBL daily for 14 consecutive days
`followed by up to 6 weeks of ABX-CBL
`twice weekly. Forty-seven patients re-
`ceived equine ATG, 30 mg/kg every other
`day for a total of 6 doses with additional
`courses as needed. By day 180, overall
`improvement was similar in the patients
`receiving ABX-CBL and in those receiv-
`ing ATG (56% versus 57%, P ⴝ .91). Pa-
`tient survival at 18 months was less favor-
`able on ABX-CBL than on ATG (35%
`
`versus 45%), with the 95% confidence
`interval ruling out that ABX-CBL provides
`at least a 10.4% improvement. Data from
`this trial suggest that ABX-CBL does not
`offer an improvement over ATG in the
`treatment of acute steroid-resistant GVHD.
`This prospective, multicenter, randomized
`clinical trial for steroid-resistant acute GVHD
`serves as a model for future evaluation of
`new agents. (Blood. 2007;109:2657-2662)
`
`© 2007 by The American Society of Hematology
`
`Acute graft-versus-host disease (GVHD) remains a major cause of
`morbidity and mortality after allogeneic hematopoietic cell trans-
`plantation (HCT). Moderate to severe GVHD grades II to IV occurs
`in up to 30% to 50% of matched related donor recipients1,2 and 50%
`to 70% of unrelated donor recipients.3,4 Despite many advances in
`the past decade in the management of complications related to
`HCT, treatment of acute GVHD remains suboptimal.4,5 Corticoste-
`roids are the standard front-line therapy with overall response (OR)
`rates of approximately 50%.1-4,6 A myriad of second-line therapies
`has been used, with none to date showing better or more durable
`efficacy than ATG.5,7-14
`GVHD is triggered by donor-derived T lymphocytes that
`recognize recipient alloantigens as foreign, resulting in cell activa-
`tion and cytokine release, leading to destruction of host tissues.15,16
`ABX-CBL is a hybridoma-generated purified murine IgM monoclonal
`antibody, which recognizes the CD147 antigen that is weakly expressed
`on human leukocytes, granulocytes, red blood cells, and several other
`cell types. Upon activation, CD147 is markedly up-regulated on
`activated lymphocytes.17 ABX-CBL is capable of inhibiting the in vitro
`mixed lymphocyte reaction by depleting monocytes and activated
`lymphocytes via a complement-dependent cytotoxic mechanism. Both
`activated T cells (CD4⫹ and CD8⫹) and B cells are depleted by
`ABX-CBL, while resting lymphocytes are unaffected. The half-life of
`ABX-CBL is 15 to 19 hours.
`
`In a pilot study of CBL-1, a murine ascites-generated precursor
`of ABX-CBL, 5 complete responses (CRs) and 4 partial responses
`(PRs) were observed in 10 pediatric patients with steroid-resistant
`acute GVHD.18 In a subsequent phase 1-2 trial of 59 patients with
`steroid-resistant acute GVHD, patients received ABX-CBL at 0.01,
`0.1, 0.2, or 0.3 mg/kg per day, and an additional 32 patients
`received ABX-CBL at 0.2 or 0.15 mg/kg per day.19 Among 51
`evaluable patients, overall response was observed in 26 (51%),
`including CRs in 13 patients and PR in 13 patients. Mylagias at
`doses of 0.2 mg/kg or higher were dose limiting but resolved
`without sequelae.19
`This current report describes the results of a multicenter,
`open-label, randomized clinical
`trial comparing ABX-CBL to
`equine ATG (Atgam) in 95 HCT recipients with steroid-resistant
`acute GVHD.
`
`Patients and methods
`
`Study design
`
`This was a multicenter, open-label, randomized, controlled study of
`ABX-CBL versus ATG as therapy for steroid-resistant acute GVHD. The
`primary end points of the study were survival at day 180 after treatment
`with ABX-CBL or ATG, and incidence of acute toxicity of ABX-CBL.
`
`Submitted August 28, 2006; accepted October 27, 2006. Prepublished online
`as Blood First Edition Paper, November 16, 2006; DOI 10.1182/blood-2006-08-
`013995.
`
`payment. Therefore, and solely to indicate this fact, this article is hereby
`marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
`
`The publication costs of this article were defrayed in part by page charge
`
`© 2007 by The American Society of Hematology
`
`BLOOD, 15 MARCH 2007 䡠 VOLUME 109, NUMBER 6
`
`2657
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`2658
`
`MACMILLAN et al
`
`BLOOD, 15 MARCH 2007 䡠 VOLUME 109, NUMBER 6
`
`Secondary end points included time to and duration of acute GVHD
`improvement, change in organ GVHD, change in ECOG performance
`status, total steroid dose, incidence and time to onset of chronic GVHD,
`development of infections, lymphoproliferative disease, and relapse of
`primary disease. All patients were evaluated through day 180 after
`randomization.
`
`Patients
`
`From April 2000 to January 2003, 95 patients with steroid-resistant acute
`GVHD were enrolled in 21 study centers. To be eligible, patients had to
`have been recipients of a single allogeneic HCT from any donor; had to be
`100 or fewer days from transplantation; had to have received no prior
`treatment for GVHD other than steroids; and had to have understood and
`signed an IRB/ERC-approved consent form or, if younger than 18 years,
`had a legal guardian sign. Institutional review board approval was obtained
`from the participating institutions (University of Minnesota, Minneapolis,
`MN; M.D. Anderson Cancer Center, Houston, TX; University of Washing-
`ton, Seattle, WA; Hadassah Hebrew University Hospital, Jerusalem, Israel;
`the Western Pennsylvania Hospital, Pittsburgh, PA; Washington University
`School of Medicine, St. Louis, MO; UCLA Medical Center, Los Angeles,
`CA; University of Nebraska Medical Center, Omaha, NE; UCSF Stanford
`Healthcare, San Francisco, CA; Baylor College of Medicine, Houston, TX;
`Fred Hutchinson Cancer Research Center, Seattle, WA; the Cleveland
`Clinic Foundation, Cleveland, OH; Roswell Park Cancer Institute, Buffalo,
`NY; University of Chicago, Chicago, IL; Cook Children’s Medical Center,
`Fort Worth, TX; Loyola University Medical Center, Maywood, IL; Emory
`University, Atlanta, GA; Florida Hospital, Orlando, FL; University of Utah
`School of Medicine, Salt Lake City, UT; Vanderbilt Clinic, Nashville, TN;
`Blood and Bone Marrow Transplant Center, Atlanta, GA; Oncology and
`Hematology Associates of Kansas City, Kansas City, MO), and patients
`provided informed consent in accordance with the Declaration of Helsinki.
`Potential patients were excluded if they were recipients of second HCTs or
`of donor lymphocyte infusions (DLIs) from their donors after HCT; were
`unwilling to relinquish the option of receiving DLIs through day 100 once
`randomized to this study; had an IBMTR GVHD Index of A or lower; had
`received a fully murine antibody product in the past; had changed their
`prophylactic regimen for acute GVHD within 72 hours of randomization
`(except change in dose to maintain proper serum levels or due to toxicity, or
`change to a different medication due to drug toxicity); were the recipients of
`ATG later than 10 days after HCT; were pregnant or breastfeeding or of
`childbearing potential not practicing birth control; were human immunode-
`ficiency virus (HIV) positive; had a history of or current substance abuse or
`any existing condition that may have increased the risks associated with the
`study; were the recipients of investigational medications (other than
`antifungals) within 30 days prior to randomization; had chronic GVHD; had
`serum creatinine 2.5 times the upper limit of normal or required renal
`dialysis; had respiratory failure; had severe veno-occlusive disease or
`multisystem organ failure; or had developed posttransplantation lymphopro-
`liferative disease.
`Steroid-resistant acute GVHD was defined as either continuing active
`GVHD despite treatment with methylprednisolone at doses of 2 mg/kg per
`day or higher or equivalent dose of another steroid for acute GVHD for at
`least 3 days, or failure during corticosteroid taper following initial
`treatment, which included 2 mg/kg per day or more of methylprednisolone
`or equivalent for at least 3 days.
`Active acute GVHD was defined as (1) skin rash on more than 25%
`body surface areas; and (2) total bilirubin level higher than 25.65 ␮M
`(1.5 mg/dL), diarrhea output of 500 mL or more per day (children, greater
`than or equal to 7 mL/kg per day) or nausea/vomiting, and epigastric pain
`with positive upper gastrointestinal histology for acute GVHD. For patients
`with isolated liver or upper GI acute GVHD, a confirmatory biopsy of the
`appropriate organ was required.
`
`Study methods
`
`Patients who met eligibility criteria were randomized in a 1:1 ratio to
`receive continuing corticosteroids plus either ABX-CBL or ATG. Patients
`were stratified according to IBMTR Severity Index (D versus B or C)20 and
`
`probability of survival based upon type and risk status of the primary
`disease at the time of randomization. Good risk was assigned to patients in
`first or second remission of acute myelocytic leukemia (AML) or acute
`lymphoblastic leukemia (ALL), patients with myelodysplastic syndrome
`(MDS), and patients with chronic myeloid leukemia (CML) in first chronic
`phase. All other patients were considered poor risk.
`Patients remained on cyclosporine or tacrolimus, and steroids were the
`only new treatment
`for acute GVHD treatment permitted before
`randomization.
`ABX-CBL was administered intravenously at a dose of 0.1 mg/kg daily
`for 14 consecutive days (induction regimen). Patients who qualified were
`eligible to receive up to 3 maintenance courses, each course consisting of 2
`infusions per week for 2 consecutive weeks. To qualify for the first
`maintenance course, a patient had to have had completed all 14 ABX-CBL
`infusions during the induction regimen, had no worsening of GVHD in any
`organ by 1 or more stages, had improvement of 1 or more stages in at least
`one organ involved with GVHD on the day of randomization, and had no
`chronic GVHD. In addition, to be eligible for maintenance therapy, patients
`had to be receiving steroids at a dose on study day 15 that was lower than
`the dose received when randomized, if they were receiving only ABX-CBL
`and steroids for GVHD treatment, and if they were able to receive the first
`dose of maintenance ABX-CBL no later than study day 17.
`Patients were eligible for a second or third maintenance course of
`ABX-CBL if they had received all 4 infusions of the previous maintenance
`regimen; had no organs involved with GVHD on day 15 (or 29, respec-
`tively) worsen by 1 or more stages and had no chronic GVHD; if the dose of
`steroids on day 29 (or 43, respectively) was lower than the dose of steroids
`on day 15 (or 29, respectively); if they were receiving only ABX-CBL
`and steroids for GVHD treatment; and if they were able to receive the
`first dose of the maintenance course no later than on study day 31 (or
`45, respectively).
`Equine ATG (Atgam) was administered at doses of 30 mg/kg per day
`every other day for a total of 6 doses. Patients were eligible for additional
`courses at the discretion of the investigator.
`The study was not blinded with respect to treatment but a blinded
`reviewer was assigned to assess GVHD and treatment responses in each
`patient. Patients were assessed weekly until 10 weeks after randomization,
`then monthly for the remainder of the follow-up period. Weekly assess-
`ments for efficacy included survival, 4 organ GVHD scores, development
`of chronic GVHD, and treatment for GVHD. Safety assessments during this
`time interval included physical examination, laboratory evaluation, occur-
`rence of adverse events, infections, and concomitant medication administra-
`tion. Lymphocyte counts were performed during the third and tenth week
`visits. Blood for human antimurine antibody (HAMA) was drawn from
`patients assigned to ABX-CBL at one week after the last infusion of the
`induction regimen and at week 15 of the study. For patients who received
`the maintenance regimen, samples for HAMA were drawn prior to the start
`of the first maintenance course, 1 week after the last dose of ABX-CBL, and
`at week 15. Blood for pharmacokinetic analysis of the ABX-CBL antibody
`was drawn at the start and completion of the first and 14th ABX-CBL
`infusion. Plasma Epstein-Barr virus (EBV)–DNA was measured at base-
`line, and at weeks 3, 7, 11, and 15.21
`
`Statistical analysis
`
`The trial was designed to assess the efficacy of ABX-CBL compared with
`ATG, where the primary end point was patient survival at 180 days after
`randomization. The primary analysis of this end point was based on the
`difference in Kaplan-Meier estimates. Based on a retrospective review of
`data on second-line therapy for treatment of acute GVHD, it was projected
`that 40% of patients receiving the ATG regimen would survive through day
`180. With 46 patients per arm, the study was designed to provide a
`screening evaluation that would rule out from further evaluation an
`intervention failing to improve 180-day survival, and that would identify
`for further evaluation an intervention providing at least 20% improvement
`in 180-day survival, when comparing with ATG.22
`Safety of ABX-CBL was assessed by comparing the percentage of
`patients in the 2 groups with grade 3 or 4 adverse events and serious adverse
`
`

`

`BLOOD, 15 MARCH 2007 䡠 VOLUME 109, NUMBER 6
`
`ABX-CBL FOR STEROID-RESISTANT ACUTE GVHD
`
`2659
`
`GVHD responses
`
`The GVHD overall response rates were similar in the 2 treatment
`groups, as assessed by a blinded review. Twenty-seven (56%) of 48
`ABX-CBL–treated patients improved (complete or partial re-
`sponse) their GVHD score at a median of 22 days (range, 7-72
`days) after randomization versus 27 (57%) of 47 ATG-treated
`patients at a median of 28 days (range, 2-50 days) (P ⫽ .99).
`Among patients who showed an improvement, the response lasted
`a median of 13 days (range, 13-70 days) in the ABX-CBL–treated
`group and a median of 23 days (range, 13-83 days) in the
`ATG-treated group.
`In the ABX-CBL group, 14 patients (29%) had CR of GVHD at
`a median of 77 days (range, 14-77 days) versus 15 patients (32%)
`of the ATG-treated group at a median of 78 days (range, 21-88
`days). Of those patients who experienced CR of acute GVHD, the
`responses lasted a median of 30 days (range, 13-70 days) for the
`ABX-CBL–treated patients and a median of 21 days (range, 18-62
`days) for the ATG-treated patients.
`Various patient characteristics and transplantation conditions
`were analyzed for their association with clinical response to
`ABX-CBL or ATG. In univariate analysis, donor type was the only
`factor statistically significantly associated with overall response
`(CR ⫹ PR). CR/PR was achieved in 25 (57%) of 44 HLA-matched
`related donor recipients, versus 25 (68%) of 37 HLA-matched
`unrelated donor (URD) recipients, versus 4 (29%) of 14 HLA-
`mismatched URD recipients (P ⫽ .04). There was not a significant
`association of CR/PR and age, year of transplantation, sex, sex
`match, underlying diagnosis, cytomegalovirus (CMV) serostatus of
`the patient and donor, GVHD prophylaxis regimen, conditioning
`regimen, initial grade of acute GVHD, time to onset of acute
`GVHD, time to therapy, and type of organ involvement.
`Chronic GVHD eventually developed in 44% of the ABX-CBL–
`treated patients and in 46% of ATG-treated patients.
`
`Survival
`
`The probability of survival at day 180 after randomization was
`lower in patients in the ABX-CBL group than in patients in the
`ATG-treated group (35.4% versus 44.7%, Figure 1). The 95%
`confidence interval for this difference (⫺0.289, 0.104) allows one
`to rule out not only the targeted 20% improvement in 180-day
`survival, but also that ABX-CBL provides a 10.4% improvement
`relative to ATG. Causes of death for the entire study duration were
`
`ABX-CBL
`ATG
`
`30
`
`33
`
`39
`
`60
`
`26
`
`32
`
`90
`
`120
`
`150
`
`180
`
`Study Day
`
`22
`
`26
`
`19
`
`23
`
`18
`
`21
`
`17
`
`21
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Cumulative % Surviving
`
`0
`
`N*
`
`ABX-CBL:
`
`48
`
` ATG:
`
`47
`
`Figure 1. Probability of survival after randomization to ABX-CBL or ATG for
`steroid-resistant acute GVHD.
`
`Table 1. Patient characteristics: ITT population
`Treated with
`ABX-CBL
`
`Characteristic
`
`48
`38.1 (2-65)
`31:17
`
`14 (29)
`3 (6)
`7 (15)
`6 (12)
`10 (21)
`8 (17)
`
`25 (52)
`23 (48)
`
`Treated with
`ATG
`
`47
`39.1 (2-65)
`27:20
`
`9 (19)
`8 (17)
`12 (26)
`4 (8)
`8 (17)
`6 (13)
`
`22 (47)
`25 (53)
`
`No. patients
`Mean age, y (range)
`Male-female ratio, nos.
`Primary diagnosis, no. (%)
`AML
`ALL
`CML
`Myelodysplastic syndrome
`Lymphoma
`Other
`Risk type, no. (%)
`Good risk
`Poor risk
`Median days from transplantation
`to randomization, no. (range)
`Donor type, no. (%)
`Matched related
`Mismatched related
`Matched unrelated
`Mismatched unrelated
`Preparative therapy, no. (%)
`Chemotherapy with TBI
`Chemotherapy alone
`GVHD prophylaxis, no. (%)
`CSA alone
`CSA ⫹ MTX
`CSA ⫹ MTX ⫹ other
`CSA ⫹ other
`FK506 ⫹ MTX
`FK506 ⫹ MTX ⫹ other
`FK506 ⫹ other
`GVHD grade, no. (%)
`B/C
`D
`
`35.5 (11-100)
`
`37.0 (14-99)
`
`19 (40)
`1 (2)
`21 (44)
`7 (14)
`
`29 (60)
`19 (40)
`
`5 (10)
`10 (21)
`5 (10)
`9 (19)
`8 (17)
`8 (17)
`3 (6)
`
`41 (85)
`7 (15)
`
`22 (47)
`2 (4)
`16 (34)
`7 (15)
`
`26 (55)
`21 (45)
`
`4 (8)
`4 (8)
`5 (10)
`14 (30)
`10 (21)
`3 (6)
`7 (15)
`
`43 (91)
`4 (9)
`
`There was no significant difference in any characteristic between treatment
`groups.
`ITT indicates intent-to-treat cohort.
`
`events. Additional safety analyses were based on laboratory data, vital
`signs, HAMA in patients assigned to ABX-CBL, the incidence of infec-
`tions, lymphoproliferative disease, and primary disease progression.
`A data monitoring committee (DMC) evaluated all grade 4 adverse
`events, serious adverse events, and grade 3 to 4 myalgias. Toxicity was
`evaluated on a monthly basis by the chair of the DMC and the entire board
`as needed. GVHD status of each patient was assessed by a blinded reviewer
`weekly using the IBMTR Severity Index.20
`
`Results
`
`Patient characteristics
`
`Patient characteristics are shown in Table 1. The groups were
`balanced for age, sex, primary diagnosis and risk type, donor type,
`preparative therapy, GVHD prophylaxis, IBMTR Severity Index,
`and time from HCT to randomization.
`The amount of secondary GVHD treatment was similar be-
`tween the 2 groups. The induction regimen was completed by 43
`patients (90%) in the ABX-CBL group and by 43 patients (92%) in
`the ATG group. The visits at week 15 and month 12 were
`completed by all patients.
`
`

`

`2660
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`MACMILLAN et al
`
`BLOOD, 15 MARCH 2007 䡠 VOLUME 109, NUMBER 6
`
`Table 2. Survival: ITT population, unblinded assessment
`Treated with
`ABX-CBL
`
`Treated with
`ATG
`
`No. patients
`Survival time
`Median d (min d, max d)*
`Censored, no.
`Cause of death, no. (%)
`GVHD related
`Primary disease related
`Other
`Probability of 180-day survival (K-M)
`95% confidence interval
`95% confidence interval for difference
`
`48
`
`47
`
`64.5 (6, 682)
`13
`
`119 (6, 768)
`8
`
`19 (40)
`3 (6)
`13 (27)
`0.354
`(0.219, 0.489)
`(⫺0.289, 0.104)
`
`9 (19)
`2 (4)
`28 (60)
`0.447
`(0.305, 0.589)
`
`Min indicates minimum uncensored time; max, maximum uncensored time.
`
`similar in the 2 groups (Table 2). There was not a significant
`association between survival and age, year of transplantation, sex,
`sex match, underlying diagnosis, CMV serostatus of the patient and
`donor, donor type, GVHD prophylaxis regimen, conditioning
`regimen, initial grade of acute GVHD, time to onset of acute
`GVHD, time to therapy, and type of organ involvement.
`
`Adverse events
`
`The administration of ABX-CBL was generally well tolerated.
`Adverse events, which were considered possibly, probably, or
`definitely related to study drug administration, were observed in
`similar numbers in both treatment groups with the exception of
`infusion-related reactions and myalgias. Twenty-nine (63%) ABX-
`CBL–treated patients and 21 (46%) ATG-treated patients had study
`drug–related adverse events (P ⫽ .09). The most common drug-
`related adverse events were myalgias, which developed in 13
`(28%) ABX-CBL–treated patients and in 1 (2%) ATG-treated
`patient (P ⱕ .001); rigors in 2 (4%) ABX-CBL–treated and 5
`(11%) ATG-treated patients (P ⫽ .44); and back pain in 6 (13%)
`ABX-CBL–treated and 1 (2.2%) ATG-treated patient (P ⫽ .11).
`Infusion-related adverse events (myalgias, rigors, and back pain)
`were reported in more ABX-CBL–treated patients (25, 54%) than
`in ATG-treated patients (16, 35%; P ⫽ .06). HAMAs to ABX-CBL
`were detected in 2 (4%) of 48 ABX-CBL–treated patients.
`Patients receiving ABX-CBL or ATG had similar rates of
`adverse events, including infections. Adverse events (AEs) occur-
`ring in more than 20% of patients are shown in Table 3. The most
`common AEs (infections, positive blood cultures, and hyperten-
`sion) occurred with similar frequency in the 2 treatment groups,
`except for pneumonia, which was observed in 15 (33%) patients in
`the ABX-CBL–treated group versus 30 (65%) patients in the
`ATG-treated group (P ⫽ .002).
`EBV titers at baseline and after treatment were available for
`only 14 ABX-CBL–treated patients and 19 ATG-treated patients.
`Increased EBV titers (any rise above baseline) were observed in 5
`ABX-CBL–treated patients and 13 ATG-treated patients. Only one
`patient developed posttransplantation lymphoproliferative disease
`(PTLD). He was a 4-year-old white male who was randomized to
`ABX-CBL for grade B acute GVHD. Two days after randomiza-
`tion, a computed tomography (CT) scan of the neck revealed
`lymphadenopathy, and a biopsy of cervical lymph nodes performed
`the subsequent day confirmed an EBV PTLD. The patient required
`intubation and his respiratory and renal functions worsened over
`the next few days. Six days after randomization, life support was
`withdrawn and the patient died.
`
`Lymphocyte counts for the ABX-CBL–treated patients and the
`ATG-treated patients did not differ significantly. The median
`lymphocyte count at baseline was 0.3 ⫻ 109/L (range,
`0-3.2 ⫻ 109/L) for 45 ABX-CBL–treated patients and 0.2 ⫻ 109/L
`(range, 0-144.4 ⫻ 109/L) for 45 ATG-treated patients. The median
`lymphocyte count at week 3 was 0.19 ⫻ 109/L (range, 0-1.3 ⫻ 109/L)
`for 39 ABX-CBL–treated patients and 0.20 ⫻ 109/L (range,
`0-232.0 ⫻ 109/L) for 42 ATG-treated patients, and the median
`lymphocyte count at week 10 was 0.40 ⫻ 109/L (range,
`0-1.56 ⫻ 109/L, n ⫽ 22) for 22 ABX-CBL–treated patients and
`0.32 ⫻ 109/L (range, 0-5.3.0 ⫻ 109/L, n ⫽ 30) for 30 ATG-
`treated patients.
`
`Discussion
`
`As ABX-CBL had shown promising results in phase 1 and 2 studies
`for treatment of steroid-resistant acute GVHD,18,19 a phase 3 study
`was developed to compare outcome between ABX-CBL and
`standard therapy. As there were no FDA-approved second-line
`therapies for acute GVHD, when designing this study we had to
`choose the optimum standard therapy for the comparator arm. After
`reviewing the literature and transplant center use, we chose ATG as
`it was the most widely used agent and there were no alternatives
`that showed higher response rates. Although this ATG treatment
`regimen has not been proven to be effective therapy in double-
`blinded, placebo-controlled randomized trials, senior investigators
`representing large transplantation centers who designed this study
`agreed that ATG had been studied in the largest numbers of steroid
`refractory GVHD patients for toxicity, efficacy, and overall sur-
`vival, leading us to elect to have the ATG control arm used in
`this study.
`The results of this prospective randomized study show that
`ABX-CBL, like equine ATG, is generally well tolerated with a
`
`Table 3. Adverse events occurring in less than 20% of patients
`Treated with
`Treated with
`ABX-CBL, no. (%)
`ATG, no. (%)
`
`Adverse event
`
`Infections and infestations*
`Blood culture positive
`Hypertension
`Graft-versus-host disease
`Hyperglycemia
`Neutropenia
`Pyrexia
`Abdominal pain
`Edema
`Depression
`Hypotension
`Back pain
`Cough
`Dyspnea
`Rigors
`Hypocalcemia
`Myalgia
`Edema lower limb
`Thrombocytopenia
`Headache
`Renal impairment
`Arthralgia
`Gastrointestinal hemorrhage
`
`45 (97.8)
`26 (56.5)
`14 (30.4)
`16 (34.8)
`11 (23.9)
`10 (21.7)
`9 (19.6)
`7 (15.2)
`14 (30.4)
`11 (23.9)
`10 (21.7)
`11 (23.9)
`6 (13.0)
`8 (17.4)
`7 (15.2)
`10 (21.7)
`14 (30.4)
`4 (8.7)
`10 (21.7)
`5 (10.9)
`6 (13.0)
`5 (10.9)
`4 (8.7)
`
`46 (100)
`21 (45.7)
`13 (28.3)
`10 (21.7)
`12 (26.1)
`13 (28.3)
`14 (30.4)
`15 (32.6)
`8 (17.4)
`10 (21.7)
`11 (23.9)
`8 (17.4)
`13 (28.3)
`11 (23.9)
`12 (26.1)
`8 (17.4)
`3 (6.5)
`13 (28.3)
`7 (15.2)
`11 (23.9)
`10 (21.7)
`10 (21.7)
`10 (21.7)
`
`For both groups, n ⫽ 46.
`*This includes all preferred terms in the System Organ Class “Infections and
`Infestations.”
`
`

`

`BLOOD, 15 MARCH 2007 䡠 VOLUME 109, NUMBER 6
`
`ABX-CBL FOR STEROID-RESISTANT ACUTE GVHD
`
`2661
`
`similar incidence of adverse events when given as therapy for
`steroid-resistant acute GVHD. However, myalgias occurred more
`frequently in patients receiving ABX-CBL.
`In the subset of patients for whom EBV polymerase chain
`reaction (PCR) was measured, EBV reactivation was more com-
`monly seen in the ATG arm. This finding may reflect the fact that
`ABX-CBL will deplete B cells (which may be EBV infected) as
`well as activated T cells, whereas ATG will deplete T cells while
`sparing B cells, making outgrowth of EBV-infected B cells more
`likely. Only one patient developed frank EBV PTLD but as this was
`diagnosed only 2 days after starting ABX-CBL, it was unlikely due
`to the antibody.
`Although the response rate for ABX-CBL was similar to that
`observed in previous studies,18,19 there was no clinically or
`statistically significant advantage in regard to treatment response
`using ABX-CBL compared with ATG, and survival was sufficiently
`unfavorable on ABX-CBL that one can rule out even moderate
`improvement relative to ATG in this randomized risk-stratified
`trial. The duration of response was also similar between the
`treatment groups despite the shorter half-life of ABX-CBL (15-19
`hours) versus ATG (5.7 ⫾ 3 days).
`The clinical responses to ATG observed in this study were
`similar to previous nonrandomized studies for patients with
`steroid-resistant GVHD. A report of patients who underwent
`transplantation at a single institution in the 1990s described an
`overall
`improvement
`in 54% of patients receiving ATG for
`steroid-resistant acute GVHD, and durable complete responses in
`20% of patients.5 The results of the current multicenter trial
`establish ATG response rates that can be used as a benchmark for
`future randomized trials.
`This study is the first reported prospective, multicenter, random-
`ized clinical trial for steroid-resistant acute GVHD. In designing
`the study, we considered that survival was the most important end
`point and that it was important to stratify patients by risk. To reduce
`bias, we also had an independent observer who was not aware of
`the randomization arm grade of GVHD at each site. This design
`may serve as a model for future testing of new agents to treat
`steroid-resistant acute GVHD.
`There are currently few options for therapy of steroid-resistant
`GVHD. Although ABX-CBL did not show an improvement in
`outcome compared with ATG and therefore did not meet FDA
`criteria for approval, it did show activity and it is possible that
`patients resistant to either ATG or ABX-CBL may respond to the
`alternate agent. Moreover, because we restricted the study to
`steroid-resistant GVHD occurring in the first 100 days after a single
`transplantation, it is also possible that the activities of the study
`drugs may differ in treating GVHD after DLI. Nevertheless, the
`activity of each agent was suboptimal and new agents are required.
`Treatment with combinations of agents may also improve outcomes.
`As novel approaches to HCT are developed, studies of the
`prevention and treatment of acute GVHD are necessary to optimize
`
`References
`
`outcomes. In a recent report from Seattle in a large cohort of
`patients undergoing nonmyeloablative HCT, a decreased incidence
`of acute GVHD was observed compared with conventional HCT.
`Of interest, the onset of acute GVHD was delayed, with some
`patients presenting with de novo acute GVHD after day 100.23
`Whether this form of acute GVHD will be amendable to the same
`therapy as acute GHVD following conventional HCT remains to
`be determined.
`
`Acknowledgments
`
`This work was supported by Abgenix.
`The authors wish to acknowledge the following investigators,
`contributors, and institutions: Other participating investigators:
`Brian Bolwell, The Cleveland Clinic Foundation, Cleveland, OH;
`Arif Aram, Roswell Park Cancer Institute, Buffalo, NY; Todd
`Zimmermann, University of Chicago, Chicago, IL; Gretchen
`Eames, Cook Children’s Medical Center, Fort Worth, TX; Patrick
`Stiff, Loyola University Medical Center, Maywood, IL; Istvan
`Redei, Emory University, Atlanta, GA; John Edwards, Florida
`Hospital, Orlando, FL; Finn Bo Petersen, University of Utah
`School of Medicine, Salt Lake City, UT; Friedrich Schuening,
`Vanderbilt Clinic, Nashville, TN; Lawrence Morris, Blood and
`Bone Marrow Transplant Center, Atlanta, GA; and Sunil Abhyan-
`kar, Oncology and Hematology Associates of Kansas City, Kansas
`City, MO. Data management: Axio Research, Seattle, WA. Study
`monitoring: ICON PLC, San Bruno, CA, and Farmastudio, Rovigo,
`Italy. Biostatistics support: Michael White, PhD, Seattle, WA.
`
`Authorship
`
`Contribution: M.L.M. wrote the paper; D.C. enrolled patients;
`D.J.W. enrolled patients and wrote the paper; G.S. designed the
`study, helped conduct the trial, and helped collect data; N.H. and
`T.R.F. helped design and conduct
`the trial; S.H. performed
`statistical design and analysis; L.R. helped design and conduct the
`trial; S.S., R.K.S., J.D., M.T., S.P., and C.L. treated patients; H.E.H.
`helped design and conduct the trial, treated patients, and helped
`write the paper; H.J.D. helped design the trial, met with investiga-
`tors, treated patients, and helped write the paper; B.R.B. helped
`design and conduct
`the trial, met with investigators,
`treated
`patients, and helped write the paper. H.J.D. and B.R.B. contributed
`equally to this work.
`Conflict-of-interest disclosure: The authors declare no compet-
`ing financial interests.
`Correspondence: Margaret L. MacMillan, Department of Pedi-
`atrics, University of Minnesota, MMC 484, 420 Delaware St, SE,
`Minneapolis, MN 55455; email: macmi002@umn.edu.
`
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`

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`MACMILLAN et al
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`BLOOD, 15 MARCH 2007 䡠 VOLUME 109, NUMBER 6
`
`8. Khoury H, K