Busulfan/Melphalan/Antithymocyte Globulin Followed by Unrelated ...

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by Unrelated Donor Cord Blood Transplantation for. Treatment of Infant Leukemia and Leukemia in. Young Children: The Cord Blood Transplantation.
Biology of Blood and Marrow Transplantation 11:637-646 (2005) 䊚 2005 American Society for Blood and Marrow Transplantation 1083-8791/05/1108-0009$30.00/0 doi:10.1016/j.bbmt.2005.05.003

Busulfan/Melphalan/Antithymocyte Globulin Followed by Unrelated Donor Cord Blood Transplantation for Treatment of Infant Leukemia and Leukemia in Young Children: The Cord Blood Transplantation Study (COBLT) Experience Donna A. Wall,1 Shelly L. Carter,2 Nancy A. Kernan,3 Neena Kapoor,4 Naynesh R. Kamani,5 Joel A. Brochstein,6 Haydar Frangoul,7 Rakesh K. Goyal,8 John T. Horan,9 Daniel Pietryga,10 John E. Wagner,11 Joanne Kurtzberg,12 for the COBLT Steering Committee 1

Texas Transplant Institute, San Antonio, Texas; 2The EMMES Corporation, Rockville, Maryland; 3Memorial Sloan-Kettering Cancer Center, New York, New York; 4Children’s Hospital of Los Angeles, Los Angeles, California; 5Children’s National Medical Center, Washington, DC; 6Hackensack University Medical Center, Hackensack, New Jersey; 7Vanderbilt-Ingram Comprehensive Cancer Center, Nashville, Tennessee; 8Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania; 9University of Rochester, Rochester, New York; 10DeVos Children’s Hospital, Grand Rapids, Michigan; 11University of Minnesota, Minneapolis, Minnesota; 12Duke University, Durham, North Carolina Correspondence and reprint requests: Donna A. Wall, MD, Texas Transplant Institute, Southwest Texas Methodist Hospital, 8201 Ewing Halsell, Suite 280, San Antonio, TX 78229 (e-mail: [email protected]). Received April 15, 2005; accepted May 12, 2005

ABSTRACT A non–total body irradiation– containing preparative regimen was studied in young children (500/␮L) at day 42 was 0.59 (95% confidence interval [CI], 0.44-0.78) at a median of 31 days (range, 23-55 days). The CINC and Kaplan-Meier estimates of platelet engraftment at day 180 were 0.53 (95% CI, 0.34-0.69) and 0.82 (95% CI, 0.61-1.00), respectively. CINC estimates of grade III/IV acute GVHD at day 100 and chronic GVHD at 1 year were 0.25 (95% CI, 0.09-0.41) and 0.26 (95% CI, 0.09-0.44), respectively. The CINC estimate of relapse was 0.31 (95% CI, 0.16-0.47) at 2 years. With a median follow-up of 27.8 months (range, 23.4-46.7 months), the probability of survival at 1 year was 0.47 (95% CI, 0.30-0.64). A preparative regimen containing a busulfan/melphalan/ antithymocyte globulin preparative regimen is well tolerated in the setting of unrelated donor cord blood transplantation for childhood leukemia and can serve as a platform preparative regimen for intensifying host immunosuppression and antileukemic therapy to allow for improved engraftment and improved relapse-free survival. © 2005 American Society for Blood and Marrow Transplantation

KEY WORDS Busulfan

BB&MT



Melphalan



Cord blood



Transplantation



Children



Acute leukemia 637

D. A. Wall et al.

INTRODUCTION Unrelated donor cord blood transplantation (CBT) is an evolving treatment option for a variety of hematologic, immunologic, and metabolic diseases [1]. The National Heart, Lung and Blood Institute–sponsored phase II Cord Blood Transplantation (COBLT) study was a multicenter study designed to determine whether cord blood is a suitable source of hematopoietic stem cells for children and adults with hematologic malignancies, immune deficiency disorders, or inborn errors of metabolism. Although allogeneic transplantation offers potentially curative therapy to children and adults with otherwise untreatable malignancies, only a fraction of patients will have an HLA-matched donor in their family. Networks of unrelated volunteer donors have been established to provide an alternative donor source for those without family donors [2]. However, with current HLA matching requirements, there remain a large proportion of patients for whom an unrelated volunteer donor is not identified in a timely fashion. This is especially true for recipients not of northern European descent and children with leukemia. Allogeneic transplantation from unrelated marrow donors is more frequently complicated by severe graft-versus-host disease (GVHD) or graft rejection [3,4]. Most prior studies with CBT have focused on total body irradiation (TBI)– based preparative regimens. There was interest in evaluating a non-TBI regimen for patients unable to tolerate TBI because of pretransplantation toxicity and leukemia patients ⬍4 years of age. However, there was concern about whether a non–TBI-based regimen would be sufficiently immunosuppressive to allow engraftment in the setting of CBT [5-8]. TBI has been shown to be superior to busulfan and cyclophosphamide in trials of acute lymphoblastic leukemia (ALL); thus, an alternative non-TBI preparative regimen was sought [9-11]. One stratum of the COBLT trial was to investigate the safety and efficacy of busulfan, melphalan, and antithymocyte globulin (ATG) as an alternative conditioning regimen to TBI. The results of the pediatric leukemia patients ⬍4 years old presented in this article also allow for analysis of CBT outcome in a cohort of leukemia patients in whom the cord blood nucleated cell dose was not limiting. MATERIALS AND METHODS Study Design

The COBLT trial was initiated in 1996 and included 8 strata. One stratum was designed to evaluate the toxicity and efficacy of busulfan/melphalan/ATG and CBT. The first 2 years of the COBLT project focused on establishing 3 cord blood banks for patients searching for an unrelated donor CBT. Stan638

dard operating procedures for the cord blood banks were written and applied [12]. While cord blood units (CBUs) were being collected, HLA typing methods and a search algorithm were developed. The transplantation protocol and manual of procedures were also developed for the transplant centers. Search activity was initiated in November 1998. The first patient was enrolled in January 1999. For each stratum, the primary end point for the study was survival at 180 days after transplantation. The secondary end points included engraftment (myeloid and platelet), incidence of acute and chronic GVHD, relapse-free survival, overall survival, incidence of relapse, and incidence of nonrelapse morbidity and mortality. Patients

The transplantation protocol was approved at the institutional review board of each of the 26 participating institutions. Consent was obtained for all patients from their legal guardian before enrollment and treatment. Thirty-eight patients with leukemia or myelodysplastic syndrome (MDS) were enrolled from January 1999 to May 2002. Eligibility for this treatment stratum included (1) age ⬍2 years at diagnosis of leukemia (resulting in an age ⬍4 years at transplantation), (2) inability to tolerate TBI because of prior radiation therapy or organ toxicity, or (3) refractory/multiply recurrent leukemia for which a traditional TBI/cyclophosphamide regimen historically carried a low likelihood of successful outcome. This article presents the outcome of transplantations in the 32 children ⬍4 years old who were enrolled on this trial. Within that subset, infant leukemia was defined as all cases diagnosed as leukemia before 6 months of age or diagnosed before 12 months of age with cytogenetic rearrangements carrying the mixed lineage leukemia gene. Patients with active central nervous system disease, human immunodeficiency virus seropositivity, Lansky performance score ⬍50%, primary myelofibrosis, or suitable related donors were ineligible. Patients with prior allogeneic stem cell transplantation within 12 months or autologous transplantation within 6 months were excluded, as were individuals with uncontrolled bacterial, viral, or fungal infections. Multiorgan assessment performed before enrollment was required to demonstrate the following: serum creatinine normal for age or a creatinine clearance ⬎50% of the lower limits of normal for age; aspartate aminotransferase ⬍5 times the upper limit of normal and total serum bilirubin ⬍2.5 mg/dL; asymptomatic cardiac status or left ventricular ejection fraction ⬎40% that improved with exercise; and asymptomatic pulmonary function or forced expiratory volume in 1 second and diffusion capacity ⬎45% of predicted

Busulfan/Melphalan Preparative Regimen for Cord Blood Transplantation

(corrected for hemoglobin). The selected CBU was required to provide a minimum of 1 ⫻ 107 total nucleated cells (before cryopreservation) per kilogram of recipient weight. Patients were characterized as high risk if they had disease features that were historically associated with poor transplantation outcomes: infant leukemia; ALL in second complete remission (CR2) with length of CR1 ⬍18 months; acute myeloid leukemia (AML) associated with monosomy 7, trisomy 8, or prior MDS; therapy-related AML; ALL or AML in ⱖCR3 or relapse; juvenile myelomonocytic leukemia in any stage of disease; and MDS. Donor Selection

For study enrollment, the donor/recipient HLA match was determined by low-/intermediate-resolution molecular typing for class I HLA-A and -B alleles and high-resolution molecular typing for HLA-DRB1 alleles (original HLA match). Retrospective high-resolution molecular typing for HLA-A, -B, and -DRB1 alleles was performed (final HLA match). Eligibility criteria required the availability of a cryopreserved CBU with a minimum 4/6 HLA match or a 3/6 HLA-matched unit provided that the 3 HLA loci were all typed by high-resolution molecular typing and there was at least 1 match for the HLA-A, -B, and -DRB1 loci. Only patients receiving 1 cord unit were eligible. Initially, the COBLT study required that CBUs had to be obtained from the COBLT cord blood banks. This criterion was subsequently expanded to allow units obtained from the New York Blood Center, National Marrow Donor Program– approved cord blood banks, or US banks meeting NETCORD-FACT standards. Treatment Plan

All patients received busulfan every 6 hours for 16 doses on day ⫺8 through day ⫺5 either orally (n ⫽ 21) or intravenously (IV; n ⫽ 11). Oral busulfan was administered at 20 mg/m2 (age ⬍3 months), 40 mg/m2 (age 3 months to 6 years), or 1 mg/kg (age ⬎6 years); IV busulfan was administered at 1 mg/kg (age ⬍4 years) or 0.8 mg/kg (age ⬎4 years). Busulfan doses were adjusted to a achieve a targeted concentration steady state of 600 to 900 ng/mL. Melphalan (45 mg/m2/d) was given on days ⫺4, ⫺3, and ⫺2. Equine ATG (30 mg/kg/d) was given on days ⫺3, ⫺2, and ⫺1. On the day of transplantation, patients received 2 doses of methylprednisolone 1 mg/kg, with 1 dose given just before the CBU infusion (day 0). GVHD prophylaxis consisted of methylprednisolone 0.5 mg/kg twice daily on day ⫹1 through ⫹4 and then 1 mg/kg twice daily from day ⫹5 to day ⫹19 or until the first day the absolute neutrophil count (ANC) reached 500/␮L, at which time the dose was tapered at the rate of 0.2 mg/kg/wk. Cyclosporine was begun on day ⫺3 and continued to at least day 180, when the dose was

BB&MT

tapered at the rate of 5% per week of the initial dose if the recipients had no evidence of GVHD. CBUs were thawed according to the process developed by Rubinstein et al. [13]. End Point Definitions

Survival was defined as the time from transplantation to the day of death or the day of last follow-up. Relapse-free survival was defined as the time from transplantation to the day of death or relapse or the day of last follow-up. Neutrophil engraftment was defined as achieving an ANC at least 500/␮L for 3 consecutive measurements on different days and demonstrated donor chimerism ⬎90%. All patients who survived at least 14 days were considered evaluable. Primary graft failure was defined as the failure to attain neutrophil engraftment by day 42. Neutrophil hematopoietic recovery was defined as achieving ANC at least 500/␮L for 3 consecutive measurements on different days. Patients who died between day 14 and day 42 and had not achieved neutrophil engraftment were classified as having primary graft failures. Secondary graft failure was defined as a loss of neutrophil engraftment. Platelet engraftment was defined as the first day of a minimum of 3 consecutive measurements on different days such that the patient achieved a platelet count ⬎20 000/␮L or 50 000/␮L and was platelet transfusion independent for a minimum of 7 days. The time to neutrophil or platelet engraftment was defined as the time from transplantation to the first day of engraftment. Acute GVHD assessments were every 7 days to day 100 after CBT and then on day 120 and day 150 after CBT. The grading of acute GVHD followed the GVHD consensus grading scheme [14]. An algorithm calculated the maximum GVHD clinical grade on the basis of the weekly organ staging in skin, upper and lower gastrointestinal tract, and liver. This calculated organ stage was decreased by 1 stage if a listed specific differential diagnosis was reported for either gastrointestinal tract or liver. An independent panel reviewed all weekly records and assigned each patient a final maximum grade, similar to the methods described by Weisdorf et al [15]. Relapse of acute leukemia was diagnosed when leukemic blasts were documented in the blood or marrow (⬎25%), when there were ⬎5% blasts and there were supporting cytogenetic abnormalities, or when disease was present at an extramedullary site. Time to relapse was defined as the time to the first observation characteristic of relapse. Causes of Morbidity and Mortality

Primary causes of death were reported by following the hierarchy developed for the Unrelated Donor 639

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Marrow Transplantation Trial (http://spitfire.emmes. com/study/tcd/). The hierarchy was developed by an expert panel and was based on refinements to the National Marrow Donor Program hierarchy for reporting causes of death. The hierarchy requires that graft failure, relapse, or GVHD (if they occur) be reported as the primary cause of death, rather than causes such as infection, organ failure, or hemorrhage, and also provides rules for reporting secondary causes of death. Clinically significant infections were reported after transplantation by site of infection, organism, and severity (moderate required oral antibiotic therapy; severe required IV antibiotic therapy and was lifethreatening or fatal). Readmissions after the initial discharge for the transplantation were reported by date and primary and secondary reasons for admission. The Bearman toxicity scale [16] was used to report maximum regimen-related toxicity by day 42 after transplantation. Data Collection

Transplant centers prospectively completed National Marrow Donor Program data-collection forms and targeted forms for secondary end points and supportive care. Clinical outcome data were collected from the date of transplantation until June 30, 2004, at which time the data file was closed. Statistical Analysis

Survival estimates were calculated by using the Kaplan-Meier (KM) method [17]. Testing for differences in survival between groups used the log-rank test. Neutrophil and platelet recoveries, acute and chronic GVHD, and relapse were analyzed by using the cause-specific failure probability method (or cumulative incidence; CINC), where death was treated as a competing risk [18]. The complement of the KM estimate for these end points was used to calculate the cumulative probability. Because of the small sample size, multivariate modeling methods were not presented. No imputation was used for any missing data. Frequency data in cross-tabulation tables were compared by using the Kruskal-Wallis test. All analyses were performed with SAS software version 8.2 (SAS Institute Inc, Cary, NC). The analysis is based on enrolled patients younger than 4 years of age. RESULTS Study Population

Thirty-eight patients were enrolled in this stratum by 11 transplant centers, and 50% of the patients were enrolled by 1 center. Six of the 38 patients, aged 8 to 17 years, were enrolled because of an inability to tolerate TBI. Of these 6, 5 died early after transplantation because of acute GVHD (n ⫽ 3), graft failure (n ⫽ 1), or 640

Table 1. Baseline Characteristics Variable Number of patients Age (y) Median Range Weight (kg) Median Range Total nucleated cell dose (ⴛ 107/kg) Median Range CD34ⴙ cell dose (ⴛ 105/kg) Median Range CD3ⴙ cell dose (ⴛ 107/kg) Median Range Bank, n (%) COBLT Other Recipient sex, n (%) Male Female Recipient ethnicity, n (%) White Black Hispanic Mixed Donor/recipient ethnicity, n (%) White/white or other/other White/other or other/white Primary disease, n (%) ALL AML JMML Myelodysplastic syndrome Undifferentiated leukemia Infant leukemia, n (%)* Infant leukemia Others Risk status, n (%) Good Poor† Performance status, n (%) 90% or 100%