Biology of Blood and Marrow Transplantation 12:204-216 (2006) 䊚 2006 American Society for Blood and Marrow Transplantation 1083-8791/06/1202-0009$32.00/0 doi:10.1016/j.bbmt.2005.10.013
Pretransplantation Consolidation Chemotherapy Decreases Leukemia Relapse after Autologous Blood and Bone Marrow Transplants for Acute Myelogenous Leukemia in First Remission Martin S. Tallman,2 Waleska S. Pérez,1 Hillard M. Lazarus,3 Robert Peter Gale,4 Richard T. Maziarz,5 Jacob M. Rowe,6 David I. Marks,7 Jean-Yves Cahn,8 Asad Bashey,9 Michael R. Bishop,10 Neal Christiansen,11 Stanley R. Frankel,12 Juan J. García,13 Osman Ilhan,14 Mary J. Laughlin,3 Jane Liesveld,15 Charles Linker,16 Mark R. Litzow,17 Selina Luger,18 Philip L. McCarthy,19 Gustavo A. Milone,20 Santiago Pavlovsky,20 Gordon L. Phillips,21 James A. Russell,22 Ruben A. Saez,23 Gary Schiller,24 Jorge Sierra,25 Roy S. Weiner,26 Axel R. Zander,27 Mei-Jie Zhang,1 Armand Keating,28 Daniel J. Weisdorf,28 Mary M. Horowitz1 1 Autologous Blood and Marrow Transplant Registry (ABMTR) Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wisconsin; 2Northwestern University Medical School, Chicago, Illinois; 3University Hospitals of Cleveland, Ireland Cancer Center, Cleveland, Ohio; 4Center for Advanced Studies in Leukemia, Los Angeles, California; 5Oregon Health and Science University, Portland, Oregon; 6Rambam Medical Center and Technion, Haifa, Israel; 7Bristol Children’s Hospital, Bristol, U.K.; 8Hopital Jean Minijoz, Besancon Cedex, France; 9University of California, San Diego, La Jolla, California; 10National Cancer Institute, Bethesda, Maryland; 11 University of South Carolina, Columbia, South Carolina; 12Merck Research Labs, Blue Bell, Pennsylvania; 13 Hospital Privado de Cordoba, Cordoba, Peia, Argentina; 14Ibini Sinai Hospital, Ankara, Turkey; 15University of Rochester Medical Center, Rochester, New York; 16University of California San Francisco Medical Center, San Francisco, California; 17Mayo Clinic and Foundation, Rochester, Minnesota; 18University of Pennsylvania Hospital, Philadelphia, Pennsylvania; 19Roswell Park Cancer Institute, Buffalo, New York; 20Angélica Ocampo-Hospital and Research Center-Fundaleu, Buenos Aires, Argentina; 21Greenbaum Cancer Center, Baltimore, Maryland; 22Tom Baker Cancer Institute, Calgary, Alberta, Canada; 23Watson Clinic, LLP, Lakeland, Florida; 24University of California Los Angeles Center for Health Sciences, Los Angeles, California; 25Hospital Sant Pau, Barcelona, Spain; 26 Tulane University Medical Center, New Orleans, Louisiana; 27Universitats-Krankenhaus Eppendorg, Hamburg, Germany; University of Toronto, Toronto, Canada; 28University of Minnesota, Minneapolis, Minnesota
Correspondence and reprint requests: Mary M. Horowitz, MD, MS, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, 8701 Watertown Plank Road, P.O. Box 26509, Milwaukee, WI 53226 (e-mail:
[email protected]). Received April 1, 2005; accepted October 3, 2005
ABSTRACT Controversy exists over whether pretransplantation consolidation chemotherapy affects the outcome of subsequent autotransplantation for acute myelogenous leukemia (AML). The current study was undertaken to determine the association between previous consolidation and outcome of autotransplantation for AML in first remission. Posttransplantation outcomes of 146 patients receiving no consolidation were compared with those of 244 patients receiving standard-dose (1 cycle standard-dose Ara-C ⴞother versus 1 cycle high-dose Ara-C ⴞother versus >1 cycle high-dose Ara-C ⴞ other versus 1 cycle other induction therapy versus >1 cycle other induction therapy Additional drugs for consolidation: yes versus no Time from diagnosis to CR1: 2 months versus missing Cycles of chemotherapy to achieve CR1: 1 versus >1 versus missing Consolidation chemotherapy cycles after CR1: 1 versus 2 versus >2 versus missing Time from diagnosis to transplantation Time from CR1 to harvest: 3 months versus missing Time from CR1 to transplant: 3 months versus missing Treatment-related: Source of stem cell: BM versus PBSC Conditioning regimen: CyTBI ⴞ other versus BuCyVP16 ⴞ other versus BuCy ⴞ other versus others Year of transplantation: 1989-1994 versus 1995-1998 Induction of GVHD: yes versus no versus missing Growth factors posttransplantation: yes versus no
FAB indicates French-American-British classification; WBC, white blood cell count; BM, bone marrow; PBSC, peripheral blood stem cells; CR, complete remission; Bu, busulfan; Cy, cyclophosphamide; TBI, total body irradiation; VP16, etoposide; GVHD, graft-versus-host disease; GF, growth factors. *Included in all models.
distribution. A greater percentage of patients receiving high-dose cytarabine had a pretransplantation Karnofsky score ⬍90%. The median white blood cell count at diagnosis was lower in the no pretransplantation consolidation group than in the standard- and high-dose cytarabine groups. There were no differences in the distribution of good, intermediate, or poor prognosis cytogenetics among the 3 groups. Approximately 30% of the patients in each group had normal cytogenetics, and 30% had unknown karyotypes. A higher percentage of patients receiving either no consolidation or standard-dose cytarabine had extramedullary disease compared with those receiving high-dose cytarabine. There were no differences among the groups in the percentage of patients with previous history of myelodysplastic syndrome. Patients receiving high-dose cytarabine were more likely to receive only 1 cycle of pretransplantation consolidation than those receiving standard-dose cytarabine. The time from diagnosis to first CR was longer in the patients receiving no consolidation. Not unexpectedly, the time between achieving CR and transplantation was longer for the patients who received consolidation. More patients not receiving consolidation or receiving standard-dose cytarabine had bone marrow as the source of stem cells compared with those receiving high-dose cytarabine. Purging the graft to
BB&MT
remove leukemia cells was more likely to be done for the patients who did not receive consolidation. The patients who received consolidation with high-dose cytarabine were more likely to receive either granulocyte or granulocyte-macrophage colony-stimulating factor to promote hematopoietic recovery. Moreover, 97% of patients receiving pretransplantation consolidation received growth factors for harvesting. Univariate Analyses
Univariate comparisons of outcomes are given in Table 3. One-year TRM rates were similar among the 3 treatment groups (Figure 1A). The 5-year relapse rate was 10% lower in the patients receiving consolidation than in those not receiving consolidation (Figure 1B). The 5-year LFS and overall survival were significantly higher in those receiving consolidation than in those not receiving consolidation. Multivariate Analyses
In all multivariate analyses, the risk of transplantation outcomes was virtually identical for the standard- and high-dose cytarabine groups. Consequently, only the RR risks with consolidation versus without consolidation are presented here. In multivariate analysis, TRM was higher among 207
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208 Table 2. Characteristics of Patients Receiving Autologous Transplantation for AML in First Complete Remission by Cytarabine (Ara-C) Pretransplantation Consolidation Therapy No Pretransplantation Consolidation Variable Number of patients Age, median (range), years Age by decade, years 50 Male Karnofsky score pretransplantation 4 Consolidation chemotherapy cycles after CR1¶ 1 2 >2 Time from diagnosis to transplantation median (range), months Time from CR1 to harvest, median (range), months Time from CR1 to transplantation, median (range), months Source of stem cells BM Peripheral blood BM ⴙ peripheral blood Purging Agents used for purging Monoclonal antibody 4-hydroperoxycyclophosphamide Mafosfamide Other# Conditioning regimen CyTBI ⴞ other BuCyVP16 ⴞ other BuCy ⴞ other (not VP16) Other
138
n(%)
No. evaluable 236
29 (21) 62 (45) 19 (14) 4 (3) 18 (13) 6 (4) NA 145 145 138
244 241 241 236
2 (
