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Journal of Clinical Oncology, Vol 22, No 18 (September 15), 2004: pp. 3798-3804 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.12.142 Autologous Hematopoietic Stem-Cell Transplantation for Children With Acute Myeloid Leukemia in First or Second Complete Remission: A Prognostic Factor AnalysisFrom the Autologous Blood and Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, WI; Oregon Health Sciences University, Portland, OR; Medical College of Virginia, Richmond, VA; Pediatric Oncology Branch, National Cancer Institute, Bethesda; Johns Hopkins Hospital, Baltimore, MD; Center for Advanced Studies in Leukemia, Los Angeles, CA; The Hospital for Sick Children, Toronto, Ontario, Canada; Children's Hospital, Louisiana State University Health Science Center, New Orleans, LA; Columbia University Hospital, New York, NY; Nemours Children's Clinic, Jacksonville; Florida Hospital Cancer Institute, Orlando, FL; and University of Pittsburgh Medical Center and Cancer Institute, Pittsburgh, PA Address reprint requests to Mary Eapen, MBBS, MS, International Bone Marrow Transplant Registry, Medical College of Wisconsin, 8701 Watertown Plank Rd, PO Box 26509, Milwaukee, WI, 53226; e-mail: meapen{at}mail.mcw.edu
PURPOSE: To determine prognostic factors correlated with outcomes after autologous hematopoietic stem-cell transplantation (HSCT) in children with acute myeloid leukemia (AML).
PATIENTS AND METHODS: We studied 219 children who received autologous HSCT for AML in first complete remission (CR) and 73 children in second CR and who were reported to the Autologous Blood and Marrow Transplant Registry. Among 29 of 73 patients who underwent transplantation in second CR, duration of first CR was
RESULTS: Three-year cumulative incidences of relapse were 37% (95% CI, 31% to 44%), 60% (95% CI, 41% to 74%), and 36% (95% CI, 20% to 53%) for children in first CR, second CR after a short (< 12 months) first CR, and second CR after a long ( CONCLUSION: Duration of first CR seems to be the most important determinant of outcome. Results in children who experience treatment failure with conventional chemotherapy support the use of autologous transplantation as salvage therapy if such patients achieve a subsequent CR.
Intensification of chemotherapy and advances in supportive care have improved survival of children with acute myeloid leukemia (AML).1-3 With intensive induction chemotherapy, 80% to 90% of children achieve remission, and with further therapy, nearly 50% are long-term survivors. In North America, hematopoietic stem-cell transplantation (HSCT) from an HLA-identical sibling is the treatment of choice for children with AML in first complete clinical remission (CR).3 In contrast, others report comparable outcomes with risk-adapted intensified chemotherapy.2,4 However, an HLA-identical family donor is available to less than one third of patients. In the absence of a suitable HLA-matched family donor, treatment options include chemotherapy, autologous HSCT, or unrelated donor HSCT. The results of randomized clinical trials for AML in children suggest equivalent outcomes after intensive chemotherapy and autologous HSCT in first CR.3,5,6 Leukemia recurrence is common with either approach. Treatment options include chemotherapy and autologous or allogeneic HSCT, and few patients are long-term survivors.7-13 Factors affecting survival after relapse, particularly the length of first CR, are well described in adults.8-10 However, there are limited data in children.11-13 Because graft-versus-host disease (GVHD) does not occur and immunosuppression is not required after autologous HSCT, transplant-related mortality (TRM) is low with this approach. Disadvantages are the possibility of infusing leukemic stem cells and the absence of a graft-versus-leukemia effect. To better define the role and outcome of autologous HSCT for AML in children, we studied 292 recipients of autologous HSCT in first or second CR and analyzed the association between outcomes and patient, disease, and treatment-related variables.
Autologous Blood and Marrow Transplant Registry (ABMTR) The ABMTR is a voluntary organization of more than 200 institutions in the United States, Canada, and Central and South America that report data on consecutive autotransplantations to a statistical center at the Medical College of Wisconsin (Milwaukee, WI). The ABMTR defines autotransplantation as treatment with a sufficiently high dose of chemotherapy to require autologous bone marrow or blood-derived hematopoietic stem-cell support. The ABMTR began collecting data in 1992. Data were collected retrospectively for patients who received autotransplants between 1989 and 1992 and prospectively thereafter. The ABMTR database includes information for approximately 50% of autologous HSCTs performed in North America. The ABMTR collects data at two levels: registration and research. Registration data include disease type, age, sex, date of diagnosis, pretransplantation disease stage, date of transplantation, graft type, high-dose conditioning regimen, posttransplantation status, and survival. Patients are followed longitudinally, and updates on disease and survival status for registered patients are requested annually. Research data are collected on subsets of registered patients by a weighted randomization scheme and include comprehensive pre- and post-transplantation clinical data. Physician review of submitted data, computerized error checks, and on-site audits ensure data accuracy.
Patients
End Points
Statistical Methods
Patient and Transplant Characteristics Two hundred nineteen patients in first CR and 73 patients in second CR fulfilled the eligibility criteria. Patient, disease, and transplant characteristics are listed in Table 2. Median age at transplantation was 10 years (range, 1 to 20 years). Median WBC count at presentation was 19 x 109/L (range, 1.2 to 690 x 109/L). Eighty-five percent of patients received consolidation therapy in first CR; cytarabine-based regimens were the most common. Most patients underwent stem-cell collection in first CR (83%) and 53% received a graft treated in vitro to remove leukemia cells (purged). The majority of patients in first CR (75%) underwent transplantation within 6 months from diagnosis. Among patients in second CR, 5% underwent transplantation within 6 months, 24% between 7 and 12 months, and 71% beyond 12 months from diagnosis. Ninety-four (43%) of 219 patients in first CR and 50 (68%) of 73 patients in second CR underwent transplantation within 3 months of achieving their most recent CR. Eighty-four percent of patients received bone marrow and 16% received peripheral-blood cells. Eighty-one percent received busulfan and cyclophosphamide for pretransplantation conditioning. Twenty-five percent of patients received planned growth factor (within the first 7 days after HSCT) to promote hematopoietic recovery. The median follow-up of survivors in this cohort was 80 months (range, 4 to 160 months). Ninety-eight percent of survivors were followed up for a minimum of 12 months.
Transplant-Related Mortality In multivariate analysis, the only variable associated with TRM was age at transplantation. TRM was higher in children older than 10 years compared with younger children (relative risk, 3.77; 95% CI, 1.59 to 8.64; P = .0024). Cumulative incidences of TRM at 3 years were 4% (95% CI, 2% to 8%) for younger children (  10 years) and 16% (95% CI, 10% to 22%) for older (> 10 years) children and adolescents (Fig 1).
Relapse Remission status was the only variable that was associated with relapse (Table 3). Relapse rates were significantly higher among children who underwent transplantation in second CR after a short (< 12 months) first CR than in children who underwent transplantation in first CR or in second CR after a long first CR. Relapse rates were similar for patients who underwent transplantation in first CR or in second CR after a long (  12 months) first CR. Cumulative incidences of relapse at 3 years were 37% (95% CI, 31% to 44%), 60% (95% CI, 41% to 74%), and 36% (95% CI, 20% to 53%) for patients who underwent transplantation in first CR, in second CR after a short first CR, and in second CR after a long first CR, respectively (Fig 2).
Leukemia-Free Survival Age and remission status were associated with treatment failure (relapse or death, inverse of LFS; Table 4). Treatment failure rates were similar in patients who underwent transplantation in first CR or in second CR after a long ( 12 months) first CR. Treatment failure was higher in children who underwent transplantation in second CR after a short first CR and in those older than 10 years. Three-year probabilities of LFS were similar for children who underwent transplantation in first CR or in second CR after a long ( 12 months) first CR: 54% (95% CI, 47% to 60%) and 60% (95% CI, 42% to 75%), respectively. The probability of LFS was significantly lower for those patients who underwent transplantation in second CR after a short (< 12 months) first CR: 23% (95% CI, 10% to 39%; Fig 3).
Overall Survival Age and remission status were associated with overall survival (Table 5). Mortality was higher in older children and in those who underwent transplantation in second CR after a short-duration (< 12 months) first CR. Three-year probabilities of overall survival were 62% (95% CI, 54% to 68%), 57% (95% CI, 40% to 70%), and 22% (95% CI, 9% to 39%) for children who underwent transplantation in first CR, in second CR after a long first CR, and in second CR after a short first CR, respectively (Fig 4).
One hundred twenty-six patients died. Leukemia relapse was the most common cause of death, accounting for 69% of deaths. Other causes were infection (10%), interstitial pneumonitis (8%), multisystem organ failure (8%), second malignancy (< 1%), and other causes (5%).
Among children with AML, leukemia relapse is common, whether treatment is with intensive chemotherapy alone or in combination with allogeneic or autologous HSCT. Relapse occurs in approximately 30% to 50% of patients who achieve remission, and only a minority are long-term survivors after further therapy.10-12,17 The objective of the current study was to determine factors that affect outcomes after autologous HSCT for children with AML in first CR and those who achieve a second CR after a first relapse and to identify children who may benefit from this approach. The data indicate that younger children have better outcomes than older children and adolescents. Perhaps the most important finding of this study is that a substantial proportion of children who underwent transplantation in second CR achieved long-term LFS, especially those experiencing relapse after a long first CR. Three-year LFS was 60% among children who underwent transplantation in second CR after a long first CR and 23% among those who underwent transplantation after a short CR. The decision to advocate transplantation and all aspects of the transplantation regimen were at the discretion of the transplant center and is an intrinsic limitation of a registry-based study. Patients in second CR after a short first CR were more likely to experience relapse and had higher treatment failure and mortality. These findings are similar to published reports in adults and children with recurrent AML.7-13,17 The length of first CR seems to be more important than the initial risk group, though the latter may influence the likelihood of achieving and sustaining a first CR.10-12 Although the duration of first CR seems to be primarily a function of the biology of the disease, remission duration may also be correlated with the intensity of treatment received before relapse.3,18 We did not observe an association between time from diagnosis and time from most recent CR to transplantation and relapse, LFS, and overall survival. Children with a short first CR had the worst outcome. But among those in second CR after an early relapse, approximately one quarter achieved long-term LFS, making autologous HSCT a reasonable salvage therapy, even in this poor risk group. However, as the current study is limited to children who achieved a second CR after a first relapse, LFS and survival rates cannot be generalized to all children with recurrent AML. Most children with recurrent leukemia in the current era achieve a second CR, but remissions are short and many are not candidates for transplantation. Other known prognostic factors such as French-American-British subtype, cytogenetics, and WBC count did not seem to influence relapse, mortality, or treatment failure. This is comparable to earlier reports in children.10,11 We did not observe an association between graft purging and HSCT outcomes. However, most patients in this cohort underwent stem-cell collection in first CR and had received consolidation therapy; this may have served as in vivo purging, minimizing the potential for additional benefit from in vitro purging. Several randomized studies in children with AML in first CR that compared intensive chemotherapy with autologous HSCT have shown no differences in overall survival.2-5,11 Our data do not support autologous HSCT in first CR. We observed a relapse rate of 37% and survival of 62% at 3 years, and these are comparable to results of chemotherapy alone. An intensive chemotherapy regimen alone may provide cytoreduction that is comparable to high-dose chemotherapy followed by autologous HSCT. We did not observe a significant difference in overall survival between patients who underwent transplantation in first CR and second CR after a long first CR. Others and we have shown that recurrent leukemia is the most common cause of mortality. Rates of relapse and treatment failure were similar in patients who underwent transplantation in first and second CR after a long first CR and may explain our inability to detect a clinically significant difference in survival. However, this analysis is limited, as only 25% of patients were in second CR at transplantation. Although small numbers of patients in second CR after a short first CR were sufficient to detect a relatively large clinically significant difference in relapse, LFS, and survival, among those in second CR after a long first CR, small numbers may have limited our ability to detect a smaller clinically significant difference. Advances in transplantation procedures have extended the donor pool to include unrelated and mismatched family donors for children with AML in second CR. Event-free survival reported in children is 30% to 42%.19,20 Data from the International Bone Marrow Transplant Registry and the National Marrow Donor Program on patients of all ages suggest higher overall survival for patients in second CR after autologous HSCT compared with unrelated donor HSCT (46% v 34%; P = .012).21 Rates of TRM are higher after unrelated donor HSCT, offsetting beneficial allograft effects against leukemia relapse. Although a retrospective analysis has limitations, such as selection bias for transplantation, and inability to adjust for unknown or unmeasured factors, these data suggest nonetheless that autotransplantation may be considered appropriate salvage therapy for children and adolescents who experience treatment failure with conventional chemotherapy if they achieve a subsequent CR. Although the best results were observed in children who experienced relapse after a long first CR, a small but not insignificant proportion of children who experienced relapse after a short first CR also achieved sustained remission.
Grant support was provided by the following: Public Health Service grant No. U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute; Agency for Healthcare Research and Quality and grants from Allianz Life/Life Trac; American Cancer Society; American Red Cross; American Society of Clinical Oncology; Amgen, Inc; Anonymous; Aventis Pharmaceuticals; Baxter Healthcare Corp; Baxter Oncology; Berlex Laboratories, Inc; Blue Cross and Blue Shield Association; The Lynde and Harry Bradley Foundation; Bristol Myers Squibb Oncology; Cedarlane Laboratories Ltd; Cell Pathways; CelMed Biosciences; Centocor, Inc; Cubist Pharmaceuticals; Darwin Medical Communications, Ltd; Dynal Biotech ASA; Edwards Lifesciences RMI; Endo Pharmaceuticals, Inc; Enzon Pharmaceuticals, Inc; ESP Pharma; Excess, Inc; Fujisawa Healthcare, Inc; Gambro BCT, Inc; GlaxoSmithKline, Inc; Human Genome Sciences; ICN Pharmaceuticals, Inc; ILEX Oncology; Kirin Brewery Company; Ligand Pharmaceuticals, Inc; Eli Lilly and Company; Nada and Herbert P. Mahler Charities; Merck & Company; Millennium Pharmaceuticals; Miller Pharmacal Group; Milliman USA, Inc; Miltenyi Biotec; The Irving I. Moskowitz Foundation; National Marrow Donor Program; NeoRx Corporation; Novartis Pharmaceuticals, Inc; Novo Nordisk Pharmaceuticals; Orphan Medical, Inc; Ortho Biotech, Inc; Osiris Therapeutics, Inc; PacifiCare Health Systems; Pall Medical; Pfizer U.S. Pharmaceuticals; Pharmacia Corporation; Pharmametrics; Pharmion Corp; Protein Design Labs; Roche Laboratories; SangStat Medical; Schering AG; StemCyte, Inc; StemCell Technologies, Inc; Stemco Biomedical; StemSoft Software, Inc; SuperGen, Inc; Sysmex; THERAKOS, a Johnson & Johnson Co; University of Colorado Cord Blood Bank; ViaCell, Inc; ViaCor Biotechnologies; W.B. Saunders Mosby Churchill; and Wellpoint Health Network and Zymogenetics, Inc.
The authors indicated no potential conflicts of interest.
Grant information for this study is found in the Appendix. Presented (in part) at the Annual Meeting of the American Society of Hematology, Orlando, FL, December 7-11, 2001. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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3. Woods WG, Neudorf S, Gold S, et al: A comparison of allogeneic bone marrow transplantation, autologous bone marrow transplantation, and aggressive chemotherapy in children with acute myeloid leukemia in remission: A report from the Children's Cancer Group. Blood 97:56-72, 2001 4. Creutzig U, Ritter J, Zimmermann M, et al: Comparison of allogeneic matched related stem cell transplantation in 1st CR with chemotherapy alone in children with high risk AML. Ann Hematol 79:S14, 2000 (abstr)
5. Ravindranath Y, Yeager AM, Chang MN, et al: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med 334:1428-1434, 1996 6. Burnett AK, Goldstone AH, Stevens RMF, et al: Randomized comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: Results of MRC AML10 trial. Lancet 351:700-708, 1998[CrossRef][Medline] 7. Keating MJ, Kantarjian H, Smith TL, et al: Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 7:1071-1080, 1989[Abstract]
8. Estey E, Kornblau S, Pierce S, et al: A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. Blood 88:756, 1996 9. Thalhammer F, Geissler K, Jager U, et al: Duration of second complete remission in patients with acute myeloid leukemia treated with chemotherapy: A retrospective single-center study. Ann Hematol 72:216-222, 1996[CrossRef][Medline] 10. Stahnke K, Boos J, Bender-Götze C, et al: Duration of first remission predicts remission rates and long-term survival in children with relapsed acute myelogenous leukemia. Leukemia 12:1534-1538, 1998[CrossRef][Medline] 11. Webb DK, Wheatley K, Harrison G, et al: Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. Leukemia 13:25-31, 1999[CrossRef][Medline] 12. Webb DKH: Management of relapsed acute myeloid leukaemia. Br J Haematol 106:851-859, 1999[CrossRef][Medline] 13. Stoiser B, Knöbl P, Fonatsc C, et al: Prognosis of patients with a second relapse of acute myeloid leukemia. Leukemia 14:2059-2063, 1999 14. Klein JP, Moeschberger ML: Survival Analysis: Techniques for Censored and Truncated Data. New York, NY, Springer Verlag, 2003 15. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-202, 1972 16. Andersen PK, Klein JP, Zhang MH: Testing for center effects in multi-center survival studies: A Monte Carlo comparison of fixed and random effects tests. Stat Med 18:1489-1500, 1999[CrossRef][Medline] 17. Tomás JF, Gómez-Garcia de Soria V, López-Lorenzo JL, et al: Autologous or allogeneic bone marrow transplantation for acute myeloblastic leukemia in second complete remission: Importance of duration of first complete remission in final outcome. Bone Marrow Transplant 17:979-984, 1996[Medline]
18. Woods WG, Kobrinsky N, Buckley JD, et al: Time-sequential induction therapy improves postremission outcome in acute myeloid leukemia: A report from the Children's Cancer Group. Blood 87:4979-4989, 1996
19. Davies SM, Shu XO, Blazar BR, et al: Unrelated donor bone marrow transplantation: Influence of HLA A and B incompatibility on outcome. Blood 86:1636-1642, 1995
20. Godder KT, Hazlett LJ, Abhyankar SH, et al: Partially mismatched related-donor bone marrow transplantation for pediatric patients with acute leukemia: Younger donors and absence of peripheral blasts improve outcome. J Clin Oncol 18:1856-1866, 2000 21. Lazarus HM, Pérez WS, Klein JP, et al: Autotransplants versus HLA-matched unrelated donor bone marrow transplants for acute myeloid leukemia (AML): A retrospective comparison from the National Marrow Donor Program, the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry. Blood 96:414a, 2000 (abstr 1781) Submitted December 19, 2003; accepted June 8, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
