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Originally published as JCO Early Release 10.1200/JCO.2005.04.5856 on May 22 2006 © 2006 American Society of Clinical Oncology. Bone Marrow Transplantation Versus Prolonged Intensive Chemotherapy for Children With Acute Lymphoblastic Leukemia and an Initial Bone Marrow Relapse Within 12 Months of the Completion of Primary Therapy: Children's Oncology Group Study CCG-1941
From the Division of Hematology-Oncology, Children’s Hospital Los Angeles, Los Angeles, CA; Bone Marrow Transplant Program and Division of Radiation Oncology, Children’s Hospital Medical Center Cincinnati, Cincinnati, OH; Department of Hematology-Oncology, Connecticut Children's Medical Center, Hartford, CT; Department of Pediatric Hematology/Oncology, Children’s Hospital and Clinics Minneapolis and St Paul, Minneapolis, MN; Department of Pediatric Oncology, Columbia Presbyterian College of Physicians and Surgeons, New York, NY; Northampton Area Pediatrics, Northampton, MA; Division of Pediatrics, M.D. Anderson Cancer Center, Houston, TX; Department of Statistics, Children's Oncology Group, Arcadia, CA; and the Alfred I. DuPont Hospital for Children, Wilmington, DE Address reprint requests to Paul S. Gaynon, MD, Children's Oncology Group Publications Office, 440 E Huntington Dr, PO Box 60012, Arcadia, CA 91066-6012; e-mail: PGaynon{at}chla.usc.edu; CC: pubs{at}childrensoncologygroup.org
PURPOSE: To compare conventional sibling bone marrow transplantation (CBMT), BMT with alternative donor (ABMT), and chemotherapy (CT) for children with acute lymphoblastic leukemia (ALL) and an early first marrow relapse. PATIENTS AND METHODS: After informed consent, 214 patients with ALL and early marrow relapse began multiagent induction therapy. One hundred sixty-three patients with fewer than 25% marrow blasts and count recovery at the end of induction (second remission [CR2]) were allocated by donor availability. Fifty patients with sibling donors were allocated to CBMT. Seventy-two patients were randomly allocated between ABMT and CT while 41 patients refused allocation. RESULTS: Overall, 3-year event free survival from entry is 19% ± 3%. Thirty-two of 50 CBMT patients (64%) and 19 of 37 ABMT patients (51%) underwent transplantation in CR2 with 3-year disease-free survival of 42% ± 7% and 29% ± 7%. The 3-year DFS is 29% ± 7%, 21% ± 7%, and 27% ± 8% for patients allocated to CBMT, ABMT, and CT, respectively. Contrary to protocol, 12 of 35 patients allocated to CT underwent BMT in CR2. Of these, five patients died after BMT and 5 patients relapsed. CONCLUSION: More than one half of patients died, failed reinduction, or relapsed again before 3 months after CR2 (median time to BMT). Intent-to-treat pair-wise comparison of ABMT with CT, CT with CBMT, and CBMT with ABMT yields hazards of 1.2, 1.1, 0.8 with P values of .56, .80, and .36, respectively. Outcomes remain similar and poor for children with ALL and early marrow relapse. BMT is not a complete answer to the challenge of ALL and early marrow relapse.
The treatment of relapsed acute lymphoblastic leukemia (ALL) remains a major challenge in pediatric oncology. ALL is the most common malignancy in childhood.1 Despite a steadily increasing event free-survival (EFS), relapsed ALL still has a higher incidence than the new diagnosis of many of the most common pediatric malignancies.2 Outcome after marrow relapse, especially after early marrow relapse (ie, relapse within 12 months of the completion of primary therapy) remains discouragingly poor.3,4 Many physicians, families, and patients look to second remission marrow ablative therapy with allogeneic bone marrow rescue (ie, bone marrow transplant [BMT]) to address the challenge of marrow relapse.5-10 While BMT is indisputably life-saving for some children, unbiased assessment of BMT's impact on the overall outcome of children with ALL and relapse has proven elusive.3,4 BMT is relevant only for a subset of patients with early marrow relapse. Some patients never achieve second remission (CR2) and some patients who achieve CR2 relapse again too soon to undergo BMT. Some second remission patients are judged too sick to tolerate BMT. Some patients have no appropriate matched stem cell donor, either related (matched related donor) or unrelated (matched unrelated donor). Selection bias, waiting time bias, and the bewildering multitude of pre-BMT preparative regimens and graft-versus-host disease preventative regimens may confound assessment of BMT. The comparison of the value of chemotherapy versus the value of BMT may be likened to a comparison of apples and oranges, which is to say that all treatments are not the same. Any comparison of chemotherapy and BMT approaches remain a specific comparison of the specific treatments actually employed and ought not be generalized too casually to all present and future possible chemotherapy and stem-cell transplantation approaches. Despite this uncertainty, treatment decisions between chemotherapy and BMT strategies are clinically imperative and made daily. In 1994, the Children's Cancer Group (CCG) initiated the CCG-1941 trial to compare chemotherapy with matched related donor and matched unrelated donor BMT, prospectively, for children and adolescents with ALL and marrow relapse within 12 months of the completion of primary therapy. Chemotherapy was based on the Berlin-Frankfurt-Münster (BFM) 1987 Therapieansätze für die Behandlung von Kindern mit Rezidiven (REZ) der akuten lymphoblastischen Leukämie.11-12 Several modifications were introduced as described in Patients and Methods. Patients, who completed induction with marrow blasts less than 25% and had a matched related donor were nonrandomly allocated to conventional BMT (CBMT). Other responding patients were randomly allocated between chemotherapy (CT) and alternative BMT (ABMT) with the hierarchy of stem cell sources being matched unrelated donor, haplo-identical related donor, and purged autologous marrow. All patients continued on protocol CT until the time of BMT. Whereas a BMT regimen was recommended by protocol, marrow ablative therapy, graft-versus-host disease prophylaxis, and supportive care remained at the discretion of the treating physician. Tracking patients from CR2, as well as from time of transplantation, facilitated identification of barriers to transplantation as well as post-transplantation outcomes, and provided an unbiased prospective comparison of the alternative strategies in the primary intent to treat analyses.
Eligibility required patient age younger than 21 years at the time of the initial diagnosis of ALL and an initial marrow relapse (> 25% marrow blasts) within 12 months of the completion of primary therapy (ie, between first remission and approximately 51 months from diagnosis in boys and 39 months from diagnosis in girls). Patients younger than 1 year of age at the time of relapse and patients with Down syndrome or with a prior extramedullary relapse were excluded. Participation required protocol approval by local institutional review boards and individual written informed consent per local guidelines and federal and state regulations. The CT regimen and optional BMT recommendations are detailed in Tables 1, 2, 3, and 4. CT was based on the BFM 1987 Relapse study.11-12 Several modifications were introduced. Dexamethasone replaced prednisone, pegylated asparaginase replaced native E coli asparaginase, and replaced 6-thioguanine replaced 6-mercaptopurine throughout. Ifosfamide and etoposide replaced cytarabine in the induction phase. In the intensification phase, etoposide replaced teniposide, vincristine replaced vindesine, and based on CCG observations, idarubicin replaced daunomycin.13 Again, based on CCG observations of the value of vincristine in CR2, patients received two weekly doses of vincristine in each 3-week treatment block every 2 weeks. Intensification block and biweekly vincristine in the maintenance phase.14 The duration of intensification was extended from 8 blocks or 24 weeks to 16 blocks or 48 weeks.
While a BMT regimen was recommended by protocol, marrow ablative therapy, graft-versus-host disease prophylaxis, and supportive care remained at the discretion of the treating physician. The recommended regimen is detailed in Table 4. Patients with less than 25% marrow blasts at the end of the induction phase and a matched related donor were allocated to CBMT. Other patients with less than 25% marrow blasts were randomly allocated to continued CT or ABMT with a stem cell source hierarchy of matched unrelated donor, haplo-identical related donors, and purged autologous marrow if they accepted random assignment. BMT was permitted after at least two 3-week intensification blocks and was performed according to institutional practice and priorities. The duration of CT treatment was 2 years. Conventional statistical techniques were employed. The principal end points were remission induction rate, EFS, and survival from study entry, and disease-free survival (DFS) for those patients who achieved a second remission. Relapse, second malignant neoplasm, and death from any cause were analytic events in the DFS assessment. Intent- to-treat was the primary analytic strategy. Treatment morbidity was estimated from duration of hospitalization. We had planned to accrue 400 patients over 48 months (approximately eight patients per month). We expected that approximately 320 patients would achieve CR2 (80%) and 64 would have matched sibling donors (20%). We expected that 224 (88%) of the remaining 256 patients would participate in the random assignment. This would allow us 82% power to discriminate between DFSs of 15% and 32%. Analyses were last performed in March 2004.
Between March 1995 and December 1998, 214 patients were enrolled (five patients per month). Accrual was halted early because of lower than expected accrual and difficulties in compliance with the random assignment (Table 5).
The median age of patients was 6.4 years. One hundred twenty-four patients were boys and 90 patients were girls. The duration of first remission was less than 18 months for 71 patients and  18 months for 143 patients. Where data were available, 17 patients had T-cell disease and 155 patients B-precursor disease (Fig 1).
One hundred fifty-five of 214 patients achieved fewer than 5% marrow blasts at the end of the induction phase (M1, 72%). Nine patients had between 5% and 25% marrow blasts (M2, 4%). Twenty-nine patients died (13%) and 21 patients had marrow blasts greater than 25% (M3, 10%). The average hospital stay for the induction phase was 28 days; the median was 27 days. Overall, EFS (± standard deviation [SD]) at 3 years and 5 years from entry on study is 19% ± 3% and 16% ± 3%. Survival at 3 years and 5 years is 21% ± 3% and 18% ± 3%. The mean hospital stay for all patients was 67 days and the median hospital stay 55 days, including induction deaths and failures. None of 9 patients with M2 marrow ratings at the end of the induction phase survived. Limiting analyses to patients known to be M1 at the end of induction (marrow blasts < 5%) yields 3-year and 5-year DFS of 28% ± 4% and 24% ± 4%, respectively. Outcomes by selected prognostic factors are presented in Figure 2 and Table 6.
Fifty-one patients with M1 or M2 marrow ratings at the end of induction had a matched related donor. One patient relapsed before formal treatment assignment and 50 patients were analyzed as CBMT. Overall, the DFS at 3 years and 5 years from the end of induction was 29% ± 7% and 29% ± 7%, respectively. Thirty-two patients actually underwent BMT in CR2 (64%). The median time from CR2 to BMT was 2.4 months (range, 1.4 months to 5.0 months). Seven patients died and 11 patients relapsed after BMT. The 3-year DFS was 42% ± 7% from BMT (Fig 3). CBMT patients experienced a mean hospitalization of 81 days from relapse though BMT, with 51 days in the peri-BMT period.
Of 113 patients lacking a matched related donor, 41 patients refused allocation and 72 patients were randomly allocated to ABMT or continued CT. For 37 patients allocated to ABMT, the DFS at 3 years and 5 years from the end of induction was 21% ± 7% and 21% ± 7%, respectively. Nineteen patients (51%) actually underwent ABMT in CR2 (18 matched unrelated donor BMT and one autologous BMT). The median time from CR2 to BMT was 3.3 months (range, 2.4 to 6.0 months). Of these, nine patients died, and four patients relapsed for a 3-year DFS of 29% ± 11% from the date of BMT (Fig 3). The patient undergoing autologous BMT relapsed. ABMT patients experienced a mean hospitalization of 81 days from relapse through BMT, with 57 days in the peri-BMT period. For 35 patients allocated to CT, the DFS at 3 years and 5 years from the end of induction was 27% ± 8% and 20% ± 7%, respectively. Contrary to protocol, 12 patients allocated to CT underwent ABMT in second remission. Five patients died after BMT and five patients relapsed. Among 23 patients continuing on CT, four patients died and 12 patients relapsed. CT patients experienced a mean hospitalization of 91 days. Overall comparisons of ABMT, CT, and CBMT from CR2 show no statistically significant differences (Fig 4). Pair-wise comparison of ABMT with CT, CT with CBMT, and CBMT with ABMT from CR2 show hazard ratios of 1.2, 1.1, and 0.8, with P values of .56, .80, and .36, respectively. When CT patients who experienced transplantation in CR2 are censored at the time of BMT, the hazard ratio becomes 0.8 in comparison with CBMT, (P = .4). Of course, censoring is valid only when the censored patients are likely to have a subsequent outcome similar to patients not censored. If patients were taken to BMT because they were at higher risk of relapse, censoring is not at all valid. When ABMT is compared with CT for patients remaining in remission for a minimum of 2.4 months in a landmark analysis, the hazard ratio is 1.1 and P = .72.
Although some patients achieved 5-year EFS after early marrow relapse, treatment failed for at least five of six patients. Outcomes were somewhat better for B-precursor patients with longer first remissions ( 30 months) and uniformly poor for T-cell patients and for patients not achieving M1 marrow status at the end of induction. A similarly poor ultimate EFS of 7% is reported for bone marrow relapse within 2 years of diagnosis for the Medical Research Council (MRC; United Kingdom) R1 trial. A somewhat better EFS of 35% is reported for bone marrow relapse at between 2 years and 2.5 years from diagnosis.15 Despite the intensive induction therapy, the M1 remission rate was 72%. The median hospital stay was 28 days. The MRC United Kingdom (UK) R1 study reported a 95% induction rate for early and late bone marrow relapse with therapy requiring hospitalization of only 14 days.15 The succeeding British R2 study obtained remission for 26 (81%) of 32 patients after early relapse.16 Abshire and the Pediatric Oncology Group17 compared every 2 week and weekly pegylated asparaginase with vincristine, doxorubicin, and prednisone and obtained CR2 rates of 82% and 97% in a population including both early and late marrow relapse. Einsiedel et al12 reported remission for 41 (73%) of 56 patients with early marrow relapse for the BFM 1987 relapse study. Our patients had relapsed perhaps after more intensive initial therapy than in some of the older studies, but our induction result is in no way better than any other. Post-BMT outcomes were quite reasonable and similar to those reported for similar patients in the United States.10 The 3-year DFS for matched related donor and ABMT were 42% and 29%, respectively, and as often reported,18 not significantly different in pair-wise comparison. A single institution study from Great Ormond Street Hospital (London, United Kingdom)4 and two well-designed, prospective MRC UK studies3,19 similarly show comparable outcomes with BMT and CT strategies. Others have claimed clear advantage for matched related donor BMT20 or for matched unrelated donor BMT21 in case control studies where selection bias may remain an issue. Selection of the CT control may be an issue. In our trial, small numbers and poor protocol adherence limit the power of comparisons. Although reasons were not gathered, one may speculate that poor adherence is related to the known poor outcome and a desire to do everything possible for children for whom aggressive CT had already failed once. However, no compelling advantage is shown for any approach. Within the limited power of the small patient population studied, outcomes were similar and thoroughly unsatisfactory both for patients pursuing the CT strategy and for those pursuing a BMT strategy, with either matched family or matched unrelated donors. CBMT and ABMT outcomes were similar to those expected. As on the MRC UK ALL R2 study,16 CT outcomes were somewhat better than expected. No statistical maneuver can correct for the effect of noncompliance with random assignment on power. Our initial design sought to discriminate between DFS of 32% and 15%. In the end, lack of power makes our results compatible with substantial differences among treatment options. However, the lower limit of a one sided 90% CI for DFS in patients treated as randomly assigned to CT is 17%, so it is unlikely the true DFS is lower than that value. Hospitalization experience was substantial and similar. A majority of treatment failures occurred before any BMT procedure rather than afterwards. We failed to obtain a second remission for one quarter of patients. Of those patients with a matched related donor who achieved CR2, one in three patients died or relapsed before any CR2 BMT. The median times from CR2 to CBMT and CR2 to ABMT was 2.4 months and 3.0 months, respectively. Overall, one half of patients with matched related donor did not achieve a remission, relapsed, or died before a BMT was performed. Among patients in CR2 allocated to ABMT, one half of patients died or relapsed before any CR2 BMT. Reinduction failure and early relapse left ABMT as a viable strategy for fewer than 40% of patients with early marrow relapse. As conducted, this study lacks substantial power to detect still clinically relevant differences between BMT and CT. However, singular focus on possible peri-BMT or post-BMT interventions will exclude most postrelapse failures. In this study, more than 50% of patients died, failed reinduction, or relapsed again before the median time to BMT. Although life-saving for some children, current BMT approaches are not an adequate response to the problem of relapse—especially early marrow relapse. Substantial improvement in the outcomes of children with early marrow relapse is unlikely to be obtained through shifting patient allocations between unsatisfactory CT and unsatisfactory BMT strategies. BMT and CT are not independent. BMT outcomes may depend on the preceding CT and the level of persisting minimal residual disease.22 Better outcomes remain the critical challenge. Inability to salvage patients after relapse maintains the imperative to continue to seek to improve initial therapy, usually by increasing treatment intensity and adding to morbidity for the still growing majority of children already cured with current therapy. BMT, although indisputably life-saving for some children, is not a complete answer to the challenge of relapse. Improved outcome after relapse may follow from better reinduction CT with a higher remission rate and lower levels of postinduction minimal residual disease, as well as better CT or BMT intensification.
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
A complete listing of grant support for research conducted by Children's Cancer Group and Pediatric Oncology Group before initiation of the Children's Oncology Group grant in 2003 is available online at http://www.childrensoncologygroup.org/admin/grantinfo.htm. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Young JL Jr, Ries LG, Silverberg E, et al: Cancer incidence, survival, and mortality for children younger than age 15 years. Cancer 58:598-602, 1986[CrossRef][Medline] 2. Gaynon PS, Qu RP, Chappell RJ, et al: Survival after relapse in childhood acute lymphoblastic leukemia: Impact of site and time to first relapse:The Children's Cancer Group Experience. Cancer 82:1387-1395, 1998[CrossRef][Medline] 3. Wheeler K, Richards S, Bailey C, et al: Comparison of bone marrow transplant and chemotherapy for relapsed childhood acute lymphoblastic leukaemia: The MRC UKALL X experience. Br J Haematol 101:94-103, 1998[CrossRef][Medline] 4. Chessells JM, Veys P, Kempski H, et al: Long-term follow-up of relapsed childhood acute lymphoblastic leukaemia. Br J Haematol 123:396-405, 2003[CrossRef][Medline] 5. Dopfer R, Henze G, Bender-Gotze C, et al: Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALL-protocols: Results of the German Cooperative Study. Blood 78:2780-2784, 1991 6. Barrett AJ: Bone marrow transplantation for acute lymphoblastic leukaemia. Baillieres Clin Haematol 7:377-401, 1994[CrossRef][Medline] 7. Hoogerbrugge PM, Gerritsen EJ, vd Does-van den Berg A, et al: Case-control analysis of allogeneic bone marrow transplantation versus maintenance chemotherapy for relapsed ALL in children. Bone Marrow Transplant 15:255-259, 1995 8. Uderzo C, Valsecchi MG, Bacigalupo A, et al: Treatment of childhood acute lymphoblastic leukemia with allogeneic bone marrow transplantation and chemotherapy: Ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association. J Clin Oncol 13:352-358, 1995 9. Borgmann A, Baumgarten E, Schmid H, et al: Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: A conceivable alternative? Bone Marrow Transplant 20:939-944, 1997[CrossRef][Medline] 10. Boulad F, Steinherz P, Reyes B, et al: Allogeneic bone marrow transplantation versus chemotherapy for the treatment of childhood acute lymphoblastic leukemia in second remission: A single-institution study. J Clin Oncol 17:197-207, 1999 11. Henze G, Fengler R, Haertmann R, et al: Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85): A relapse study of the BFM group. Blood 78:1166-1172, 1991 12. Einsiedel HG, von Stackelberg A, Hartmann R, et al: Long-term outcome in children with relapsed ALL by risk-stratified slavage therapy: Results of trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster group 87. J Clin Oncol 23:7942-7950, 2005 13. Feig SA, Ames MM, Sather HN, et al: Comparison of idarubicin to daunomycin in a randomized multidrug treatment of childhood acute lymphoblastic leukemia at first bone marrow relapse: A report from the Children's Cancer group. Med Pediatr Oncol 27:505-514, 1996[CrossRef][Medline] 14. Baum E, Nachman J, Ramsay N, et al: Prolonged second remissions in childhood acute lymphocytic leukemia: A report from the Childrens Cancer Study group. Med Pediatr Oncol 11:1-7, 1983[Medline] 15. Lawson SE, Harrison G, Richards S, et al: The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: A report on the medical research council UKALLR1 study. Br J Haematol 108:531-543, 2000[CrossRef][Medline] 16. Roy A, Cargill A, Love S, et al: Outcome after first relapse in childhood acute lymphoblastic leukaemia: Lessons from the United Kingdom R2 trial. Br J Haematol 130:67-75, 2005[CrossRef][Medline] 17. Abshire TC, Pollock BH, Billett AL, et al: Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: A Pediatric Oncology Group study. Blood 96:1709-1715, 2000 18. Al-Kasim FA, Thornley I, Rolland M, et al: Single-centre experience with allogeneic bone marrow transplantation for acute lymphoblastic leukaemia in childhood: Similar survival after matched-related and matched-unrelated donor transplants. Br J Haematol 116:483-490, 2002[Medline] 19. Harrison G, Richards S, Lawson S, et al: Comparison of allogeneic transplant versus chemotherapy for relapsed acute lymphoblastic leukaemia in the MRC UKALL R1 trial: MRC Childhood Leukaemia Working Party. Ann Oncol 11:999-1006, 2000 20. Barrett AJ, Horowitz MM, Pollock BH, et al: Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission. N Engl J Med 331:1253-1258, 1994 21. Borgmann A, von Stackelberg A, Hartmann R, et al: Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: A matched-pair analysis. Blood 101:3835-3839, 2003 22. Bader P, Hancock J, Kreyenberg H, et al: Minimum residual disease (matched related donor) status prior to allogeneic stem cell transplant is a powerful predictor for post-transplant status in children with ALL. Leukemia 16:1668-1672, 2002[CrossRef][Medline] Submitted October 14, 2005; accepted April 10, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
