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© 2003 American Society for Clinical Oncology Mitoxantrone and Cytarabine Induction, High-Dose Cytarabine, and Etoposide Intensification for Pediatric Patients With Relapsed or Refractory Acute Myeloid Leukemia: Children’s Cancer Group Study 2951From the M.D. Anderson Cancer Center, Houston, TX; LifeSource Upper Midwest Organ Procurement Organization, Inc, St Paul; University of Minnesota, Minneapolis, MN; University of Southern California Keck School of Medicine, Los Angeles; Children’s Oncology Group, Arcadia, CA; Johns Hopkins Hospital, Baltimore, MD; Children’s Mercy Hospital and Clinics, Kansas City, MO; Cancer Institute of New Jersey, New Brunswick, NJ; Indiana University, Riley Children’s Hospital, Indianapolis, IN; University of Nebraska Medical Center, Omaha, NE; and Pediatric Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN. Address reprint requests to Robert J. Wells, MD, Children’s Oncology Group, 440 E Huntington Dr, Suite 300, PO Box 60012, Arcadia, CA 91066-6012; email: rjwells{at}mdanderson.org.
Purpose: To evaluate the response rate, survival, and toxicity of mitoxantrone and cytarabine induction, high-dose cytarabine and etoposide intensification, and further consolidation/maintenance therapies, including bone marrow transplantation, in children with relapsed, refractory, or secondary acute myeloid leukemia (AML). To evaluate response to 2-chlorodeoxyadenosine (2-CDA) and etoposide (VP-16) in patients who did not respond to mitoxantrone and cytarabine. Patients and Methods: Patients with relapsed/refractory AML (n = 101) and secondary AML (n = 13) were entered. Results: Mitoxantrone and cytarabine induction achieved a remission rate of 76% for relapsed/refractory patients and 77% for patients with secondary AML, with a 3% induction mortality rate. Cytarabine and etoposide intensification exceeded the acceptable toxic death rate of 10%. The response rate of 2-CDA/VP-16 was 8%. Two-year overall survival was estimated at 24% and was better than historical control data. Patients with secondary AML had similar outcomes to relapsed or refractory patients. Initial remission longer than 1 year was the most important prognostic factor for patients with primary AML (2-year survival rate, 75%), whereas for patients with primary AML, with less than 12 months of initial remission, survival was 13% and was similar to that of refractory patients (6%). Conclusion: Mitoxantrone and cytarabine induction is effective with reasonable toxicity in patients with relapsed/refractory or secondary AML. The cytarabine and etoposide intensification regimen should be abandoned because of toxicity. Patients with relapsed AML with initial remissions longer than 1 year have a relatively good prognosis.
OUTCOMES OF pediatric acute myeloid leukemia (AML) have improved gradually over the last 20 or more years. Approximately 75% to 85% of patients now have initial complete remissions, and 50% to 70% of those patients will survive for longer than 3 years.1–6 Prognosis remains bleak for patients who do not achieve complete remissions with first therapy or who experience relapse after achieving remissions. Review of outcome data from Children’s Cancer Group (CCG) studies 251, 213, and 2861, conducted from 1979 to 1989, indicate that only 12% (SE, ± 2%) of patients were alive 3 years after relapse or inability to achieve remission when given the initial therapy (J.W. Lee, personal communication, November 1995).7–9 In the more recent study CCG-2891 (1989 to 1995), 3-year survival was slightly better at 17% (SE, ± 2%; J.W. Lee, personal communication, November 1999). The outcome data from CCG studies 251, 213, 2861, and 2891 have limited usefulness because only survival outcome is available. Little information is available about therapies associated with survival or treatment failure. Most reports in the literature that address patients with relapsed or refractory pediatric AML are essentially phase II trials of induction therapies or transplantation regimens for those who have attained second complete responses.10–13 This Children’s Cancer Group study, CCG-2951, was designed to test the efficacy of a promising induction therapy that used mitoxantrone and cytarabine. It was combined with very high–dose cytarabine and etoposide intensification. This combination was being considered for front-line pediatric AML therapy.14,15 Patients who did not have complete responses to mitoxantrone cytarabine induction were given an alternate induction of 2-chlorodeoxyadenosine (2-CDA) and etoposide. We believed that most patients who had remissions would proceed to some form of bone marrow or stem-cell transplantation. It was the hope of the study committee that this would lead to an overall improvement in survival for this group of patients compared with historic control data. CCG-2951 included a separate cohort of patients with newly diagnosed, untreated (for AML) patients with secondary AML. This report describes outcomes for the induction and intensification portions of CCG-2951 and some preliminary follow-up information about the outcome of patients with relapsed or refractory AML.
CCG-2951 opened on August 18, 1997. The study was suspended to new patient entry on January 26, 2000, and later closed (May 11, 2001) without additional patients entered. Patients with AML who did not have complete remissions with their first therapy (refractory) or who had relapses after initial remission were eligible for this study, provided that they received no additional therapy for AML. Patients also had to be younger than 22 years at enrollment and were required to have normal or near normal renal, hepatic, and cardiac function. Patients or their parents or guardians were required to sign an informed consent document, and the treating institution’s institutional review board must have approved this protocol before enrollment. Patients also were enrolled in this protocol who had AML as a second malignant neoplasm, provided no prior therapy for AML had been given. Patients with Fanconi’s anemia were specifically excluded from participation.
Therapy Salvage induction therapy. Patients who had more than 15% blasts in their bone marrow at the end of induction were considered to have failed to achieve remission. These patients were given salvage induction therapy comprising 2-CDA 9 mg/m2 as a 2-hour infusion for 5 days and etoposide 150 mg/m2 as another 2-hour infusion for 5 days each. Therapy was to be repeated once if patients did not achieve bone marrow remission after the first course. Intrathecal cytarabine was given once per course of therapy. Intensification. Patients who achieved responses (M1 or M2a marrow [< 15% blasts]) with induction or salvage induction were eligible to receive intensification therapy that consisted of cytarabine 3.0 g/m2 as a 3-hour infusion every 12 hours for 6 days (12 doses of 3 g/m2) followed by daily infusions of etoposide 400 mg/m2 as a 2-hour infusion for 3 days starting 12 hours after the last dose of cytarabine. No intrathecal therapy was given during this phase. Continuation therapy. After intensification, patients were treated at the discretion of responsible physicians with no further therapy, a suggested consolidation with chemotherapy (2-CDA/etoposide similar to the salvage induction), other chemotherapy, or with various forms of stem-cell or bone marrow transplantation (BMT). Investigators were responsible for reporting which option they chose and the outcome, such as death or relapse, so that survival and disease-free survival (DFS) could be calculated.
Statistics Patients lost to follow-up were censored at their last known points of study, with a cutoff of May 8, 2001. Confidence intervals were calculated using Greenwood’s formula.18 Differences in OS, EFS, and DFS were tested for significance using the log-rank statistic.19 Univariate analyses of potential prognostic factors were used to compare induction outcomes using Fisher’s exact test. Continuous variables were considered using defined discrete categories. Factors univariately significant at P < .05 were considered for inclusion in multivariate models. Multivariate models were constructed for induction outcome and survival using stepwise logistic regression and Cox regression,20 respectively. Forward and backward elimination procedures were used. The likelihood ratio test was used to determine whether variables should be added or dropped from the multivariate model. Exact logistic regression was used with sparse data.21 Multivariate analyses for complete response (CR) and OS included patients with complete covariate data.
In the approximately 2.5 years that this study was open for accrual, 116 patients were entered, 101 with primary AML (ie, refractory or first-relapse AML), 13 with secondary AML, one incorrect diagnosis, and one enrolled when the study was suspended. The median follow-up on 38 patients alive at last contact was 16.3 months (range, 0.2 to 36.8 months). Patient outcomes for the phases of therapy are described in Figures 1  and 2 for patients with primary and secondary AML, respectively.
Patient characteristics are listed in Table 1 . The median age of the 101 patients with primary AML was 10.2 years (range, 0.7 to 19.9 years). The most prevalent French-American-British (FAB) classification of acute leukemias was M2 (25.9%), followed by M4 (18.8%). Sixteen percent of patients had refractory AML, 27% had prior remissions of less than 7 months, 35% had prior remissions of 7 to 12 months, and 23% had prior remissions greater than 12 months. Prior malignancies for 13 patients with secondary AML included Ewing’s sarcoma (two patients), acute lymphoblastic leukemia (ALL; three patients), non-Hodgkin’s lymphoma (NHL; two patients), glioblastoma (one patient), osteosarcoma (three patients), medulloblastoma (one patient), and ependymoma (one patient). Their median age at study enrollment was 14.4 years (range, 6.6 to 18.7 years). Most patients with secondary AML were classified as having FAB M0 disease (50%), whereas 25% had FAB M4 disease. The four patients with secondary AML who were alive at last contact had a median follow-up time of 16.6 months. The lengths of follow-up for these patients were 1.8, 10.4, 22.7, and 34.4 months.
Induction Outcome Among 101 primary patients entered, one withdrew before completing induction therapy. Two more could not be evaluated for response because responsible investigators did not collect end-of-induction bone marrow samples. Ninety-eight patients were evaluated for induction outcome. Seventy-two patients had M1 (< 5% blasts) bone marrow and three patients had M2a (6% to 15% blasts) bone marrow at the end of induction, with slightly hypocellular to cellular biopsy results, for a response rate of 77% (95% confidence interval [CI], 67% to 85%). Among those, 40 with M1 and 0 with M2a also had full recovery of peripheral-blood counts, with absolute neutrophils greater than 1,000/µL and platelets greater than 100,000/µL before they were given the next course of therapy. Five patients had partial responses (M2b bone marrow [16% to 25% blasts]), three patients died during induction therapy, and 15 patients survived induction therapy but did not respond (> 25% blasts in bone marrow at the end of induction). The deaths were on days 5, 11, and 12 of induction. Two of the three deaths were related to infectious complications (bacterial sepsis) and the other was from disease progression. Among patients with secondary AML, 10 patients (77%; 95% CI, 46% to 95%) had M1 marrow responses, one patient had a partial response (M2b bone marrow), one patient died during induction, and one patient survived induction but did not respond. The induction death was caused by disseminated fungemia (aspergillosis) at day 57 of induction. That patient’s bone marrow was severely hypocellular after induction therapy and never showed evidence of recovery.
Salvage Induction Outcome Two patients with secondary AML also were treated with salvage induction. They did not respond to the therapy.
Intensification Among 58 patients who received intensification, 42 patients (72%; 95% CI, 59% to 83%) completed intensification in remission (M1 or M2a marrow), 10 patients (17%; 95% CI, 9% to 29%) died, generally from infectious complications, and four patients relapsed by the end of intensification. The number of deaths during intensification exceeded study toxicity limits designed to assure that the number of toxic deaths during that phase did not exceed approximately 10% mortality, which was normal with high-dose cytarabine and asparaginase consolidation in several CCG AML therapies.1,8 The toxicity led to suspension of new patient accrual and then study closure. Four patients (three patients with primary AML and one patient with secondary AML) were entered on the induction phase at the time of suspension, so intensification was omitted from treatment of those four patients when they attained CRs at the end of induction. Six patients with secondary AML also received intensification therapy. Three patients had CRs at the end of induction, one patient died of sepsis, one patient was inaccessible, and one patient had no data available. Among the four remaining patients with secondary AML with CRs at the end of induction, three patients received BMT. The reason the other patient did not receive intensification is not known.
Follow-On Therapy Seventeen of 35 patients who underwent BMT were alive with a median follow-up of 17.6 months (range, 0.3 to 36.8 months), and 18 patients died (five from progressive or recurrent leukemia, five from infection, one from hemorrhage, two from toxicity, four from graft-versus-host disease, and one from other cause), with median survival of 8.0 months (range, 3.4 to 18.4 months). The two patients who underwent transplantation without achieving CRs died (one from progressive disease 8 months after transplantation and one from veno-occlusive disease 2 months after transplantation). The status of 13 patients with primary AML who received chemotherapy is that eight were alive with median follow-up of 15.5 months (range, 3.5 to 34.8 months) and five died (three from progressive leukemia and two from infections) after a median of 14.5 months (range, 4.6 to 16.5 months). For the secondary AML group, three patients ended intensification with M1 or M2a bone marrow. One patient underwent BMT, another patient had chemotherapy, and the follow-on treatment of the third patient is unknown. They died at 5.7 (toxicity), 13.1 (progressive disease), and 5.8 (progressive disease) months from start of therapy, respectively. Among four patients with secondary AML who did not receive intensification, three underwent BMT and were alive at 10.5, 22.7, and 34.4 months from start of therapy. The remaining patient died of progressive leukemia at 2.4 months.
Survival
DFS was similar to OS. For patients with primary AML, survival was 31% (95% CI, 20% to 44%) at 2 years from the end of induction and 45% (95% CI, 27% to 61%) at 2 years from the end of intensification (Table 2 ). Survival from the end of induction for patients who received intensification (33%; 95% CI, 20% to 47%; n = 58) was similar to that of those who did not receive intensification according to the protocol or investigator choice (31% [95% CI, 10% to 55%] at 2 years; P = .676; n = 17). DFS also was similar (P = .890).
OS from start of therapy for the 39 patients with primary AML with M1 marrow who had end-of-induction BMTs with blood count recoveries (absolute neutrophil count [ANC] >1,000/µL and platelets >100,000/µL) was similar to OS for the 32 patients with primary AML with M1 marrow who had end-of-induction BMTs without full blood count recoveries before the start of the next course of therapy (P = .692).
OS (Fig 4
Toxicity The primary toxicity during induction, salvage induction, and intensification in this study was bone marrow suppression caused by chemotherapy or leukemia, indicated by prevalence of ANC (weeks < 500/µL) and platelet (weeks < 105/µL) toxicities during those treatments. For induction, ANC greater than 500/µL was achieved by 50% of patients by day 21 and by 91% of patients by day 35. For intensification, ANC greater than 500/µL was achieved by 38% of patients by day 21 and by 81% by day 35. Platelet recovery was 60% recovered to greater than 50,000/µL by day 28 and 81% by day 42 for induction and 48% and 78%, respectively, for intensification. During induction and intensification, 54% and 78% of patients, respectively, had at least one infection. Gastrointestinal (23%) and hepatic (15%) toxicities were the next most common. Fifty percent of patients reported at least grade 3 toxicities during induction and 81% reported at least grade 3 toxicities during intensification. Gastrointestinal toxicities and hepatic toxicities were most common.
Prognostic Factors
Prior Studies
This study provided mixed results overall. Patients seemed to have slightly better outcomes than our historical control population. The activity of mitoxantrone and cytarabine induction was confirmed clearly. That induction was able to induce a remission in all patients whose initial remissions were longer than 12 months (Table 4). It also was able to induce remissions in 57% of patients who did not have remissions after initial treatment with anthracycline, standard-dose cytarabine, and etoposide regimens and who were clinically resistant to those drugs. The mitoxantrone and cytarabine regimen also induced responses in 77% of patients with secondary AML, a traditionally difficult group to treat. For example, in our last study (CCG-2891), only 12 of 24 patients who had secondary AML achieved remissions.22 The toxicity-related death rate during induction using this therapy was quite low (3%) compared with that of most AML induction therapies. This study was not successful in combining induction with what we hoped would be a better intensification. The high-dose cytarabine and etoposide regimen proved to be too toxic and forced closure of the study. The high relapse rate in patients who survived the treatment indicates that even highly toxic high-dose chemotherapy with standard agents is not effective in producing long-lasting remissions in this group of patients. Our prejudice that some form of bone marrow transplantation could produce a high survival rate when used for patients in second remissions also was not supported by our results. Just under 50% of those patients who underwent transplantation survive, and as a group, patients who underwent transplantation did no better than those who received follow-on chemotherapy. However, follow-up is relatively short, and the number of patients who received chemotherapy in this study is quite small. The salvage induction of 2-CDA and etoposide was disappointing; however, the patient population treated is a very refractory group likely to be clinically resistant to most conventional therapy. The OS rate remained unsatisfactory. This study confirmed observations of many others that the most important prognostic factor for patients with AML who experience relapse is the length of initial remission. It also found that many patients who have initial remissions of more than 12 months can be successfully treated with salvage therapy and have a reasonable chance for long-term survival.14,23,24 No other prognostic factors seemed to have much significance, although the FAB M1 group identified here may be useful in future studies. We confirmed activity and acceptable toxicity of mitoxantrone and cytarabine induction and recommend that therapy be incorporated into initial treatment regimens for AML. Preliminary data from this study on patients with secondary AML were also somewhat encouraging and should be extended. The intensification regimen should be abandoned, as should the salvage induction. We did not find benefit of allogeneic bone marrow transplantation over postremission chemotherapy in patients who had AML in second remissions after mitoxantrone and cytarabine reinduction therapy.
1. Woods WG, Kobrinsky N, Buckley JD, et al: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: A report from the Children’s Cancer Group. Blood 87:4979–4989, 1996 2. Stevens RF, Hann IM, Wheatley K, et al: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukemia: Results of the United Kingdom Medical Research Council’s 10th AML trial—MRC Childhood Leukaemia Working Party. Br J Haematol 101:130–140, 1998[CrossRef][Medline]
3. Ravindranath Y, Yeager AM, Chang MN, et al: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood: Pediatric Oncology Group. N Engl J Med 334:1428–1434, 1996
4. Creutzig U, Ritter J, Zimmermann M, et al: Does cranial irradiation reduce the risk for bone marrow relapse in acute myelogenous leukemia? Unexpected results of the Childhood Acute Myelogenous Leukemia Study BFM-87. J Clin Oncol 11:279–286, 1993
5. 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. Blood 97:56–62, 2001 6. Dahl GV, Kalwinsky DK, Mirro J Jr, et al: Allogeneic bone marrow transplantation in a program of intensive sequential chemotherapy for children and young adults with acute nonlymphocytic leukemia in first remission. J Clin Oncol 8:295–303, 1990[Abstract] 7. Nesbit ME Jr, Buckley JD, Feig SA, et al: Chemotherapy for induction of remission of childhood acute myeloid leukemia followed by marrow transplantation or multiagent chemotherapy: A report from the Children’s Cancer Group. J Clin Oncol 12:127–135, 1994[Abstract]
8. Wells RJ, Woods WG, Buckley JD, et al: Treatment of newly diagnosed children and adolescents with acute myeloid leukemia: A Children’s Cancer Group Study. J Clin Oncol 12:2367–2377, 1994
9. Woods WG, Kobrinsky N, Buckley J, et al: Intensively timed induction therapy followed by autologous or allogeneic bone marrow transplantation for children with acute myeloid leukemia or myelodysplastic syndrome: A Children’s Cancer Group pilot study. J Clin Oncol 11:1448–1457, 1993 10. Yeager AM, Kaizer H, Santos GW, et al: Autologous bone marrow transplantation in patients with acute nonlymphocytic leukemia, using ex vivo marrow treatment with 4-hydroperoxycyclophosphamide. N Engl J Med 315:141–147, 1986[Abstract] 11. Bosi A, Bacci S, Miniero R, et al: Second allogeneic bone marrow transplantation in acute leukemia: A multicenter study from the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO). Leukemia 11:420–424, 1997[CrossRef][Medline] 12. Leahey A, Kelly K, Rorke LB, et al: A phase I/II study of idarubicin (Ida) with continuous infusion fludarabine (F-ara-A) and cytarabine (ara-C) for refractory or recurrent pediatric acute myeloid leukemia (AML). J Pediatr Hematol Oncol 19:304–308, 1997[CrossRef][Medline]
13. Santana VM, Mirro J Jr, Kearns C, et al: 2-Chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J Clin Oncol 10:364–370, 1992 14. Wells RJ, Gold SH, Krill CE, et al: Cytosine arabinoside and mitoxantrone induction chemotherapy followed by bone marrow transplantation or chemotherapy for relapsed or refractory pediatric acute myeloid leukemia. Leukemia 8:1626–1630, 1994[Medline] 15. Whitlock JA, Wells RJ, Hord JD, et al: High-dose cytosine arabinoside and etoposide: An effective regimen without anthracyclines for refractory childhood acute non-lymphocytic leukemia. Leukemia 11:185–189, 1997[CrossRef][Medline] 16. Mann HB, Whitney DR: On a test of whether one of two random variables is stochastically larger than the other. Ann Math Stat 18:50–60, 1947 17. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 18. Greenwood M: The natural duration of cancer, in: Reports on Public Health and Medical Subjects. London, England, His Majesty’s Stationery Office, 33:1–26, 1926 19. Peto R, Peto J: Asymptotically efficient rank in variant test procedures. J R Stat Soc A 135:185–206, 1972 20. Cox DR: Regression models and life-tables. J R Stat Soc B 34:187–220, 1972 21. Hirji KF, Mehta CR, Patel NR: Computing distributions for exact logistic regression. J Am Stat Assoc 82:1110–1117, 1987[CrossRef]
22. Barnard DR, Lange B, Alonzo TA, et al: Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: Comparison with primary presentation. Blood 100:427–434, 2002 23. 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: MRC Childhood Leukaemia Working Party. Leukemia 13:25–31, 1999[CrossRef][Medline] 24. Keating MJ, Kantarjian H, Smith TS, et al: Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 7:1071–1080, 1989[Abstract] Submitted June 21, 2002; accepted May 15, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
