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© 2001 American Society for Clinical Oncology Improved Treatment Results in High-Risk Pediatric Acute Myeloid Leukemia Patients After Intensification With High-Dose Cytarabine and Mitoxantrone: Results of Study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster 93From the Department of Pediatric Hematology/Oncology, University Children’s Hospital, Münster, Jena, Cologne, Berlin, Hamburg, Essen, Giessen, and Magdeburg, Germany; St Anna Children’s Hospital, Vienna, Austria; and Department of Pediatric Hematology/Oncology, University Children’s Hospital, Zurich, Switzerland. Address reprint requests to Ursula Creutzig, Prof, Klinik und Poliklinik für Kinderheilkunde, Pädiatrische Hämatologie/Onkologie, Albert-Schweitzer-Str 33, D-48129 Münster, Germany; email: ucreutzig@ aol.com.
PURPOSE: To improve outcome in high-risk patients, high-dose cytarabine and mitoxantrone (HAM) was introduced into the treatment of children with acute myelogenous leukemia (AML) in study AML-BFM 93. Patients were randomized to HAM as either the second or third therapy block, for the purpose of evaluation of efficacy and toxicity. PATIENTS AND METHODS: A total of 471 children with de novo AML were entered onto the trial; 161 were at standard risk and 310 were at high risk. After the randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical in the two risk groups and also comparable to that in study Acute Myeloid Leukemia–Berlin-Frankfurt-Münster (AML-BFM) 87. RESULTS: Overall, 387 (82%) of 471 patients achieved complete remission, and 5-year survival, event-free survival (EFS), and disease-free survival rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell reduction in the bone marrow on day 15. Estimated survival and probability of EFS were superior in study AML-BFM 93 compared with study AML-BFM 87 (P = .01, log-rank test). This improvement, however, was restricted to the 310 high-risk patients (remission rate and probability of 5-year EFS in study AML-BFM 93 v study AML-BFM 87: 78% v 68%, P = .007; and 44% v 31%, P = .01, log-rank test). Probability of 5-year EFS among standard-risk patients in study AML-BFM 93 was similar to that in study AML-BFM 87 (65% v 63%, P = not significant). Whether HAM was placed as the second or third therapy block was of minor importance. However, patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. CONCLUSION: Improved treatment results in children with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.
THE GOAL OF remission and increased overall survival in acute myelogenous leukemia (AML) is best accomplished through administration of several courses of combination chemotherapy consisting of the antipyrimidine drug cytarabine (Ara-C) and intercalating agents such as anthracyclines. Moreover, the addition of etoposide (VP-16) to standard therapy has improved disease-free survival (DFS).1 Over the last 15 years, mitoxantrone, an anthracenedione derivative that has activity against AML blasts when given as a single agent,2 has become more important, specifically in the treatment of resistant leukemia.3 Another means of improving outcome is intensification with high-dose Ara-C in either the postremission or induction phase, as demonstrated by several studies in adults4-6 and children.7-9 The dose effect of cytarabine given at a standard dose of 100 mg/m2, a medium dose of 400 mg/m2, or the high-dose of 3 g/m2 during postremission treatment was first shown by the Cancer and Leukemia Group B.6 The efficacy of high-dose Ara-C in combination with mitoxantrone (HAM) was demonstrated in adult patients with refractory AML by Hiddemann et al10 and in adult patients with de novo AML by Arlin et al,11 who reported a higher complete remission (CR) rate after a single induction course of the mitoxantrone-based regimen (mitoxantrone 3 x 12 mg/m2) compared with the standard regimen using daunorubicin (3 x 45 mg/m2). Büchner et al4,12 demonstrated that HAM given in a second induction course benefited poor-risk adult patients. In study AML-BFM 87, an intensive combination chemotherapy regimen including high-dose Ara-C and VP-16 given during postremission treatment produced favorable results in standard-risk patients, whereas results in high-risk patients were unsatisfactory. To improve outcome in the latter group, we introduced HAM in study AML-BFM 93. Because the dose-intensity of HAM during the first two treatment courses has been shown to be of prognostic significance,12 we attempted in the current study to determine whether placing HAM as the first versus second postinduction treatment block affects prognosis. In view of reports that this intensification regimen is associated with increased toxicity and the need for more supportive care, including transfusion of blood products, especially platelets,13 HAM was restricted to high-risk patients. The regimen was not given to standard-risk patients, with their estimated survival rate of 70% at 5 years, to avoid impairment of prognosis by severe adverse effects.14
Eligibility The entry criteria for studies AML-BFM 93 and 87 included newly diagnosed AML, patient age 0 to 17 years, and written informed consent of the patient or parent. Patients with myelosarcoma, secondary AML, myelodysplastic syndrome, or Down’s syndrome were excluded.
Diagnosis
Treatment
After induction, patients were treated according to risk level. The risk stratification was based on the initial morphologic parameters and the blast cell reduction in the bone marrow on day 15 (standard-risk group: FAB M1 or M2 with Auer rods, FAB M3 [an exception follows], and FAB M4Eo with  5% blasts in the bone marrow on day 15; high-risk group: all others).14 Thus, patients initially allocated to the standard-risk group on the basis of morphology were shifted to the high-risk group if they had more than 5% blasts in the bone marrow on day 15. Patients with FAB M3 were always treated as being at standard risk, regardless of blast count on day 15.
High-risk patients were randomized to either HAM (high-dose Ara-C 3 g/m2 every 12 hours for 3 days and mitoxantrone 10 mg/m2 days 4 and 5) followed by consolidation therapy (early HAM) or consolidation therapy followed by HAM (late HAM). Consolidation therapy consisted of 6 weeks of treatment with seven drugs (thioguanine 60 mg/m2 PO days 1 to 43; prednisolone 40 mg/m2 PO days 1 through 28; vincristine 1.5 mg/m2 days 1, 8, 15, and 22; doxorubicin 30 mg/m2 days 1, 8, 15, and 22; Ara-C 75 mg/m2 days 3 through 6, 10 through 13, 17 through 20, 24 through 27, 31 through 34, and 38 through 41; intrathecal Ara-C standard dose
Subsequently, all patients were treated with an intensification block of high-dose Ara-C and VP-16 (high-dose Ara-C 3 g/m2 every 12 hours for 3 days and VP-16 125 mg/m2 days 2 through 5). This was followed by cranial irradiation with 18 Gy (standard dose in children The main difference between studies AML-BFM 87 and 93 was that in the earlier study, there were two blocks of intensification after consolidation treatment with high-dose Ara-C and VP-16. Also in study AML-BFM 87, patients without CNS involvement were randomized to cranial irradiation with 18 Gy or no irradiation, during the first part of the study.
Definitions and Statistics Randomization of high-risk patients was carried out after the bone marrow evaluation on day 15, when risk classification of all patients was possible. The planned sample size was 160 for each group. The end point was event-free survival (EFS). The power to detect an increase in probability of EFS (pEFS) from 50% to 66% was 80%. All patients were randomized to AIE or ADE immediately after diagnosis. Both randomizations were done with permuted blocks. EFS was calculated from the date of diagnosis to last follow-up or first event (failure to achieve remission, early death, resistant leukemia, relapse, second malignancy, or death from any cause). For patients who failed to achieve remission, EFS was set at zero. Survival was calculated from the date of diagnosis to death from any cause or last follow-up. DFS of patients achieving remission was calculated from the date of remission to first event (relapse or death from any cause). The end point for determining the efficacy of early versus late HAM was EFS. Toxicity was assessed using National Cancer Institute common toxicity criteria.20
Univariate analysis was conducted using the Wilcoxon test for quantitative variables and Fisher’s exact test for qualitative variables. When frequencies were sufficiently large, the
Patient Characteristics
One hundred ninety-six (63%) of 310 high-risk patients were randomized to early or late HAM (Fig 2). Of the 114 high-risk patients who were not randomized, 25 did not receive HAM (18 died before randomization, mainly because of initial complications related to leukostasis or hemorrhage; five patients experienced severe toxicity that necessitated therapy reduction or modification; and two children had been assigned to the wrong risk group) and 89 patients were allocated to either early HAM (n = 12) or late HAM (n = 77) by choice. Late HAM was often selected by parents or physicians, because it was presumed to be less toxic. Four of these patients had initially been allocated to the wrong risk group (standard risk). Eleven patients allocated to early HAM received late HAM, and three children allocated to late HAM received early HAM. However, for the intent-to-treat analysis, these patients remained in their randomization groups. Allogeneic matched related-donor SCT was performed in 14 patients each in the early and late HAM groups.
Table 1 lists the characteristics of the patients as a whole and by group. Nonrandomized and randomized patients showed no major difference in age (P = .75, Wilcoxon test) or initial WBC count (P = .16, Wilcoxon test). The FAB classification distribution was similar for nonrandomized and randomized patients (P = .71,
Study AML-BFM 93 Overall outcome. In study AML-BFM 93, 387 (82%) of 471 patients achieved CR. Estimated probabilities of 5-year survival, EFS, and DFS (± SE) were 60% ± 3%, 51% ± 2%, and 62% ± 3%, respectively. Overall results were significantly better than those of study AML-BFM 87 ( Table 2, Fig 3).
Outcome by risk group. Five-year survival, EFS, and DFS rates (± SE) were 74% ± 4%, 65% ± 4%, and 73% ± 4%, respectively, among the 161 standard-risk patients; and 52% ± 3%, 44% ± 3%, and 56% ± 3%, respectively, among the 310 high-risk patients. Outcome among the 28 high-risk patients who underwent allogeneic matched related-donor SCT during first CR was in the same range (DFS rate, 64% ± 9%) as that among the high-risk patients who did not undergo SCT.
Outcome by induction treatment.
Overall, patients initially treated with idarubicin had significantly better blast cell reductions in the bone marrow on day 15 (17% patients with > 5% blasts compared with 31% of patients on the daunorubicin arm; P = .01, Outcome by HAM group. One hundred ninety-six high-risk patients were randomized to either early HAM (n = 98) or late HAM (n = 98). Overall results in terms of response and relapse rate were similar on the two arms (5-year survival, EFS, and DFS rates [± SE] in the early-HAM group compared with the late-HAM group were 58% ± 5% v 57% ± 6%; 52% ± 5% v 45% ± 5%; and 59% ± 5% v 53% ± 6%, respectively [ Fig 4]). Results of the treatment actually administered were in the same range (5-year EFS rate, 48% ± 5% [both groups]).
The pEFS was slightly higher among patients initially treated with daunorubicin who received early HAM compared with patients who received daunorubicin and late HAM (Table 3 and Fig 5), whereas results associated with early or late HAM were similar for patients initially treated with idarubicin. This finding was confirmed by tests for interaction in a Cox regression model, which showed a tendency for a worse outcome only in patients randomized to daunorubicin followed by late HAM (risk ratio, 1.52; 95% confidence interval, 0.99 to 2.32; P = .054).
Toxicity. Fatal events occurred in four (4%) of 110 patients during or after early HAM and in nine (5%) of 186 in connection with late HAM. One of the latter patients who met standard-risk criteria died after having achieved remission. All four patients who died during or after early HAM had severe sepsis or pneumonia in aplasia; these conditions were resistant to therapy in two cases. Eight of the nine patients whose deaths were related to late HAM had infections (fungal sepsis or aspergillosis in five cases), and one patient had cardiac insufficiency and alveolar proteinosis. Three of the nine children were nonresponders.
Toxicities, namely bleeding, hepatotoxicity and nephrotoxicity, peripheral and central neurotoxicity, and cardiotoxicity, were similar in the early-HAM and late-HAM groups. However, the late-HAM group, compared with the early-HAM group, showed a tendency toward a higher infection rate during the third treatment block (no infection v infection: 43 of 62 v 50 of 58 patients; P = .03,
Studies AML-BFM 87 and 93
In study AML-BFM 87, fatal events occurred in 17 (8%) of the 208 high-risk patients between days 15 and 90, the exact time in the treatment course of study AML-BFM 93 when assessment of early- versus late-HAM toxicity was performed. Nine of the 17 events occurred in nonresponders and were mostly due to infections. Seven of the remaining patients died during the first 6 weeks of treatment, because of infections (n = 6) or bleeding (n = 1). One patient had severe sepsis and died shortly after achieving remission.
The results of study AML-BFM 93 in terms of estimated 5-year survival rate (60% ± 3% [SE]) and EFS rate (51% ± 2%) for the total group of patients are significantly better than those of our previous study (AML-BFM 87) and similar to those of the successful Medical Research Council (MRC) AML 10 trial in children.7 This improvement is most probably due to the intensification with HAM in high-risk patients (two thirds of our patients). The new treatment course with HAM had been shown to be an effective, though toxic, therapy element in adults with AML.5,11,12 In children, the impact of high-dose Ara-C was demonstrated in the Nordic Society of Pediatric Haematology and Oncology’s AML 93 trial: outcome was improved after four intensification blocks of high-dose Ara-C.8 The MRC AML 10 protocol, which specified two highly intensive courses, one of them including mitoxantrone and high-dose Ara-C, resulted in a significantly better outcome than in previous MRC studies.7 The effect of dose scheduling and dose-intensity during postremission treatment was demonstrated in the Children’s Cancer Group 213P study. Two courses of high-dose Ara-C and asparaginase administered at 7-day intervals resulted in superior survival rates compared with administration at 28-day intervals.9 Furthermore, in the Children’s Cancer Group study, 2,861 patients receiving intensive-timing induction chemotherapy (second cycle 10 days after the first cycle) had a significantly better DFS than did patients receiving standard-timing induction therapy (second cycle 14 days or more after the first cycle, depending on bone marrow status).23 A study involving adults demonstrated that the time to achievement of remission is an important predictor of survival and DFS.24 This supports the hypothesis that rapid blast clearance may prevent development of resistance. The main difference between studies AML-BFM 93 and 87 related to the introduction of the HAM combination and the scheduling of HAM, rather than to administration of high-dose Ara-C, which in study AML-BFM 87 was given as intensification after consolidation therapy in combination with VP-16. Furthermore, all patients in study AML-BFM 87 received daunorubicin as induction therapy. In study AML-BFM 93, the efficacy of idarubicin and daunorubicin as induction treatments was compared by randomized allocation; standard-risk patients were included. The results indicated a significantly better blast cell reduction in the bone marrow on day 15 in the idarubicin-therapy group, whereas long-term outcome was similar on both treatment arms22 and was also comparable to that of standard-risk patients in study AML-BFM 87. Treatment intensity for standard-risk patients, who in study AML-BFM 87 received two late courses with high-dose Ara-C and VP-16, was similar in the two studies. CNS irradiation was not generally performed. In the second randomization, high-risk patients were assigned to early or late HAM. Through early administration of HAM, we tried to enhance cytotoxic activity and thus achieve higher efficacy. It was suggested that this approach, compared with a treatment course with lower dose-intensity, might overcome resistance by more rapid blast cell clearance and a reduction in the rate of minimal residual disease. The randomization to early versus late HAM was necessary to evaluate whether a possibly improved blast cell reduction owing to early administration might be compounded by more toxicity after the course. HAM treatment, however, was not offered to standard-risk patients, because of the expected higher rate of acute adverse events and possible late cardiotoxicity associated with administration of additional cardiotoxic drugs. The cumulative dose of anthracyclines, including the anthracycline analog mitoxantrone (assuming a dose ratio of daunorubicin to mitoxantrone of 5:1), was 300 mg/m2 in standard-risk patients and 400 mg/m2 in high-risk patients. Results of the randomized scheduling of HAM as the second or third treatment course after induction did not reveal major differences in outcome. However, the induction treatment must be considered as well. Induction with idarubicin, as opposed to daunorubicin, was more effective in reducing the blast cell count in the bone marrow by day 15.25 Patients who received the less intensive daunorubicin treatment during induction benefited from early HAM. This was in contrast to the effects of late HAM after daunorubicin induction ( Table 3). Moreover, when we compared high-risk patients in study AML-BFM 87 (the historical control group) with high-risk patients treated initially with daunorubicin and then with late HAM, we found that results were similar: the probability of 5-year EFS [± SE] in the former group was 31.1% ± 3.2%, v 35.6% ± 7.3% for the latter group (P = .54). This finding suggests that induction with idarubicin followed by HAM might have a cumulative effect in high-risk patients. The results are in line with those of a German AML Cooperative Group trial in adults, which showed that mainly poor-risk patients benefited from a two-course induction combining thioguanine, Ara-C, and daunorubicin, with HAM as the second course, rather than two courses of that induction therapy.12 In several studies, the rate of toxicity associated with HAM treatment was increased, and more severe neutropenia, thrombocytopenia, nausea, vomiting, and eye toxicity were noted compared with standard induction treatment,5 indicating that not only HAM treatment per se but also the placement of HAM within the sequence of treatment courses might influence tolerability. This led to a higher selection on the late-HAM arm in study AML-BFM 93, presuming a higher rate of toxicity with early HAM. However, the rate of infections was only slightly increased in the early-HAM group compared with late HAM and with study AML-BFM 87. The incidence of therapy-related deaths was similar, indicating that this therapy is feasible in children with AML. We have demonstrated the efficacy of HAM treatment, with a tolerable rate of toxicity, in high-risk children. As a consequence, in the ongoing study AML-BFM 98, HAM has been introduced into the second therapy course of all pediatric patients with AML, our aim being to improve the survival rate among standard-risk patients as well.
APPENDIX Principal investigators in Austria: C. Urban, Universitäts-Kinderklinik d. Landeskrankenhauses, Graz; F.M. Fink, Universitäts-Kinderklinik d. A.ö. Landeskrankenhauses, Innsbruck; K. Schmitt, G. Ebetsberger Landes-Kinderkrankenhaus, Linz; I. Slavc, AKH-Universitäts-Kinderklinik, Vienna; H. Gadner, St. Anna-Kinderspital, Vienna. Principal investigators in Switzerland: P. Imbach, Kinderklinik d. Kantonsspital, Aarau; P.A. Avoledo, Universitäts-Kinderspital, Basel; A. Feldges, Ostschweizerisches Kinderspital, St. Gallen; M. Nenadov-Beck, C. Desseng, CHUV-Kinderklinik, Lausanne; U. Caflisch, Kinderspital, Lucerne; L. Nobile Buetti, Kinderklinik Hospital La Carità, Locarno; F. Niggli, Universitäts-Kinderklinik, Zurich. Study coordinators: J. Ritter, U. Creutzig, Universitäts-Kinderklinik, Münster, Germany; J. Hermann, Universitäts-Kinderklinik, Jena, Germany; and H. Gadner, St. Anna-Kinderspital, Vienna, Austria.
Supported by the Deutsche Krebshilfe. We thank P. Stappert, E. Kurzknabe, and J. Meltzer for their excellent technical assistance, Enno Müller for his competent data management, and Christa Lausch for her valuable assistance in the management of the AML Trial Office in Münster.
1. Bishop JF, Lowenthal RM, Joshua D, et al: Etoposide in acute nonlymphocytic leukemia: Australian Leukemia Study Group. Blood 75: 27-32, 1990 2. Estey EH, Keating MJ, McCredie KB, et al: Phase II trial of mitoxantrone in refractory acute leukemia. Cancer Treat Rep 67: 389-390, 1983[Medline] 3. Thomas X, Archimbaud E: Mitoxantrone in the treatment of acute myelogenous leukemia: A review. Hematol Cell Ther 39: 63-74, 1997[Medline] 4. Büchner T, Hiddemann W, Löffler G, et al: Improved cure rate by very early intensification combined with prolonged maintenance chemotherapy in patients with acute myeloid leukemia: Data from the AML Cooperative Group. Semin Hematol 28: 76-79, 1991[Medline]
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Bishop JF, Matthews JP, Young GA, et al: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87: 1710-1717, 1996
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Mayer RJ, Davis RB, Schiffer CA, et al: Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331: 896-903, 1994 7. Stevens RF, Hann IM, Wheatley K, et al: Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukaemia: Results of the United Kingdom Medical Research Council’s 10th AML trial. Br J Haematol 101: 130-140, 1998[Medline] 8. Lie SO, Clausen N, Gustafsson G, et al: A reduction in therapy intensity may improve outcome in childhood AML. Med Pediatr Oncol 29: 437, 1997 (abstr)
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Wells RJ, Woods WG, Lampkin BC, et al: Impact of high-dose cytarabine and asparaginase intensification on childhood acute myeloid leukemia: A report from the Childrens Cancer Group. J Clin Oncol 11: 538-545, 1993
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Hiddemann W, Kreutzmann H, Straif K, et al: High-dose cytosine arabinoside and mitoxantrone: A highly effective regimen in refractory acute myeloid leukemia. Blood 69: 744-749, 1987 11. Arlin Z, Case DC, Moore J, et al: Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL): Lederle Cooperative Group. Leukemia 4: 177-183, 1990[Medline]
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Büchner T, Hiddemann W, Wörmann B, et al: Double induction strategy for acute myeloid leukemia: The effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine—A randomized trial by the German AML Cooperative Group. Blood 93: 4116-4124, 1999 13. Kern W, Schleyer E, Unterhalt M, et al: High antileukemic activity of sequential high dose cytosine arabinoside and mitoxantrone in patients with refractory acute leukemias: Results of a clinical phase II study. Cancer 79: 59-68, 1997[Medline] 14. Creutzig U, Zimmermann M, Ritter J, et al: Definition of a standard-risk group in children with AML. Br J Haematol 104: 630-639, 1999[Medline] 15. Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia. Ann Intern Med 103: 626-629, 1985 16. Bennett JM, Catovsky D, Daniel MT, et al: Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7): A report of the French-American-British Cooperative Group. Ann Intern Med 103: 460-462, 1985 17. Bennett JM, Catovsky D, Daniel MT, et al: Proposal for the recognition of minimally differentiated acute myeloid leukaemia (AML-M0). Br J Haematol 78: 325-329, 1991[Medline]
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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 19. Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute-sponsored workshop on definitions and response in acute myeloid leukemia. J Clin Oncol 8: 813-819, 1990[Abstract] 20. National Cancer Institute: Investigators Handbook: A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of Cancer Treatment. Bethesda MD, National Cancer Institute, 1986 21. Creutzig U, Körholz D, Niemeyer CM, et al: Toxicity and effectiveness of high-dose idarubicin during AML induction therapy: Results of a pilot study in children. Klin Padiatr 212: 163-168, 2000[Medline] 22. Creutzig U, Ritter J, Zimmermann M, et al: Idarubicin improves blast cell clearance during induction therapy in children with AML: Results of study AML-BFM 93. AML-BFM Study Group. Leukemia 15: 348-354, 2001[Medline]
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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 Childrens Cancer Group pilot study. J Clin Oncol 11: 1448-1457, 1993
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Estey EH, Shen Y, Thall PF: Effect of time to complete remission on subsequent survival and disease-free survival time in AML, RAEB-t, and RAEB. Blood 95: 72-77, 2000 25. Creutzig U, Körholz D, Niemeyer CM, et al: 3 x 14 mg/m2 idarubicin during induction: Results of a pilot study in children with AML. Leukemia 14: 340-342, 2000[Medline] Submitted December 1, 2000; accepted February 9, 2001. This article has been cited by other articles:
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TOP
ABSTRACT
INTRODUCTION
3 years 40 mg days 1, 15, 29, and 43; and cyclophosphamide 500 mg/m2 days 29 and 43.) Standard-risk patients received consolidation therapy only, without HAM. 
2 statistic was used. For testing trends in frequency tables for toxicity scales, the Cochran-Armitage test was applied, which takes into account the ordered nature of the scales. Analysis of efficacy data was performed according to the intent-to-treat principle. Toxicity data were evaluated by treatment group. Computations were performed using SAS, Version 6.12 (SAS Institute, Cary, NC). 
