Acute Myeloid Leukemia in Adults: Is Postconsolidation Maintenance Therapy Necessary?

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1 Progress in Hematology International Journal of HEMATOLOGY Acute Myeloid Leukemia in Adults: Is Postconsolidation Maintenance Therapy Necessary? Thomas Büchner, a, * Wolfgang Hiddemann, b Bernhard Wörmann, c Helmut Löffler, d Wolf-Dieter Ludwig, e Claudia Schoch, b Torsten Haferlach, b Georg Maschmeyer, e Peter Staib, f Carlo Aul, g Axel Heyll, h Andreas Grüneisen, i Herbert Rasche, j Hartmut Eimermacher, k Leopold Balleisen, l Hermann-Josef Pielken, m Hans Edgar Reis, n Frank Griesinger, o Albrecht Reichle, p Maria-Cristina Sauerland, q Achim Heinecke q, for the German AMLCG a Department of Hematology/Oncology, University of Münster, Germany; b Department of Hematology/Oncology, University of Munich, Germany; c Department of Internal Medicine, Municipal Hospital Braunschweig, Germany; d Department of Hematology/Oncology, University of Kiel, Germany; e Department of Hematology/Oncology, Robert-Rössle Medical Center, Humboldt University Berlin, Germany; f Department of Hematology/Oncology, University of Cologne, Germany; g Department of Internal Medicine, St. Johannes-Hospital, Duisburg, Germany; h Department of Hematology/Oncology, University of Düsseldorf, Germany; i Department of Hematology/Oncology, Krankenhaus Neukölln Berlin, Germany; j Department of Hematology/Oncology, Zentralkrankenhaus St. Jürgen-Strasse Bremen, Germany; k Department of Internal Medicine, Katholisches Krankenhaus Hagen, Germany; l Department of Hematology/Oncology, Evangelisches Krankenhaus Hamm, Germany; m Department of Hematology/Oncology, St. Johannes-Hospital Dortmund, Germany; n Department of Internal Medicine, Maria-Hilf-Hospital Mönchengladbach, Germany; o Department of Internal Medicine, University of Göttingen, Germany; p Department of Hematology/Oncology, University of Regensburg, Germany; q Department of Biostatistics, University of Münster, Germany Received June 1, 2000; accepted June 6, 2000 Abstract Maintenance treatment for patients with acute myeloid leukemia (AML) in remission has recently been controversially discussed and even abandoned by several groups. An analysis of 14 recently published multicenter trials, however, revealed the highest probabilities of relapse-free survival (RFS), in the range of 35% to 42% at 4 to 5 years, only in patients assigned to maintenance treatment as far as adult age and intent-to-treat conditions were considered. After having demonstrated a superior RFS rate from 3 years of maintenance after standard-dose consolidation compared with that from consolidation alone (P =.00004), the German AMLCG requestioned the effect of maintenance randomly compared with sequential high-dose cytosine arabinoside (Ara-C) and mitoxantrone in patients who received intensified induction treatment. The results show an advantage for maintenance treatment (RFS rate of 32%) versus the sequential Ara-C and mitoxantrone treatment (RFS rate of 25%) (P =.021).We conclude that maintenance treatment continues to substantially contribute to the management of adult patients with AML, even as part of recent strategies using intensified induction treatment, and thus appears necessary in these settings. Int J Hematol. 2000;72: The Japanese Society of Hematology Key words: Acute myeloid leukemia; postremission therapy; maintenance 1. Introduction *Correspondence and reprint requests: Prof. Dr. Thomas Büchner, Department of Hematology/Oncology, University of Münster, Albert-Schweitzer-Str. 33, D Münster, Germany; ; fax: ( buechnr@uni-muenster.de). 285 Even at the onset of the 2000s, acute myeloid leukemia (AML) in adults remains a great challenge. Whereas combined efforts in the field of intensified chemotherapy, allogeneic and autologous transplantation, and refined supportive treatment have been producing increasing cure rates, the 50% level has not yet been reached in the overall number of patients not even in patients <60 years of age when the unselected series are considered. Thus, coming back to the title question, any effective and feasible contribution to therapeutic potential appears necessary. Asking about the effectiveness of postconsolidation treatment, the present

2 Table 1. Comparison of Major Acute Myeloid Leukemia Trials According to Treatment, Outcome, Age Range, and Patient Selection During Remission* Patients in Remission Induction Not Included in the OS at RFS at Publication Year Ref. N Age, y Regimen CR, % Consolidation Maintenance Long-Term Results, % 4-5 Years, % P 4-5 Years, % P Preisler et al 1987 [4] Std 56 No Yes mo 35 3 y Bishop et al 1990 [5] Std 58 Yes 0 w/o VP-16 w/o VP with VP-16 with VP Dillmann et al 1991 [6] Std 61 No 8 mo Cassileth et al 1992 [7] Std 68 No Yes HD Ara-C No NS 27 Ohno et al 1993 [8] Std 78 Std Yes 0 35 Std Std Mayer et al 1994 [9] Std 64 Yes Yes 0 27 Ara-C 100 mg/m mo 21 Ara-C 400 mg/m mo Ara-C 3 g/m mo 39 Zittoun et al 1995 [14] Std 66 + HD Ara-C then: No HD Ara-C or 30 AutoBMT or AlloBMT 55 Rees et al 1996 [10] Std 63 Std Yes/no 5 d d Kobayashi et al 1996 [11] Std 77 Std Std Bishop et al 1996 [12] Std Yes Std HD Ara-C Porwit-MacDonald 1996 [15] Std 81 + HD Ara-C No 38 et al Weick et al 1996 [16] No Std Std or HD Ara-C 14 22/11 21/9 + HD Ara-C 32/13 33/4 Hann et al 1997 [19] Std 82 + HD Ara-C No Burnett et al 1998 [17] See Ref Std See Ref HD Ara-C then: No Early autobmt or No further treatment Cassileth et al 1998 [18] Std 78 Std then: No HD Ara-C or 35 AutoBMT or NS AlloBMT 43 Büchner et al 1999 [13] Std Yes w/o HD Ara-C with HD Ara-C *CR indicates complete remission; OS, overall survival; RFS, relapse-free survival; Std, standard dose regimen not containing high-dose AraC; VP-16, etoposide; HD, high-dose; Ara-C, cytosine arabinoside; NS, not significant; autobmt, autologous bone marrow transplantation; allobmt, allogeneic bone marrow transplantation. Age <50 y/age >50 y

3 Maintenance Treatment for AML 287 Percent Relapse-Free Survival Years Since Complete Remission Figure 1. Relapse-free survival in the 1981 AMLCG study: Patients aged 16 to 78 years received 1 to 2 courses of standard-dose 6-thioguanine- AraC-daunorubicin (TAD) for remission induction, and patients entering complete remission were randomized to receive 1 course of TAD for consolidation and no further treatment or the same consolidation followed by maintenance for 3 years. Maintenance included monthly courses of 5-day standard-dose cytosine arabinoside combined with a second drug, which rotated among daunorubicin, 5-thioguanine, or cyclophosphamide. Tick marks indicate patients alive without relapse at the most recent follow-up. analysis focuses on chemotherapy, whereas transplantation strategies are discussed separately in this issue [1]. According to common terminology, postremission chemotherapy can be divided into consolidation and maintenance treatment. Whereas consolidation immediately follows the achievement of complete remission and represents a repetition or an intensification of the induction regimen, maintenance uses drug combinations that, compared with induction regimens, are reduced in duration and/or dosage and are administered intermittently over a longer period. Maintenance was determined by a study of Cancer and Leukemia Group B (CALGB) in which 5-day courses of standard-dose cytosine arabinoside (Ara-C) were given monthly and were combined by rotation with a second agent such as daunorubicin, 6-thioguanine (TG), or cyclophosphamide [2]. Maintenance is an approach to progressively eliminate chemoresistant residual leukemic cells when they are spontaneously recruited from a dormant state into proliferation. Other strategies against minimal residual disease are growth factor priming [3] and allogeneic transplantation or cell therapy using the graft-versus-leukemia effect. In this study, we analyzed the effect of maintenance on the basis of both data from major multicenter trials, almost all published during the 1990s, and recent data from 2 studies of the Acute Myeloid Leukemia Cooperative Group (AMLCG). 2. Analysis of Published Data Table 1 gives a synopsis of trials with strategies in the induction, consolidation, and maintenance therapy and details of standard-dose regimens or the inclusion of highdose Ara-C and randomization among treatments, drugs, dosages, durations, or numbers of courses. Of the 14 trials listed, 10 used maintenance regimens [4-13], 3 without preceding consolidation [4,6,7] and 7 with maintenance after consolidation [5,8-13]. As representative end points, overall survival and relapse-free survival (RFS) at 4 to 5 years and the percentage of patients in remission not included in these results are given. The exclusions are because of randomization in remission after some relapses and deaths and prior toxicity or patient refusal, not allowing a randomization. Randomization in remission was done in 8 of the trials [4,7-9,14,16-18]; therefore, absolute results of randomized treatments cannot be compared on an intent-to-treat basis. If the overall unselected results are given in the references, these data are listed in Table 1, in addition to the data from randomizations in the related trials [4,8,9]. In intent-to-treat results including all patients in remission, RFS in the range of 35% to 42% is found only in 5 trials using maintenance [5,8,11-13]; 1 trial without maintenance but with an age range of 0 to 55 years reported a 43% RFS [19]. 3. Special Studies on Maintenance After the CALGB had published their results from monthly myelosuppressive maintenance [2], their regimen was investigated in a randomized study by the AMLCG and resulted in highly superior RFS rate in the study arm with consolidation and maintenance over that with consolidation alone [20,21]. An update is shown in Figure 1. In contrast, in a study by the CALGB using a reduced intensity maintenance regimen given only bimonthly and without preceding consolidation, 8 months versus 3 years of maintenance resulted in a similar RFS rate [4]. A low-dose weekly maintenance regimen of 40 mg/m 2 TG every 12 hours for 4 days and

4 288 Büchner et al / International Journal of Hematology 72 (2000) Percent Relapse-Free Survival Figure 2. Relapse-free survival in the combined 1986 and 1992 AMLCG studies in patients aged 16 to 83 years. Induction treatment in patients aged <60 years was doubled with 2 courses of standard-dose TAD or TAD followed by high-dose Ara-C/mitoxantrone (HAM), and in patients aged 60 years, 1 to 2 courses of standard-dose TAD or HAM were used as the second course. All patients entering complete remission received 1 course of standard-dose TAD for consolidation and randomly received either 3 years of maintenance (see Figure 1) or 1 course of sequential HAM and no further treatment. Tick marks indicate patients alive without relapse at the last follow-up. 60 mg/m 2 subcutaneous Ara-C on day 5 with no preceding consolidation was inferior to 1 course of consolidation with high-dose (3 g/m 2 ) Ara-C every 12 hours for 6 days (P =.068) in a study by the Eastern Cooperative Oncology Group [7]. After 3 courses of consolidation, 12 courses of intensive maintenance administered every 6 weeks tended to be superior to 4 courses (P =.066) in a study by the Japan Adult Leukemia Group [8]. In summary, in the published data, the association of the most favorable RFS rate with the administration of maintenance in unselected adult patients and the results of randomized studies in favor of full-dose maintenance after consolidation give support to a consolidation/maintenance strategy in adults with AML. 4. Recent Data on Maintenance From the AMLCG Because the contribution of maintenance has to be regarded in the context of the complete strategy including the induction and consolidation treatment, the AMLCG requestioned the role of maintenance in patients receiving highly intensive induction. In our 1986 and 1992 studies, we used the novel strategy of double induction in patients 16 to 60 years of age [13], which contained 2 courses of standarddose 6-thioguanine-AraC-daunorubicin (TAD) or TAD followed by high-dose Ara-C/mitoxantrone (HAM) [22]. Patients aged 60 years received 1 to 2 TAD induction courses (1986) or HAM as a second course (1992). All patients in complete remission received TAD consolidation. Monthly maintenance was as published previously [13,20] in the 1986 study and was randomly compared with 1 course of sequential HAM (S-HAM) (high-dose Ara-C [1 g/m 2 in younger patients and 500 mg/m 2 in older patients] every 12 hours on days 1, 2, 8, and 9 and 10 mg/m 2 mitoxantrone on days 3, 4, 10, and 11) [23] instead of maintenance in the 1992 study (details to be published elsewhere). Figure 2 compares the RFS rate in the S-HAM arm with that in the combined maintenance groups of the 1986 and 1992 studies in patients of all ages. The 4-year RFS rate is 32% for maintenance and 25% for S-HAM (P =.021). The remission duration in terms of freedom from relapse shows a similar difference (P =.032), and there is a tendency of survival in favor of maintenance (42% versus 37%, P =.15). Thus, 1 course of S-HAM compared with maintenance on an intent-to-treat basis failed to further improve the survival over that from maintenance treatment. This result is not explained by an insufficient intensity because S-HAM proved highly myelotoxic, producing a median recovery time of blood neutrophils and platelets as long as 6 weeks. Maintenance treatment, however, was confirmed to more effectively prolong RFS rate than S-HAM. These recent study results by the AMLCG strongly suggest the administration of maintenance therapy, even in patients who have received intensified induction treatment in which maintenance further contributed to the antileukemic effect of this strategy. In their current trial, the AMLCG is investigating maintenance treatment prospectively compared with autologous and allogeneic transplantation in which randomization for the 3 options is done in every subset of AML, such as primary AML, secondary AML, high-risk myelodysplasia, and favorable and unfavorable karyotype. Acknowledgments The studies of the AMLCG were supported by Bundesministerium für Forschung und Technologie (grants 01ZP0123 and 01ZP8701) and Deutsche Krebshilfe (grants M17/92/Bü1 and Bü3).

5 Maintenance Treatment for AML 289 References 1. Burnett AK, Kell J, Rowntree C. Role of allogeneic and autologous hematopoietic stem cell transplantation in acute myeloid leukemia. Int J Hematol. 2000;72: Rai K, Holland J, Gildewell O, et al. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood. 1981;58: Büchner T, Hiddemann W, Wörmann B, et al. Hematopoietic growth factors in acute myeloid leukemia: supportive and priming effects. Semin Oncol. 1998;24: Preisler H, Davis R, Kirshner J, et al. Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia B Group study. Blood. 1987;69: Bishop J, Lowenthal R, Joshua D, et al. Etoposide in acute nonlymphocytic leukemia. Blood. 1990;75: Dillmann R, Davis R, Green M, et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood. 1991; 78: Cassileth P, Lynch E, Hines J, et al. Varying intensity of postremission therapy in acute myeloid leukemia. Blood. 1992;79: Ohno R, Kobayashi T, Tanimoto M, et al. Randomized study of individualized induction therapy with or without vincristine, and of maintenance-intensification therapy between 4 or 12 courses in adult acute myeloid leukemia. Cancer. 1993;71: Mayer R, Davis R, Schiffer C, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994;331: Rees J, Gray R, Weathly K. Dose intensification in acute myeloid leukemia: greater effectiveness at lower cost: principal report of the Medical Research Councils s AML9 study. Br J Haematol. 1996;94: Kobayashi T, Miyawaki S, Tanimoto M, et al. Randomized trials between behenoyl cytarabine and cytarabine in combination induction and consolidation therapy, and with or without ubenimex after maintenance/intensification therapy in adult acute myeloid leukemia. J Clin Oncol. 1996;14: Bishop J, Matthews J, Young G, et al. A randomized study of highdose cytarabine in induction in acute myeloid leukemia. Blood. 1996;87: 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. 1999;93: Zittoun R, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995;332: Porwit-MacDonald A, Janossy G, Ivory K, et al. Leukemia-associated changes identified by quantitative flow cytometry-iv: CD34 overexpression in acute myelogenous leukemia M2 with t(8;21). Blood. 1996;87: Weick J, Kopecky K, Appelbaum F, et al. A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 1996;88: Burnett A, Goldstone A, Stevens R, et al. Randomized comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukemia in first remission: results of MRC AML10 trial. Lancet. 1998;351: Cassileth P, Harrington D, Appelbaum F, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998;339: Hann I, Stevens R, Goldstone A, et al. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council s 10th AML trial (MRC AML10). Blood. 1997;89: Büchner T, Urbanitz D, Hiddemann W, et al. Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol. 1985;3: Büchner T, Urbanitz D, Rühl H, et al. Role of chemotherapy for AML in remission. Lancet. 1985;25: Hiddemann W, Kreutzmann H, Straif K, et al. High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia. Blood. 97;69: Kern W, Schleyer E, Unterhalt M, Wörmann B, Büchner T, Hiddemann W. High antileukemic activity of sequential high dose cytosine arabinoside and mitoxantrone in patients with refractory acute leukemias. Cancer. 1997;79:59-68.