Mitoxantrone, Etoposide, and Intermediate-Dose Cytarabine: An Effective and Tolerable Regimen for the Treatment of Refractory Acute Myeloid Leukemia By Sergio Amadori, William Arcese, Giancarlo Isacchi, Giovanna Meloni, Maria C. Petti, Bruno Monarca, Anna M. Testi, and Franco Mandelli Thirty-two patients with refractory acute myeloid leukemia (AML) received salvage therapy with a single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus, etoposide 80 mg/m2 IV for a period of 1 hour, and cytarabine (Ara-C) 1 g/m 2 IV for a period of 6 hours daily for 6 days (MEC). Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment; eight patients had relapsed within 6 months from initial remission; six patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall, 21 patients (66%) achieved a complete remission (CR), two (6%) died of infection during induction, and nine (28%) had resis-
CURRENT
INTENSIVE chemotherapy programs result in complete remission (CR) for 50% to 80% of patients with newly diagnosed acute myeloid leukemia (AML). Unfortunately, up to 70% to 80% of responders develop recurrent disease within 2 to 3 years."12 The prognosis of patients who fail to achieve CR or who experience recurrence of their leukemia remains ominous. Results of salvage chemotherapy have been generally disappointing with low response rates and occasional long-term survivors in most studies.3 Since therapeutic failure seems to be inevitable in the great majority of AML patients, development of more effective salvage therapy is warranted. New active drugs such as amsacrine, 4 mitoxantrone, 56 newer anthracycline derivatives,7 or established agents such as cytarabine (Ara-C)
From the Section of Hematology, Department of Human Biopathology, University La Sapienza, Rome, Italy. Submitted November 8, 1990; acceptedJanuary25, 1991. Supported by Ministero Universita' e Ricerca Scientifica e Tecnologica,progetto 40%. Presented in part at the 26th Annual Meeting of the American Society of ClinicalOncology, Washington, May 20 to 22, 1990. Address reprint requests to Sergio Amadori, MD, Section of Hematology, Department of Human Biopathology, University La Sapienza, Via Benevento 6, 00161 Rome, Italy. & 1991 by American Society of ClinicalOncology. 0732-183X91/0907-0015$3.00/0
1210
tant disease. Age greater than 50 years was the only factor predictive for a significantly lower response rate (P = .03). The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal. We conclude that the MEC regimen has significant antileukemic activity and acceptable toxicity in salvage AML. Its benefit in front-line AML therapy is being investigated. J Clin Oncol 9:1210-1214. © 1991 by American Society of Clinical Oncology.
administered according to novel dosages and schedules 8 were investigated most extensively in recent years with variable results. Recently, we reported that a combination of intermediate-dose Ara-C (1 g/m 2/d for a period of 6 hours, days 1 to 6) and mitoxantrone (6 mg/m 2/d, days 1 to 6) was highly effective in reinducing CR in relapsed AML patients with first remission length of more than 6 months (CR rate, 85%), without excessive toxicity.' The same regimen proved to be less active in patients with disease resistant to conventional front-line therapy (CR rate, 28%) and in those with initial remission lasting for less than 6 months (CR rate, 33%). Primary drug resistance and early occurring relapse, therefore, may identify categories of patients at very high risk of treatment failure with standard therapy, for whom newer and more effective salvage programs should be developed. Etoposide is a drug with established activity in AML."' As a single agent, the drug induced CRs in 10% to 20% of patients with advanced AML. A significant increase in response rates has been reported in trials combining etoposide with other active drugs such as mitoxantrone" or anthracyclines.12 In an attempt to improve on the results of salvage therapy for patients with primary resistant disease or early occurring relapse, a modified regimen of mitoxantrone, etoposide, and Ara-C
Journal of Clinical Oncology, Vol 9, No 7 (July), 1991: pp 1210-1214
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1211
MEC SALVAGE IN REFRACTORY AML Table 1. Patient Characteristics
(MEC) was developed at our institution with the addition of etoposide to the basic intermediatedose Ara-C plus mitoxantrone combination. We summarize here our results using this approach in patients with refractory AML. MATERIALS AND METHODS Between February 1988 and March 1990, 32 consecutive eligible patients with refractory AML were treated with the MEC regimen after informed consent was obtained. Eligible patients included only those considered to have refractory AML according to the following criteria: (1) failure to enter CR after two conventional induction courses, or earlier evidence of absolute drug resistance as defined by the reappearance of circulating blasts and/or persistence of a hypercellular leukemic marrow 14 to 21 days from initiation of therapy; (2) relapse within 6 months after achieving CR; (3) relapse after bone marrow transplantation (BMT) (autologous or allogeneic). In particular, patients whose relapses occurred more than 6 months from initial CR were excluded from the study. Diagnosis and classification of AML were made according to the French-American-British (FAB) criteria." All patients were recruited from the current Italian multicenter trials (European Organization for Research and Treatment of Cancer-Gruppo Italiano Malattie Ematologiche Maligne Adulto [GIMEMA] AML-8 for adults; Associazione Italiana Ematologia ed Oncologia Pediatrica LAM-87 for children) and had received a standardized induction treatment with daunorubicin (45 mg/m 2/d for 3 days) and conventional-dose Ara-C (200 mg/m2/d continuous infusion for 7 days). Postremission therapy varied according to the two age-specific protocols. Children in CR were consolidated with two courses of daunorubicin, Ara-C, and thioguanine (DAT), and then randomized to autologous BMT or further chemotherapy consisting of four drug combinations administered sequentially for a total of eight courses (DAT; etoposide/Ara-C; Ara-C/thioguanine; daunorubicin/AraC). On achieving CR, adults (aged > 16 years) were given a course of intensive consolidation with amsacrine and intermediate-dose Ara-C and then randomized to a second intensification course with daunorubicin and high-dose Ara-C or bone marrow autograft. Patients younger than 45 years of age with a histocompatible sibling were allografted within 3 months from remission. At entry, all patients were required to have evidence of active leukemia with greater than 30% blasts in the marrow, bilirubin less than 3.0 mg/dL, creatinine less than 2.0 mg/dL, left ventricular ejection fraction greater than 50% with no evidence of cardiac dysfunction, and performance status of 0 to 2 according to the World Health Organization (WHO) scale. Clinical characteristics of the patients are detailed in Table 1. The MEC regimen consisted of a single 6-day course of mitoxantrone 6 mg/m2, etoposide 80 mg/m 2, and intermediate-dose Ara-C 1 g/m 2 daily on days 1 through 6. The three drugs were administered intravenously (IV) according to the sequence depicted in Fig 1. The 6-hour infusion of Ara-C was preceded by a short infusion (1 hour) of etoposide and followed, 3 hours later, by a bolus of mitoxantrone.
Characteristic
No.
No. of patients Male/female Age (years) Median Range Morphology (FAB) M1-M3 M4-M5 Disease status Primary resistance Early relapse Relapse after BMT
32 19/13 24 5-56 10 22 18 8 6
Patients who achieved CR were given a second 4-day course of MEC as consolidation and then submitted to an individualized program of postremission therapy. Depending on the patient's age, performance status, and history of past drug exposure, a full spectrum of therapeutic options was offered to complete responders ranging from allogeneic BMT for younger patients with a histocompatibility locus antigenidentical sibling, or marrow autograft for those lacking a suitable donor, to conventional maintenance therapy or no further treatment. Complete remission was defined as less than 5% blasts in a normohypercellular marrow with normal peripheral and differential counts (granulocytes > 1,500/mm3 ; platelets > 100,000/mm 3 ) and with normal physical findings for at least 1 month. Toxicity was assessed by WHO criteria.14 Survival was calculated from the beginning of salvage therapy to the date of last follow-up or death. Remission duration was measured from the time of achievement of CR to the date of most recent follow-up or documented relapse at any site or death in remission. Differences among subgroups in the CR rate were compared using the x2 test. Survival and remission duration curves were plotted by the method of Kaplan and Meier." RESULTS Of the 32 patients entered on to the study, all
were assessable for response and toxicity. Overall, 21 patients (66%) achieved CR, two patients (6%) died during marrow hypoplasia of infection, and nine patients (28%) had resistant disease. Among Hour
0 1
+
Etoposide
* +
80 mg/sqm
El
Ara-C
1 g/sqm
I
Mitoxantrone
6 mg/sqm Repeat daily for 6 days
Fig 1. MEC regimen.
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
7
10
1212
AMADORI ET AL
the 21 responders, median time from the initiation of chemotherapy to documentation of CR was 33 days and ranged from 25 to 55 days. Response rate by various pretreatment characteristics is shown in Table 2. Of the clinical, morphologic, and treatment variables examined, only age was significantly correlated with attaining a CR. The 25 patients younger than 50 years of age had a CR rate of 76% compared with 29% for older patients (P = .03). Though not statistically significant, a difference was seen in the rate of response when patients were grouped by status of disease. Patients refractory to first-line induction treatment had a CR rate of 56% compared with 87% for patients who presented in early relapse and to 67% for those who relapsed after BMT. Patients with FAB M1-M3 appeared to be more likely to respond than those with the M4-M5 subtypes, but again this was not statistically significant. The median remission duration was 16 weeks (range, 6 to 115 + weeks), and six patients are presently alive in continuous CR for 12 to more than 115 weeks. Four of the six patients in CR underwent BMT (three autologous, one allogeneic), while the other two received no further postconsolidation therapy. Overall, relapse has occurred in 14 patients 6 to 52 weeks from CR (median, 12 weeks); one additional patient died in CR at 32 weeks of massive intracranial bleeding while persistently thrombocytopenic following a bone marrow autograft. The overall median survival for the 32 patients on the study was 36 weeks, with a range of 2 to more than 118 weeks. The MEC regimen was severely myelosuppresTable 2. Response by Patient Characteristics Characteristic
No. of CR/Total
%CR
P
19/25 2/7
76 29
.03
12/19 9/13
63 69
NS
8/10 1'3/22
80 59
.42
10/18 7/8 4/6
56 87 67
Age (years)
50 Sex Male Female FAB M1-M3 M4-M5 Disease status Primary resistance Early relapse Relapse after BMT
.28
Table 3. Nonhematologic Toxicity (32 patients) Toxicity
Documented infections Fever of unknown origin Hemorrhage Nausea and vomiting Mild to moderate Severe Mucositis Mild to moderate Severe Liver toxicity Mild to moderate Severe Cardiac toxicity Mild to moderate
No. of Patients
%
17 15 16
53 47 50
19 7
59 22
15 4
47 13
1 1
3 3
3
9
sive, with all patients developing profound granulocytopenia (< 100/mm 3) and thrombocytopenia (< 20,000/mm') by day 10 from start of therapy. This was associated with a high incidence of infections or fever of unknown origin requiring IV antibiotic therapy in 29 patients (91%). These included Staphylococcus epidermidis bacteremia (six patients), Streptococcus sepsis (four patients), other septic episodes (four patients), pneumonia (one patient), fungal infections (two patients), herpes virus reactivation (two patients), and fever of undetermined etiology (15 patients). Two patients had more than one documented febrile episode during induction therapy. Infectious deaths occurred in only two patients, both aged older than 50 years (gram-negative sepsis and pneumonia, respectively). During thrombocytopenia, 16 patients (50%) developed hemorrhagic episodes, which were mild to moderate in 14 patients and severe in two. In responding patients, the median times to granulocyte count greater than 500/mm3 and platelet count greater than 50,000/mm3 were 25 days (range, 12 to 32) and 27 days (range, 12 to 62), respectively. The nonhematologic toxicity associated with MEC therapy is detailed in Table 3. Overall, the induction regimen was well tolerated. Nausea, vomiting, and oral mucositis were common but severe in only a small percentage of patients. Cardiotoxicity was limited to transient episodes of moderate supraventricular tachycardia, which occurred in the setting of febrile complications in three patients. No neurologic or other significant toxicity were noted.
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1213
MEC SALVAGE IN REFRACTORY AML DISCUSSION
In this study, the MEC combination was a very effective antileukemic regimen for patients with refractory AML. Overall, 66% of patients entered CR after a single induction course, with median remission duration and survival of 16 and 36 weeks, respectively. As noted by others, older age, the presence of a monocytic component, and refractoriness to first-line therapy were associated with a lower rate of response. The toxicity of the regimen was acceptable with a mortality rate of only 6% during remission induction. These results compare favorably with other salvage programs including high-dose Ara-C alone8 or combined with other agents such as amsacrine,'"' 7 mitoxantrone,' 8' 9 anthracyclines,8 or asparaginase.2-1 However, the comparative efficacy of the MEC program with other regimens is difficult to evaluate if one considers the great heterogeneity of the patient populations entered onto these trials. Major differences in criteria for patient selection may have a significant impact on the outcome of salvage therapy and must be taken into account. In recent years, it has been clearly shown by several investigators that response to salvage therapy varies widely in relation to selected host and disease characteristics, including age, leukemic blast morphology, history of past drug exposure, and status of disease. 22 24 In partic-
ular, the latter variable was found to be the most important predictor of induction response. Patients refractory to first-line induction treatment and those who relapse early after CR (within 6 months) respond poorly to salvage chemotherapy, with CR rates rarely exceeding 20% to 30%. In our experience, salvage therapy is also scarcely effective in patients with AML relapsing after ablative programs of chemoradiotherapy with autologous or allogeneic bone marrow support (unpublished results). This contrasts with the high degree of chemosensitivity generally shown by patients with late occurring relapse, in whom CR can be easily reinduced in more than 50% to 70% of cases. In two recent trials of salvage therapy for AML, inclusion criteria comparable to ours were adopted. Hiddemann et al 25 reported a CR rate of 52% with a regimen of high-dose Ara-C and mitoxantrone (HAM). However, the toxicity associated with the HAM regimen was substantial as evidenced by an
early death rate in excess of 25%. In the study by Ho et al," the combination of mitoxantrone and etoposide induced CR in 42% of patients with heavily pretreated or poor-risk AML, without undue toxicity (toxic mortality, 3%). In a previous study,9 we tested a novel combination of intermediate-dose Ara-C and mitoxantrone for the treatment of poor-risk AML. The results confirmed the poor prognosis of patients with primary refractory and early relapse disease in whom CR rates of 28% and 33%, respectively, were obtained. Addition of a third active drug such as ctoposide, apparently resulted in a potentiation of the antileukemic activity of the basic intermediate-dose Ara-C/mitoxantrone combination in these prognostically unfavorable categories of patients, without adding too much toxicity. CR rates of 56% and 87%, respectively, for patients with primary refractory and early-relapse AML, are among the best ever reported in the literature. Furthermore, the 67% CR rate observed in patients relapsing after a BMT procedure confirms the high antileukemic activity of the MEC regimen, which may even be superior to the previously used salvage therapy. Unfortunately, even with the most successful salvage programs, remissions continue to be brief, with no evidence that conventional postremission therapy prolongs disease-free survival. Allogeneic or autologous BMT, performed early during remission, represents the only available therapeutic modality that may hold out the promise of longterm benefit in these poor-risk categories of patients. The major toxic effects of the program were related to the treatment-induced myelosuppression. Overall, 91% of the patients developed febrile episodes requiring IV antibiotics, and 53% had documented infections. However, mortality associated with myelosuppression occurred in only two patients, both aged older than 50 years. This compares favorably with more myelosuppressive programs, such as those using megadoses of Ara-C, for which morbidity and mortality are significantly higher. In conclusion, the results of this study indicate that the MEC combination is an effective regimen with acceptable toxicity in refractory AML. Its benefit in front-line AML therapy is being investigated.
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1214
AMADORI ET AL REFERENCES
1. Champlin RE, Gale RP: Acute myelogenous leukemia: Recent advances in therapy. Blood 69:1551-1562, 1987 2. Mandelli F, Rees JKH, Gorin NC, et al: Postremission treatment in acute myeloid leukemia: Chemotherapy or autologous or allogeneic bone marrow transplantation. Haematologica 75:203-211, 1990 3. Hiddemann W, Buchner Th: Treatment strategies in acute myeloid leukemia (AML). B. Second line treatment. Blut 60:163-171, 1990 4. Legha SS, Keating MJ, McCredie KB, et al: Evaluation of AMSA in previously treated patients with acute leukemia: Results of therapy in 109 adults. Blood 60:484490, 1982 5. Prentice HG, Robbins G, Ma DDF, et al: Mitoxantrone in relapsed and refractory acute leukemia. Semin Oncol 11:32-35, 1984 6. Lazzarino M, Morra E, Alessandrino EP, et al: Mitoxantrone and etoposide: An effective regimen for refractory or relapsed acute myelogenous leukemia. Eur J Haematol 43:411-416, 1989 7. Harousseau JL, Hurteloup P, Reiffers J, et al: Idarubicin in the treatment of relapsed or refractory acute myeloid leukemia. Cancer Treat Rep 71:991-992, 1987 8. Herzig RH, Lazarus HM, Wolff SN, et al: High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia. J Clin Oncol 3:992-997, 1985 9. Amadori S, Meloni G, Petti MC, et al: Phase II trial of intermediate dose Ara-C (IDAC) with sequential mitoxantrone (MITOX) in acute myelogenous leukemia. Leukemia 3:112-114, 1989 10. O'Dwyer PJ, Leyland-Jones B, Alonso MT, et al: Etoposide (VP-16-213)-Current status of an active anticancer drug. N Engl J Med 312:692-700, 1985 11. Ho AD, Lipp T, Ehninger G, et al: Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia. An active and well-tolerated regimen. J Clin Oncol 6:213-217, 1988 12. Tschopp L, von Fliedner VE, Sauter C, et al: Efficacy and clinical cross-resistance of a new combination therapy (AMSA/VP-16) in previously treated patients with acute nonlymphocytic leukemia. J Clin Oncol 4:318-324, 1986 13. Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Ann Intern Med 103:620-624, 1985
14. World Health Organization: WHO handbook for reporting results of cancer treatment. WHO publication 38, Geneva, 1979 15. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 16. Hines JD, Oken MM, Mazza JJ, et al: High-dose cytosine arabinoside and m-AMSA is effective therapy in relapsed acute nonlymphocytic leukemia. J Clin Oncol 2:545-549, 1984 17. Latagliata R, Petti MC, Aloe Spiriti MA, et al: High doses of Ara-C and m-AMSA in the treatment of refractory acute non lymphocytic leukemia. Haematologica 75:249251, 1990 18. Brito-Babapulle F, Catovsky D, Slocombe G, et al: Phase 11 study of mitoxantrone and cytarabine in acute myeloid leukemia. Cancer Treat Rep 71:161-163, 1987 19. 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 20. Amadori S, Papa G, Avvisati G, et al: Sequential combination of high-dose Ara-C (HiDAC) and asparaginase (ASP) for the treatment of advanced acute leukemia and lymphoma. Leuk Res 8:729-735, 1984 21. Capizzi RL, Davis R, Powell B, et al: Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia. A Cancer and Leukemia Group B study. J Clin Oncol 6:499-508, 1988 22. Smits P, Schoots L, de Pauw BE, et al: Prognostic factors in adult patients with acute leukemia at first relapse. Cancer 59:1631-1634, 1987 23. Keating MJ, Kantarjian H, Smith TL, et al: Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 7:1071-1080, 1989 24. Uhlman DL, Bloomfield CD, Hurd DD, et al: Prognostic factors at relapse for adults with acute myeloid leukemia. Am J Hematol 33:110-116, 1990 25. Hiddemann W, Martin W-R, Sauerland C-M, et al: Definition of refractoriness against conventional chemotherapy in acute myeloid leukemia: A proposal based on the results of retreatment by thioguanine, cytosine arabinoside, and daunorubicin (TAD 9) in 150 patients with relapse after standardized first line therapy. Leukemia 4:184-188, 1990
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
CURRENT
INTENSIVE chemotherapy programs result in complete remission (CR) for 50% to 80% of patients with newly diagnosed acute myeloid leukemia (AML). Unfortunately, up to 70% to 80% of responders develop recurrent disease within 2 to 3 years."12 The prognosis of patients who fail to achieve CR or who experience recurrence of their leukemia remains ominous. Results of salvage chemotherapy have been generally disappointing with low response rates and occasional long-term survivors in most studies.3 Since therapeutic failure seems to be inevitable in the great majority of AML patients, development of more effective salvage therapy is warranted. New active drugs such as amsacrine, 4 mitoxantrone, 56 newer anthracycline derivatives,7 or established agents such as cytarabine (Ara-C)
From the Section of Hematology, Department of Human Biopathology, University La Sapienza, Rome, Italy. Submitted November 8, 1990; acceptedJanuary25, 1991. Supported by Ministero Universita' e Ricerca Scientifica e Tecnologica,progetto 40%. Presented in part at the 26th Annual Meeting of the American Society of ClinicalOncology, Washington, May 20 to 22, 1990. Address reprint requests to Sergio Amadori, MD, Section of Hematology, Department of Human Biopathology, University La Sapienza, Via Benevento 6, 00161 Rome, Italy. & 1991 by American Society of ClinicalOncology. 0732-183X91/0907-0015$3.00/0
1210
tant disease. Age greater than 50 years was the only factor predictive for a significantly lower response rate (P = .03). The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal. We conclude that the MEC regimen has significant antileukemic activity and acceptable toxicity in salvage AML. Its benefit in front-line AML therapy is being investigated. J Clin Oncol 9:1210-1214. © 1991 by American Society of Clinical Oncology.
administered according to novel dosages and schedules 8 were investigated most extensively in recent years with variable results. Recently, we reported that a combination of intermediate-dose Ara-C (1 g/m 2/d for a period of 6 hours, days 1 to 6) and mitoxantrone (6 mg/m 2/d, days 1 to 6) was highly effective in reinducing CR in relapsed AML patients with first remission length of more than 6 months (CR rate, 85%), without excessive toxicity.' The same regimen proved to be less active in patients with disease resistant to conventional front-line therapy (CR rate, 28%) and in those with initial remission lasting for less than 6 months (CR rate, 33%). Primary drug resistance and early occurring relapse, therefore, may identify categories of patients at very high risk of treatment failure with standard therapy, for whom newer and more effective salvage programs should be developed. Etoposide is a drug with established activity in AML."' As a single agent, the drug induced CRs in 10% to 20% of patients with advanced AML. A significant increase in response rates has been reported in trials combining etoposide with other active drugs such as mitoxantrone" or anthracyclines.12 In an attempt to improve on the results of salvage therapy for patients with primary resistant disease or early occurring relapse, a modified regimen of mitoxantrone, etoposide, and Ara-C
Journal of Clinical Oncology, Vol 9, No 7 (July), 1991: pp 1210-1214
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1211
MEC SALVAGE IN REFRACTORY AML Table 1. Patient Characteristics
(MEC) was developed at our institution with the addition of etoposide to the basic intermediatedose Ara-C plus mitoxantrone combination. We summarize here our results using this approach in patients with refractory AML. MATERIALS AND METHODS Between February 1988 and March 1990, 32 consecutive eligible patients with refractory AML were treated with the MEC regimen after informed consent was obtained. Eligible patients included only those considered to have refractory AML according to the following criteria: (1) failure to enter CR after two conventional induction courses, or earlier evidence of absolute drug resistance as defined by the reappearance of circulating blasts and/or persistence of a hypercellular leukemic marrow 14 to 21 days from initiation of therapy; (2) relapse within 6 months after achieving CR; (3) relapse after bone marrow transplantation (BMT) (autologous or allogeneic). In particular, patients whose relapses occurred more than 6 months from initial CR were excluded from the study. Diagnosis and classification of AML were made according to the French-American-British (FAB) criteria." All patients were recruited from the current Italian multicenter trials (European Organization for Research and Treatment of Cancer-Gruppo Italiano Malattie Ematologiche Maligne Adulto [GIMEMA] AML-8 for adults; Associazione Italiana Ematologia ed Oncologia Pediatrica LAM-87 for children) and had received a standardized induction treatment with daunorubicin (45 mg/m 2/d for 3 days) and conventional-dose Ara-C (200 mg/m2/d continuous infusion for 7 days). Postremission therapy varied according to the two age-specific protocols. Children in CR were consolidated with two courses of daunorubicin, Ara-C, and thioguanine (DAT), and then randomized to autologous BMT or further chemotherapy consisting of four drug combinations administered sequentially for a total of eight courses (DAT; etoposide/Ara-C; Ara-C/thioguanine; daunorubicin/AraC). On achieving CR, adults (aged > 16 years) were given a course of intensive consolidation with amsacrine and intermediate-dose Ara-C and then randomized to a second intensification course with daunorubicin and high-dose Ara-C or bone marrow autograft. Patients younger than 45 years of age with a histocompatible sibling were allografted within 3 months from remission. At entry, all patients were required to have evidence of active leukemia with greater than 30% blasts in the marrow, bilirubin less than 3.0 mg/dL, creatinine less than 2.0 mg/dL, left ventricular ejection fraction greater than 50% with no evidence of cardiac dysfunction, and performance status of 0 to 2 according to the World Health Organization (WHO) scale. Clinical characteristics of the patients are detailed in Table 1. The MEC regimen consisted of a single 6-day course of mitoxantrone 6 mg/m2, etoposide 80 mg/m 2, and intermediate-dose Ara-C 1 g/m 2 daily on days 1 through 6. The three drugs were administered intravenously (IV) according to the sequence depicted in Fig 1. The 6-hour infusion of Ara-C was preceded by a short infusion (1 hour) of etoposide and followed, 3 hours later, by a bolus of mitoxantrone.
Characteristic
No.
No. of patients Male/female Age (years) Median Range Morphology (FAB) M1-M3 M4-M5 Disease status Primary resistance Early relapse Relapse after BMT
32 19/13 24 5-56 10 22 18 8 6
Patients who achieved CR were given a second 4-day course of MEC as consolidation and then submitted to an individualized program of postremission therapy. Depending on the patient's age, performance status, and history of past drug exposure, a full spectrum of therapeutic options was offered to complete responders ranging from allogeneic BMT for younger patients with a histocompatibility locus antigenidentical sibling, or marrow autograft for those lacking a suitable donor, to conventional maintenance therapy or no further treatment. Complete remission was defined as less than 5% blasts in a normohypercellular marrow with normal peripheral and differential counts (granulocytes > 1,500/mm3 ; platelets > 100,000/mm 3 ) and with normal physical findings for at least 1 month. Toxicity was assessed by WHO criteria.14 Survival was calculated from the beginning of salvage therapy to the date of last follow-up or death. Remission duration was measured from the time of achievement of CR to the date of most recent follow-up or documented relapse at any site or death in remission. Differences among subgroups in the CR rate were compared using the x2 test. Survival and remission duration curves were plotted by the method of Kaplan and Meier." RESULTS Of the 32 patients entered on to the study, all
were assessable for response and toxicity. Overall, 21 patients (66%) achieved CR, two patients (6%) died during marrow hypoplasia of infection, and nine patients (28%) had resistant disease. Among Hour
0 1
+
Etoposide
* +
80 mg/sqm
El
Ara-C
1 g/sqm
I
Mitoxantrone
6 mg/sqm Repeat daily for 6 days
Fig 1. MEC regimen.
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
7
10
1212
AMADORI ET AL
the 21 responders, median time from the initiation of chemotherapy to documentation of CR was 33 days and ranged from 25 to 55 days. Response rate by various pretreatment characteristics is shown in Table 2. Of the clinical, morphologic, and treatment variables examined, only age was significantly correlated with attaining a CR. The 25 patients younger than 50 years of age had a CR rate of 76% compared with 29% for older patients (P = .03). Though not statistically significant, a difference was seen in the rate of response when patients were grouped by status of disease. Patients refractory to first-line induction treatment had a CR rate of 56% compared with 87% for patients who presented in early relapse and to 67% for those who relapsed after BMT. Patients with FAB M1-M3 appeared to be more likely to respond than those with the M4-M5 subtypes, but again this was not statistically significant. The median remission duration was 16 weeks (range, 6 to 115 + weeks), and six patients are presently alive in continuous CR for 12 to more than 115 weeks. Four of the six patients in CR underwent BMT (three autologous, one allogeneic), while the other two received no further postconsolidation therapy. Overall, relapse has occurred in 14 patients 6 to 52 weeks from CR (median, 12 weeks); one additional patient died in CR at 32 weeks of massive intracranial bleeding while persistently thrombocytopenic following a bone marrow autograft. The overall median survival for the 32 patients on the study was 36 weeks, with a range of 2 to more than 118 weeks. The MEC regimen was severely myelosuppresTable 2. Response by Patient Characteristics Characteristic
No. of CR/Total
%CR
P
19/25 2/7
76 29
.03
12/19 9/13
63 69
NS
8/10 1'3/22
80 59
.42
10/18 7/8 4/6
56 87 67
Age (years)
50 Sex Male Female FAB M1-M3 M4-M5 Disease status Primary resistance Early relapse Relapse after BMT
.28
Table 3. Nonhematologic Toxicity (32 patients) Toxicity
Documented infections Fever of unknown origin Hemorrhage Nausea and vomiting Mild to moderate Severe Mucositis Mild to moderate Severe Liver toxicity Mild to moderate Severe Cardiac toxicity Mild to moderate
No. of Patients
%
17 15 16
53 47 50
19 7
59 22
15 4
47 13
1 1
3 3
3
9
sive, with all patients developing profound granulocytopenia (< 100/mm 3) and thrombocytopenia (< 20,000/mm') by day 10 from start of therapy. This was associated with a high incidence of infections or fever of unknown origin requiring IV antibiotic therapy in 29 patients (91%). These included Staphylococcus epidermidis bacteremia (six patients), Streptococcus sepsis (four patients), other septic episodes (four patients), pneumonia (one patient), fungal infections (two patients), herpes virus reactivation (two patients), and fever of undetermined etiology (15 patients). Two patients had more than one documented febrile episode during induction therapy. Infectious deaths occurred in only two patients, both aged older than 50 years (gram-negative sepsis and pneumonia, respectively). During thrombocytopenia, 16 patients (50%) developed hemorrhagic episodes, which were mild to moderate in 14 patients and severe in two. In responding patients, the median times to granulocyte count greater than 500/mm3 and platelet count greater than 50,000/mm3 were 25 days (range, 12 to 32) and 27 days (range, 12 to 62), respectively. The nonhematologic toxicity associated with MEC therapy is detailed in Table 3. Overall, the induction regimen was well tolerated. Nausea, vomiting, and oral mucositis were common but severe in only a small percentage of patients. Cardiotoxicity was limited to transient episodes of moderate supraventricular tachycardia, which occurred in the setting of febrile complications in three patients. No neurologic or other significant toxicity were noted.
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1213
MEC SALVAGE IN REFRACTORY AML DISCUSSION
In this study, the MEC combination was a very effective antileukemic regimen for patients with refractory AML. Overall, 66% of patients entered CR after a single induction course, with median remission duration and survival of 16 and 36 weeks, respectively. As noted by others, older age, the presence of a monocytic component, and refractoriness to first-line therapy were associated with a lower rate of response. The toxicity of the regimen was acceptable with a mortality rate of only 6% during remission induction. These results compare favorably with other salvage programs including high-dose Ara-C alone8 or combined with other agents such as amsacrine,'"' 7 mitoxantrone,' 8' 9 anthracyclines,8 or asparaginase.2-1 However, the comparative efficacy of the MEC program with other regimens is difficult to evaluate if one considers the great heterogeneity of the patient populations entered onto these trials. Major differences in criteria for patient selection may have a significant impact on the outcome of salvage therapy and must be taken into account. In recent years, it has been clearly shown by several investigators that response to salvage therapy varies widely in relation to selected host and disease characteristics, including age, leukemic blast morphology, history of past drug exposure, and status of disease. 22 24 In partic-
ular, the latter variable was found to be the most important predictor of induction response. Patients refractory to first-line induction treatment and those who relapse early after CR (within 6 months) respond poorly to salvage chemotherapy, with CR rates rarely exceeding 20% to 30%. In our experience, salvage therapy is also scarcely effective in patients with AML relapsing after ablative programs of chemoradiotherapy with autologous or allogeneic bone marrow support (unpublished results). This contrasts with the high degree of chemosensitivity generally shown by patients with late occurring relapse, in whom CR can be easily reinduced in more than 50% to 70% of cases. In two recent trials of salvage therapy for AML, inclusion criteria comparable to ours were adopted. Hiddemann et al 25 reported a CR rate of 52% with a regimen of high-dose Ara-C and mitoxantrone (HAM). However, the toxicity associated with the HAM regimen was substantial as evidenced by an
early death rate in excess of 25%. In the study by Ho et al," the combination of mitoxantrone and etoposide induced CR in 42% of patients with heavily pretreated or poor-risk AML, without undue toxicity (toxic mortality, 3%). In a previous study,9 we tested a novel combination of intermediate-dose Ara-C and mitoxantrone for the treatment of poor-risk AML. The results confirmed the poor prognosis of patients with primary refractory and early relapse disease in whom CR rates of 28% and 33%, respectively, were obtained. Addition of a third active drug such as ctoposide, apparently resulted in a potentiation of the antileukemic activity of the basic intermediate-dose Ara-C/mitoxantrone combination in these prognostically unfavorable categories of patients, without adding too much toxicity. CR rates of 56% and 87%, respectively, for patients with primary refractory and early-relapse AML, are among the best ever reported in the literature. Furthermore, the 67% CR rate observed in patients relapsing after a BMT procedure confirms the high antileukemic activity of the MEC regimen, which may even be superior to the previously used salvage therapy. Unfortunately, even with the most successful salvage programs, remissions continue to be brief, with no evidence that conventional postremission therapy prolongs disease-free survival. Allogeneic or autologous BMT, performed early during remission, represents the only available therapeutic modality that may hold out the promise of longterm benefit in these poor-risk categories of patients. The major toxic effects of the program were related to the treatment-induced myelosuppression. Overall, 91% of the patients developed febrile episodes requiring IV antibiotics, and 53% had documented infections. However, mortality associated with myelosuppression occurred in only two patients, both aged older than 50 years. This compares favorably with more myelosuppressive programs, such as those using megadoses of Ara-C, for which morbidity and mortality are significantly higher. In conclusion, the results of this study indicate that the MEC combination is an effective regimen with acceptable toxicity in refractory AML. Its benefit in front-line AML therapy is being investigated.
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
1214
AMADORI ET AL REFERENCES
1. Champlin RE, Gale RP: Acute myelogenous leukemia: Recent advances in therapy. Blood 69:1551-1562, 1987 2. Mandelli F, Rees JKH, Gorin NC, et al: Postremission treatment in acute myeloid leukemia: Chemotherapy or autologous or allogeneic bone marrow transplantation. Haematologica 75:203-211, 1990 3. Hiddemann W, Buchner Th: Treatment strategies in acute myeloid leukemia (AML). B. Second line treatment. Blut 60:163-171, 1990 4. Legha SS, Keating MJ, McCredie KB, et al: Evaluation of AMSA in previously treated patients with acute leukemia: Results of therapy in 109 adults. Blood 60:484490, 1982 5. Prentice HG, Robbins G, Ma DDF, et al: Mitoxantrone in relapsed and refractory acute leukemia. Semin Oncol 11:32-35, 1984 6. Lazzarino M, Morra E, Alessandrino EP, et al: Mitoxantrone and etoposide: An effective regimen for refractory or relapsed acute myelogenous leukemia. Eur J Haematol 43:411-416, 1989 7. Harousseau JL, Hurteloup P, Reiffers J, et al: Idarubicin in the treatment of relapsed or refractory acute myeloid leukemia. Cancer Treat Rep 71:991-992, 1987 8. Herzig RH, Lazarus HM, Wolff SN, et al: High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia. J Clin Oncol 3:992-997, 1985 9. Amadori S, Meloni G, Petti MC, et al: Phase II trial of intermediate dose Ara-C (IDAC) with sequential mitoxantrone (MITOX) in acute myelogenous leukemia. Leukemia 3:112-114, 1989 10. O'Dwyer PJ, Leyland-Jones B, Alonso MT, et al: Etoposide (VP-16-213)-Current status of an active anticancer drug. N Engl J Med 312:692-700, 1985 11. Ho AD, Lipp T, Ehninger G, et al: Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia. An active and well-tolerated regimen. J Clin Oncol 6:213-217, 1988 12. Tschopp L, von Fliedner VE, Sauter C, et al: Efficacy and clinical cross-resistance of a new combination therapy (AMSA/VP-16) in previously treated patients with acute nonlymphocytic leukemia. J Clin Oncol 4:318-324, 1986 13. Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Ann Intern Med 103:620-624, 1985
14. World Health Organization: WHO handbook for reporting results of cancer treatment. WHO publication 38, Geneva, 1979 15. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 16. Hines JD, Oken MM, Mazza JJ, et al: High-dose cytosine arabinoside and m-AMSA is effective therapy in relapsed acute nonlymphocytic leukemia. J Clin Oncol 2:545-549, 1984 17. Latagliata R, Petti MC, Aloe Spiriti MA, et al: High doses of Ara-C and m-AMSA in the treatment of refractory acute non lymphocytic leukemia. Haematologica 75:249251, 1990 18. Brito-Babapulle F, Catovsky D, Slocombe G, et al: Phase 11 study of mitoxantrone and cytarabine in acute myeloid leukemia. Cancer Treat Rep 71:161-163, 1987 19. 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 20. Amadori S, Papa G, Avvisati G, et al: Sequential combination of high-dose Ara-C (HiDAC) and asparaginase (ASP) for the treatment of advanced acute leukemia and lymphoma. Leuk Res 8:729-735, 1984 21. Capizzi RL, Davis R, Powell B, et al: Synergy between high-dose cytarabine and asparaginase in the treatment of adults with refractory and relapsed acute myelogenous leukemia. A Cancer and Leukemia Group B study. J Clin Oncol 6:499-508, 1988 22. Smits P, Schoots L, de Pauw BE, et al: Prognostic factors in adult patients with acute leukemia at first relapse. Cancer 59:1631-1634, 1987 23. Keating MJ, Kantarjian H, Smith TL, et al: Response to salvage therapy and survival after relapse in acute myelogenous leukemia. J Clin Oncol 7:1071-1080, 1989 24. Uhlman DL, Bloomfield CD, Hurd DD, et al: Prognostic factors at relapse for adults with acute myeloid leukemia. Am J Hematol 33:110-116, 1990 25. Hiddemann W, Martin W-R, Sauerland C-M, et al: Definition of refractoriness against conventional chemotherapy in acute myeloid leukemia: A proposal based on the results of retreatment by thioguanine, cytosine arabinoside, and daunorubicin (TAD 9) in 150 patients with relapse after standardized first line therapy. Leukemia 4:184-188, 1990
Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 23, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
