Postremission Chemotherapy for Adults With Acute Myelogenous Leukemia: Improved Survival With High-Dose Cytarabine and Daunorubicin Consolidation Treatment By Richard Champlin, James Gajewski, Stephen Nimer, Stein Vollset, Elliot Landaw, Drew Winston, Gary Schiller, and Winston Ho Results of postremission chemotherapy for adults with acute myelogenous leukemia (AML) were assessed in two sequential prospective studies involving similar induction therapy and two courses of intensive consolidation treatment. Fifty-six patients achieving remission on the acute leukemia protocol (ALP3) study received high-dose cytarabine and daunorubicin as course one and standard-dose cytarabine and daunorubicin as course two. Results are compared with forty-six patients achieving remission on the ALP2 study who received azacitidine and doxorubicin as consolidation course one and standard-dose cytarabine, daunorubicin, and thioguanine as course two. The ALP3 regimen resulted in a significantly improved 5-year disease-free survival of 32% + 19% versus 20% ± 11% for the ALP2 study (P = .03). Survival from remission was also improved, 40% + 14% versus 24% + 12% (P < .01). Favorable prognostic factors for
W
ITH MODERN induction chemotherapy,
complete remission can be achieved in the majority of patients with acute myelogenous leukemia (AML). However, despite further chemotherapy, most patients relapse and ultimately succumb to the disease. Median duration of remission has typically been approximately 1 year with less than 25% of patients surviving free of recurrence for more than 5 years.' Optimal management of patients achieving a complete remission is controversial. Treatment recommendations range from postremission consolidation and/or maintenance chemotherapy to allogeneic or autologous bone marrow transplantation (BMT).' 4 High-dose cytarabine alone, or in combination with an anthracycline or asparaginase, is an effective treatment of relapsed AML, inducing a second remission in 35% to 65% of cases.5 '7 When compared with standard doses of cytarabine, administration of high-dose cytarabine increases intracellular levels and incorporation of the active metabolite arabinosylcytosine triphosphate (ara-CTP) into the DNA of leukemia cells. 8 Preliminary data suggest an efficacy of high-dose
disease-free survival included receiving the ALP3 treatment regimen, absence of a prior preleukemic syndrome, and female sex. These factors and younger patient age were significant for survival following first chemotherapy and survival after achieving remission. Six of 34 patients who relapsed after receiving the ALP3 regimen successfully achieved prolonged second remissions with high-dose cytarabine-based chemotherapy and/or allogeneic bone marrow transplantation (BMT). Overall survival for adults _-30%. Leukocyte transfusions were not used.
StatisticalAnalysis Patients were analyzed for survival from time of induction therapy and from time of remission as well as disease-free survival (ie, leukemia-free survival) by the product-limit method of Kaplan and Meier." Summary estimates include survival fractions + 2 x SE for 95% confidence intervals (CIs) and approximate CIs for median survival time.' 8' 9 Survival curves were compared using the log-rank test.' Treatment comparisons adjusted for prognostic factors were performed using the Cox proportional hazards model.2 0 Factors prognostic for entering remission were analyzed using logistic regression. Age was tricotomized into three groups: age _ 45 years, 46 to 60 years, and greater than 60 years. Analyses were carried out using the BMDP statistical package.'" P values were two-sided throughout. RESULTS Induction Chemotherapy One hundred eleven consecutive adults with
AML, aged 16 to 84 years (median, 47 years) entered into the ALP3 study. Fifty-six were males and 55 were females. Twenty-one had a
previous myelodysplastic syndrome. Ninety had de novo AML with no known preexisting hemato-
logic disorder. Seventy patients (63%) achieved complete remission; 41 patients failed to achieve remission because of persistent leukemia in 23,
early death in 17, and persistent aplasia in one. Results in this group were compared with 91
consecutive patients treated according to our previous study ALP2" in which a similar proportion of patients, 59 (65%), achieved remission. Thirty-two ALP2 patients were induction failures, 19 with persistant leukemia and 13 with
early death. As indicated in Table 1, patient characteristics for the ALP2 and ALP3 studies
are comparable. Patients with secondary leukemia occurring after treatment for another malignancy or leukemia developing after aplastic anemia were not eligible for either the ALP3 or
ALP2 analysis. Considering patients in both the ALP2 and ALP3 studies, 129 of 202 patients (64%) achieved complete remission. Younger age and absence of an antecedent preleukemic syndrome were the only significant prognostic factors by multivari-
ate analysis for achieving remission (Table 2). Complete remission was achieved in 73 of 96 (76%) patients less than 45 years of age, 24 of 36
(67%) aged 45 to 60, and 32 of 70 (46%) patients greater than 60 years of age. Fourteen of 39
patients (36%) with a previous myelodysplastic
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1201
POSTREMISSION CHEMOTHERAPY FOR ADULT AML Table 1. Patient Characteristics All Patients ALP3 N Sex M/F Preleukemia Chromosome abnormality Y/N/Unk Age yrs, median (range) : 45 46-60 > 60 Achieved remission BMT in first remission BMT after relapse
Eligible for Consolidation* ALP2
ALP3
ALP2
111 56/55 21
91 52/39 18
56 28/28 7
49 29/20 7
27/38/46 47 (16-84) 42/53 (79%)t 13/17 (76%)t 15/41 (37%)t 70 (63%) 14
23/42/26 48 (16-81) 31/43 (72%)t 11/19 (58%)t 17/29 (59%) 59 (65%) 10 -
14/19/23 45 (19-71) 28 13 15
10/24/15 49 (17-75) 21 11 17
6-
2
Abbreviation: Y/N/Unk, yes/no/unknown. *Includes all patients achieving remission who did not receive allogeneic BMT in first complete remission.
"tNumberof patients achieving complete remission/total patients (%). syndrome achieved remission compared with 115 of 161 (71%) with de novo AML (P s .01). Twenty-four patients less than 45 years of age had an HLA-identical sibling and received allogeneic BMT while in first complete remission; these patients are not considered further in this report. ALP3 Consolidation Fifty-six patients on the ALP3 study were eligible to receive consolidation chemotherapy treatment; all are considered assessable including two patients who relapsed and died before receiving the first consolidation chemotherapy course. Patient characteristics are summarized in Table 1. Thirty of these patients required one course of induction chemotherapy to achieve remission and 26 required two courses. Fifty-three patients received the first course of consolidation. Two other patients relapsed before receiving consolidation chemotherapy, one left the area while in remission and was lost to follow-up. Forty-six patients received both consolidation courses; the second course was not given because of death or relapse in four patients, cerebellar toxicity in two, and persistent hepatitis in one. Median follow-up of survivors following remission is 4.6 years, with a range of 2.1 to 6.3 years. The first consolidation course consisting of high-dose cytarabine and daunorubicin was relatively well tolerated. Major toxicities included mild to moderate nausea and vomiting in all
patients. Mild conjunctivitis typically occurred despite use of prophylactic topical corticosteroids. Profound myelosuppression occurred with granulocytes recovering to 0.5 x 109/L after a median of 24 (range, 16 to 47) days and platelets recovering to greater than 20 x 109/L after 23 (range, 14 to 37) days. Two patients, aged 63 and 67 years, developed irreversible grade 3 neurotoxicity with cerebellar ataxia and speech disturbance and one, aged 26, had grade 2 neurotoxicity. Three of the 53 patients (6%) receiving the first consolidation course died from treatment complications, two from infection and one from multisystem failure. No deaths occurred in the Table 2. Favorable Prognostic Factors for Combined ALP3 and ALP2 Studies For achieving complete remission* Younger age No prior preleukemic syndrome
P < .001 P < .001
For disease-free survival (for patients entering remission)t Protocol ALP3 vALP2 Female sex No prior preleukemic syndrome
P= .04 P= .005 P= .05
(0.61) (0.51) (0.54)
For survival from induction chemotherapy (for all patients)t Protocol ALP3 vALP2 Female sex Younger age No prior preleukemic syndrome
P P P P
(0.58) (0.49)
= = = =
.03 .005 .04 .02
(0.48)
*Logistic regression. tProportional hazards regression. For binary factors, the estimated hazard ratio or reduced risk is indicated in parentheses.
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1202
CHAMPLIN ET AL
B
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0
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Fig 1. Results of postremission chemotherapy for the ALP3 (N = 56) or ALP2 (N = 49) studies. The differences are significant for (A) disease-free survival (P = .02) and (B) survival after remission (P = .01).
46 patients receiving the second consolidation chemotherapy course, which was relatively welltolerated with a similar degree of gastrointestinal and hematopoietic toxicity. ALP3 Disease-FreeSurvival and Survival Disease-free survival and survival after remission for patients in the ALP3 study are indicated in Figure 1. Median remission duration is 23 months (95% CI, 13 to 31 months) and actuarial disease-free survival is 32 -+ 12% at 5 years. Disease-free survival for females was 45 + 19% compared with 18 ± 15% for males (P = .03) (Fig 2). There was a trend toward poorer diseasefree survival at 5 years with advancing age, 39 + 18% for age < 45 years, 31 ± 28% for 46 to 60 years, and 20 + 20% for greater than 60 years (P = .14) (Fig 3). Acturial disease-free survival was 33 + 14% for 49 patients with de novo
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leukemia and 28 + 17% for the seven patients with a prior preleukemic syndrome (Fig 4). Thirty-four patients relapsed. Treatment was variable. Twenty-eight received further intensive chemotherapy and 16 (57%) achieved a second remission. Median survival after relapse was 26 months. Six patients are alive in continuous second remission from 2.5 to 5.5 years after relapse, two remain in second remission exceeding 4 years after high-dose cytarabine and daunorubicin reinduction chemotherapy alone, and four survive after allogeneic BMT performed in second remission. One patient, aged 46 years, had an HLA-identical sibling, two had an HLA partially matched parent, and one had an unrelated HLA-matched individual as the donor. Two other patients receiving BMTs after relapse died of complications. Twenty-four patients remain alive. Actuarial survival after achieving remission was 40 + 14% at 5 years for the ALP3 group. Survival was most favorable in younger patients as indicated in Fig 3. Actuarial 5-year survival from remission was 58 ± 19% for patients aged _ 45 years compared with 27 + 28% for age 46 to 60, and 18 + 20% for age greater than 60 years (P < 0.01). Actuarial 5-year survival for all ALP3 patients receiving induction chemotherapy (and not receiving marrow transplants in first remission) was 26 + 13%.
-1-I
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Days Fig 2. Effect of sex on disease-free survival in ALP3 study; N = 28 males and 28 females (P = .03).
Comparisonof ALP3 and ALP2 Postremission Chemotherapy Results of the ALP3 study involving high-dose cytarabine and daunorubicin consolidation are compared in Fig 1 with the ALP2 study that
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1203
POSTREMISSION CHEMOTHERAPY FOR ADULT AML I-
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Effect of patient age on (A) disease-free survival and (B) survival from remission in ALP3 study.
involved azacitidine and doxorubicin as the initial consolidation course. Patients enrolled on the ALP2 study had a median remission duration of 9 months (95% CI, 7 to 15 months), actuarial disease-free survival of 20 ± 11%, and actuarial survival after achieving remission of 24 ± 12% at 5 years. Actuarial disease-free survival was 21 ± 12% for ALP2 patients with de novo leukemia and 0% for patients with a prior preleukemic syndrome. Nine ALP2 patients survive in continuous remission, and one survives in second remission more than 7 years following relapse. Actuarial 5-year survival from induction chemotherapy for all ALP2 patients was 12% + 8%. Unlike the ALP3 results, there was no substantial difference in 5-year disease-free survival or survival related to patient age in the ALP2 study. Actuarial disease-free survival was 19 ± 17% for age less than 45 years, 18 + 23% for age 45 to 60, and 22 ± 11% for age greater than 60 years. Results were significantly improved with the ALP3 regimen compared with the ALP2 study for median remission duration (P < .01), diseasefree survival (P = .02), survival after remission (P = .01), and survival from first chemotherapy (P = .01). Of patients with a prior preleukemic syndrome who achieved remission, all seven patients on the ALP2 study relapsed or died within 1 year, but five of seven ALP3 patients remained in remission beyond 1 year and two continue without relapse over 6 years; the difference in disease-free survival and survival was significant (P < .02). The difference in disease-free survival for de novo leukemia patients on the ALP3 and ALP2 studies was of borderline significance (P = .10).
Considering patients in both the ALP3 and ALP2 studies, several prognostic factors predictive of prolonged remission or survival were identified by multivariate analysis (Table 2). Independent favorable prognostic factors for disease-free survival included the ALP3 treatment regimen (P = .04), absence of a preleukemic syndrome (P = .05), and female sex (P < .01). An additional favorable factor for survival from induction chemotherapy was younger patient age (P = .04). There was no significant difference in survival or disease-free survival in patients requiring one or two courses of induction therapy to achieve remission. Estimated relative risk (hazard ratios) are indicated in Table 2. DISCUSSION These data indicate that intensive consolidation chemotherapy using high-dose cytarabine 1009080o 70W 0
If)
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----------ALP3- Preleukemia
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Days Fig 4. Actuarial disease-free survival for patients with de novo leukemia or prior preleukemic syndromes for the ALP2 and ALP3 study.
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1204
CHAMPLIN ET AL
and daunorubicin has efficacy in postremission chemotherapy for AML. The ALP3 regimen involving an initial consolidation course of highdose cytarabine and daunorubicin, followed by a second course of standard-dose cytarabine and daunorubicin was relatively well tolerated and more effective than a comparably myelosuppressive consolidation regimen, ALP2, involving azacitidine and doxorubicin followed by a similar standard-dose cytarabine and daunorubicin second consolidation course. The duration of the initial complete remission and survival was significantly improved in the ALP3 study. Although the ALP2 regimen was not concurrent with the ALP3 study, patient characteristics, referral patterns, and supportive care were similar. Each study used similar induction chemotherapy and had nearly identical rates of initial complete remission. The induction regimen used cytarabine by IV bolus in ALP2 and by constant IV infusion in ALP3; this difference in schedule could theoretically have contributed to the observed difference in outcome. These data, as well as data from other centers, indicate improved disease-free and overall survival in young adults when treated with intensive consolidation chemotherapy. Five-year diseasefree survival with the ALP3 regimen was 32%. Six of 34 (18%) patients who relapsed have achieved prolonged second remissions either with high-dose cytarabine-based chemotherapy or with BMT. For patients less than 45 years of age, 5-year survival after first remission was 54%, which was comparable or superior to results typically achieved in adults with BMT.21 Up to 30% of young patients with an HLA-identical donor can be salvaged with BMT after relapse.22 Autologous,23 partially matched, and unrelated donor allogeneic transplants 24-26 may also be considered for patients after first relapse or in second remission. These data suggest that initial consolidation chemotherapy may be appropriate treatment in most adults. In both the ALP2 and ALP3 studies, superior disease-free survival occurred in females compared with males. This effect of sex has not been noted in other large trials and requires confirmation. Treatment results were less favorable in elderly patients; actuarial 5-year survival was only 16% for patients greater than 60 years of age.
There was no advantage for the ALP3 compared with the ALP2 regimen in this group. High-dose cytarabine is associated with a greater risk of neurotoxicity in older patients,27 and the results of treatment are not substantially different from less intensive regimens.28' 29 Wolff et al recently reported a somewhat more intensive program involving one or more 6-day courses of high-dose cytarabine, followed by daunorubicin as consolidation chemotherapy; 49% of patients remain in remission after 4 years. 9 In that study, patients were carefully selected so that patients with borderline remissions, early relapse, persistent infections, or toxic complications of induction treatment were excluded. Many patients were entered after achieving remissions elsewhere and some had been in remission for an extended period, biasing this study to select patients with a relatively favorable prognosis. Our study involved consecutively entered patients, in which all individuals were evaluated. A recent randomized study by the Eastern Cooperative Oncology Group reported improved remission duration with a single course of consolidation high-dose cytarabine 3 g/m 2 every 12 hours for 6 days and amsacrine 100 mg/m 2 for 3 days; actuarial event-free survival at 2 years was 32% compared with 21% for patients receiving standard maintenance chemotherapy.' 0 It is possible that our regimen involving 4 days of high-dose cytarabine and daunorubicin may be less toxic and provide comparable results to these more intensive programs. Results achieved in our study were consistent with other recent reports 30involv35 ing intensive consolidation chemotherapy. The optimal form of postremission treatment of acute myelogenous leukemia remains controversial and may vary according to age group and disease characteristics. High-dose cytarabine alone or in combination with an anthracycline, amsacrine, or mitoxantrone has been used in many effective regimens. 1,2 The optimal dose and schedule of cytarabine is unclear, and doses lower than 3 g/m 2 may be equally effective and less toxic. 36 38 Some studies involving highly myelosuppressive regimens without high-dose cytarabine have reported similar results in young patients. 32 34 Overall dose intensity may be important.
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1205
POSTREMISSION CHEMOTHERAPY FOR ADULT AML
In conclusion, for young adults, intensive consolidation chemotherapy involving high-dose cytarabine and daunorubicin improved remission duration and survival compared with a regimen involving azacitidine and doxorubicin, with overall survival comparable to recent studies involv-
ing BMT. Advances in postremission treatment of AML in the elderly remain elusive. The efficacy of intensive chemotherapy such as the ALP3 regimen versus less intensive maintenance chemotherapy has not been established.
REFERENCES 1. Champlin RE, Gale RP: Acute myelogenous leukemia. Blood 69:1551-1562, 1987 2. Mayer RJ: Current chemotherapeutic treatment approaches to the management of previously untreated adults with de novo acute myelogenous leukemia. Semin Oncol 14:384-396, 1987 3. Thomas ED: Bone marrow transplantation for malignant disease. J Clin Oncol 1:517-531, 1983 4. Santos GW: Marrow transplantation in acute nonlymphocytic leukemia. Blood 74:901-908, 1989 5. Rudnick SA, Cadman ED, Capizzi RL, et al: Highdose cytosine arabinoside (HDARAC) in refractory acute leukemia. Cancer 44:1189-1193, 1979 6. Herzig RH, Lazarus HM, Wolff SM, 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 7. Hines JD, Oken MM, Mazza J, et al: High-dose cytosine arabinoside and M-AMSA is effective therapy in relapsed acute nonlymphocytic leukemia. J Clin Oncol 2:545549, 1984 8. Kufe DW, Spriggs DR: Biochemical and cellular pharmacology of cytosine arabinoside. Semin Oncol 12:34-48, 1985 (suppl 3) 9. Wolff SW, Herzig RN, Fay JW, et al: High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission. Long-term followup and results. J Clin Oncol 7:1260-1267, 1989 10. Cassileth PA, McGlave P, Harrington JD, et al: Comparison of post remission therapy in AML; maintenance versus intensive consolidation therapy versus allogeneic bone marrow transplantation. Proc Am Soc Clin Oncol 8:197, 1989 (abstr) 11. Geller RD, Burke PJ, Karp JE, et al: A two step timed sequential chemotherapy for acute myelocytic leukemia. Blood 1499-1506, 1989 12. Champlin R, Jacobs A, Gale RP, et al: Prolonged survival in acute myelogenous leukemia without maintenance chemotherapy. Lancet 1:894-896, 1984 13. Ellison RR, Holland JF, Weil M, et al: Arabinoside cytosine: A useful agent in the treatment of acute leukemia in adults. Blood 32:507-523, 1968 14. Miller AB, Hoogstratten B, Staquet M, et al: Reporting the results of cancer treatment. Cancer 47:207-214, 1981 15. Winston DJ, Ho WG, Young LS, et al: Moxalactam plus piperacillin therapy versus moxalactam plus amikacin therapy in febrile granulocytopenic patients. Am J Med 77:442-449, 1984 16. Winston DJ, Ho WG, Bruckner DA, et al: Controlled trials of double beta-lactam therapy with cefoperazone plus
piperacillin in febrile granulocytopenic patients. Am J Med 85:21-30, 1988 (suppl lA) 17. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 18. Dixon WJ (ed): BMDP Statistical Software Manual. Los Angeles, CA, University of California Press, 1988 19. Bookmeyer R, Crowley J: A confidence interval for the median survival time. Biometrics 38:29-41, 1982 20. Cox DR: Regression models and life tables. J Royal Stat Soc 20:187-220, 1972 (series B) 21. Champlin RE, Gale RP: Bone marrow transplantation for acute leukemia: Recent advances and comparison with alternative therapies. Semin Hematol 24:55-67, 1987 22. Appelbaum FR, Clift RA, Buckner CD, et al: Allogeneic bone marrow transplantation for non-lymphoblastic leukemia after first relapse. Blood 61:949-953, 1983 23. 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 315:141147, 1986 24. Beatty PG, Clift RA, Mickelson EM, et al: Marrow transplantation from related donors other than HLAidentical siblings. N Engl J Med 314:1006-1010, 1986 25. Hows JM, Yin J, March J, et al: Histocompatible unrelated volunteer donors compared with HLA-nonidentical family donors in marrow transplantation for aplastic anemia and leukemia. Blood 68:1322-1328, 1986 26. Gajewski J, Champlin RE: Bone marrow transplantation from closely matched unrelated donors: Evidence for an enhanced graft-versus-leukemia effect. Transplantation 1990 (in press) 27. Herzig RH, Hines JD, Herzig GP, et al: Cerebellar toxicity with high dose cytosine arabinoside. J Clin Oncol 5:927-932, 1987 28. Kahn SB, Bogg CB, Mazza JJ, et al: Full dose versus attenuated dose daunorubicin, cytosine arabinoside and 6thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 2:865-870, 1984 29. Champlin RE, Gajewski JD, Golde DW: Acute myelogenous leukemia in the elderly. Semin Oncol 16:51-56, 1989 30. Tallman MS, Appelbaum FR, Amos D, et al: Evaluation of intensive postremission chemotherapy for adults with acute nonlymphocytic leukemia using high-dose cytarabine with L-asparaginase and amsacrine with etoposide. J Clin Oncol 5:918-926, 1987 31. Willemze R, Jager U, Jehn U, et al: Intermediate and high dose Ara-C and m-AMSA for remission induction and consolidation treatment of patients with acute myeloid leuke-
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mia: In EORTC leukemia cooperative group phase II study. Eur J Cancer Clin Oncol 24:1721-1725, 1988 32. Preisler HD, Raza A, Early A, et al: Intensive remission consolidation therapy in the treatment of acute nonlymphocytic leukemia. J Clin Oncol 5:722-730, 1987 33. Creutzig U, Ritter J, Riehm H, et al: Improved treatment results in childhood acute myelogenous leukemia: A report of the German Cooperative Study AML-BFM78. Blood 65:298-304, 1985 34. Machover D, Rappaport H, Schwarzenberg L, et al: Treatment of acute myeloid leukemia with a combination of intensive induction chemotherapy, early consolidation, splenectomy and long term maintenance chemotherapy. Cancer 53:1644-1650, 1984
35. Tricot G, Boogaerts MA, Vlietnck R, et al: The role of intensive remission induction and consolidation therapy in patients with acute myeloid leukemia. Br J Hematol 66:3744, 1986 36. Duffy TD: How much is too much high-dose cytosine arabinoside. J Clin Oncol 3:601-603, 1985 37. Heinemann V, Estey E, Keating MJ, et al: Patientspecific dose rate for continuous infusion high-dose cytarabine in relapsed acute myelogenous leukemia. J Clin Oncol 7:622-628, 1989 38. van Prooijen HC, Dekker AW, Punt K: The use of intermediate-dose cytosine arabinoside in the treatment of acute non-lymphocytic leukemia in relapse. Br J Hematol 57:291-294, 1984
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W
ITH MODERN induction chemotherapy,
complete remission can be achieved in the majority of patients with acute myelogenous leukemia (AML). However, despite further chemotherapy, most patients relapse and ultimately succumb to the disease. Median duration of remission has typically been approximately 1 year with less than 25% of patients surviving free of recurrence for more than 5 years.' Optimal management of patients achieving a complete remission is controversial. Treatment recommendations range from postremission consolidation and/or maintenance chemotherapy to allogeneic or autologous bone marrow transplantation (BMT).' 4 High-dose cytarabine alone, or in combination with an anthracycline or asparaginase, is an effective treatment of relapsed AML, inducing a second remission in 35% to 65% of cases.5 '7 When compared with standard doses of cytarabine, administration of high-dose cytarabine increases intracellular levels and incorporation of the active metabolite arabinosylcytosine triphosphate (ara-CTP) into the DNA of leukemia cells. 8 Preliminary data suggest an efficacy of high-dose
disease-free survival included receiving the ALP3 treatment regimen, absence of a prior preleukemic syndrome, and female sex. These factors and younger patient age were significant for survival following first chemotherapy and survival after achieving remission. Six of 34 patients who relapsed after receiving the ALP3 regimen successfully achieved prolonged second remissions with high-dose cytarabine-based chemotherapy and/or allogeneic bone marrow transplantation (BMT). Overall survival for adults _-30%. Leukocyte transfusions were not used.
StatisticalAnalysis Patients were analyzed for survival from time of induction therapy and from time of remission as well as disease-free survival (ie, leukemia-free survival) by the product-limit method of Kaplan and Meier." Summary estimates include survival fractions + 2 x SE for 95% confidence intervals (CIs) and approximate CIs for median survival time.' 8' 9 Survival curves were compared using the log-rank test.' Treatment comparisons adjusted for prognostic factors were performed using the Cox proportional hazards model.2 0 Factors prognostic for entering remission were analyzed using logistic regression. Age was tricotomized into three groups: age _ 45 years, 46 to 60 years, and greater than 60 years. Analyses were carried out using the BMDP statistical package.'" P values were two-sided throughout. RESULTS Induction Chemotherapy One hundred eleven consecutive adults with
AML, aged 16 to 84 years (median, 47 years) entered into the ALP3 study. Fifty-six were males and 55 were females. Twenty-one had a
previous myelodysplastic syndrome. Ninety had de novo AML with no known preexisting hemato-
logic disorder. Seventy patients (63%) achieved complete remission; 41 patients failed to achieve remission because of persistent leukemia in 23,
early death in 17, and persistent aplasia in one. Results in this group were compared with 91
consecutive patients treated according to our previous study ALP2" in which a similar proportion of patients, 59 (65%), achieved remission. Thirty-two ALP2 patients were induction failures, 19 with persistant leukemia and 13 with
early death. As indicated in Table 1, patient characteristics for the ALP2 and ALP3 studies
are comparable. Patients with secondary leukemia occurring after treatment for another malignancy or leukemia developing after aplastic anemia were not eligible for either the ALP3 or
ALP2 analysis. Considering patients in both the ALP2 and ALP3 studies, 129 of 202 patients (64%) achieved complete remission. Younger age and absence of an antecedent preleukemic syndrome were the only significant prognostic factors by multivari-
ate analysis for achieving remission (Table 2). Complete remission was achieved in 73 of 96 (76%) patients less than 45 years of age, 24 of 36
(67%) aged 45 to 60, and 32 of 70 (46%) patients greater than 60 years of age. Fourteen of 39
patients (36%) with a previous myelodysplastic
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1201
POSTREMISSION CHEMOTHERAPY FOR ADULT AML Table 1. Patient Characteristics All Patients ALP3 N Sex M/F Preleukemia Chromosome abnormality Y/N/Unk Age yrs, median (range) : 45 46-60 > 60 Achieved remission BMT in first remission BMT after relapse
Eligible for Consolidation* ALP2
ALP3
ALP2
111 56/55 21
91 52/39 18
56 28/28 7
49 29/20 7
27/38/46 47 (16-84) 42/53 (79%)t 13/17 (76%)t 15/41 (37%)t 70 (63%) 14
23/42/26 48 (16-81) 31/43 (72%)t 11/19 (58%)t 17/29 (59%) 59 (65%) 10 -
14/19/23 45 (19-71) 28 13 15
10/24/15 49 (17-75) 21 11 17
6-
2
Abbreviation: Y/N/Unk, yes/no/unknown. *Includes all patients achieving remission who did not receive allogeneic BMT in first complete remission.
"tNumberof patients achieving complete remission/total patients (%). syndrome achieved remission compared with 115 of 161 (71%) with de novo AML (P s .01). Twenty-four patients less than 45 years of age had an HLA-identical sibling and received allogeneic BMT while in first complete remission; these patients are not considered further in this report. ALP3 Consolidation Fifty-six patients on the ALP3 study were eligible to receive consolidation chemotherapy treatment; all are considered assessable including two patients who relapsed and died before receiving the first consolidation chemotherapy course. Patient characteristics are summarized in Table 1. Thirty of these patients required one course of induction chemotherapy to achieve remission and 26 required two courses. Fifty-three patients received the first course of consolidation. Two other patients relapsed before receiving consolidation chemotherapy, one left the area while in remission and was lost to follow-up. Forty-six patients received both consolidation courses; the second course was not given because of death or relapse in four patients, cerebellar toxicity in two, and persistent hepatitis in one. Median follow-up of survivors following remission is 4.6 years, with a range of 2.1 to 6.3 years. The first consolidation course consisting of high-dose cytarabine and daunorubicin was relatively well tolerated. Major toxicities included mild to moderate nausea and vomiting in all
patients. Mild conjunctivitis typically occurred despite use of prophylactic topical corticosteroids. Profound myelosuppression occurred with granulocytes recovering to 0.5 x 109/L after a median of 24 (range, 16 to 47) days and platelets recovering to greater than 20 x 109/L after 23 (range, 14 to 37) days. Two patients, aged 63 and 67 years, developed irreversible grade 3 neurotoxicity with cerebellar ataxia and speech disturbance and one, aged 26, had grade 2 neurotoxicity. Three of the 53 patients (6%) receiving the first consolidation course died from treatment complications, two from infection and one from multisystem failure. No deaths occurred in the Table 2. Favorable Prognostic Factors for Combined ALP3 and ALP2 Studies For achieving complete remission* Younger age No prior preleukemic syndrome
P < .001 P < .001
For disease-free survival (for patients entering remission)t Protocol ALP3 vALP2 Female sex No prior preleukemic syndrome
P= .04 P= .005 P= .05
(0.61) (0.51) (0.54)
For survival from induction chemotherapy (for all patients)t Protocol ALP3 vALP2 Female sex Younger age No prior preleukemic syndrome
P P P P
(0.58) (0.49)
= = = =
.03 .005 .04 .02
(0.48)
*Logistic regression. tProportional hazards regression. For binary factors, the estimated hazard ratio or reduced risk is indicated in parentheses.
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1202
CHAMPLIN ET AL
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Fig 1. Results of postremission chemotherapy for the ALP3 (N = 56) or ALP2 (N = 49) studies. The differences are significant for (A) disease-free survival (P = .02) and (B) survival after remission (P = .01).
46 patients receiving the second consolidation chemotherapy course, which was relatively welltolerated with a similar degree of gastrointestinal and hematopoietic toxicity. ALP3 Disease-FreeSurvival and Survival Disease-free survival and survival after remission for patients in the ALP3 study are indicated in Figure 1. Median remission duration is 23 months (95% CI, 13 to 31 months) and actuarial disease-free survival is 32 -+ 12% at 5 years. Disease-free survival for females was 45 + 19% compared with 18 ± 15% for males (P = .03) (Fig 2). There was a trend toward poorer diseasefree survival at 5 years with advancing age, 39 + 18% for age < 45 years, 31 ± 28% for 46 to 60 years, and 20 + 20% for greater than 60 years (P = .14) (Fig 3). Acturial disease-free survival was 33 + 14% for 49 patients with de novo
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leukemia and 28 + 17% for the seven patients with a prior preleukemic syndrome (Fig 4). Thirty-four patients relapsed. Treatment was variable. Twenty-eight received further intensive chemotherapy and 16 (57%) achieved a second remission. Median survival after relapse was 26 months. Six patients are alive in continuous second remission from 2.5 to 5.5 years after relapse, two remain in second remission exceeding 4 years after high-dose cytarabine and daunorubicin reinduction chemotherapy alone, and four survive after allogeneic BMT performed in second remission. One patient, aged 46 years, had an HLA-identical sibling, two had an HLA partially matched parent, and one had an unrelated HLA-matched individual as the donor. Two other patients receiving BMTs after relapse died of complications. Twenty-four patients remain alive. Actuarial survival after achieving remission was 40 + 14% at 5 years for the ALP3 group. Survival was most favorable in younger patients as indicated in Fig 3. Actuarial 5-year survival from remission was 58 ± 19% for patients aged _ 45 years compared with 27 + 28% for age 46 to 60, and 18 + 20% for age greater than 60 years (P < 0.01). Actuarial 5-year survival for all ALP3 patients receiving induction chemotherapy (and not receiving marrow transplants in first remission) was 26 + 13%.
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Days Fig 2. Effect of sex on disease-free survival in ALP3 study; N = 28 males and 28 females (P = .03).
Comparisonof ALP3 and ALP2 Postremission Chemotherapy Results of the ALP3 study involving high-dose cytarabine and daunorubicin consolidation are compared in Fig 1 with the ALP2 study that
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1203
POSTREMISSION CHEMOTHERAPY FOR ADULT AML I-
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Effect of patient age on (A) disease-free survival and (B) survival from remission in ALP3 study.
involved azacitidine and doxorubicin as the initial consolidation course. Patients enrolled on the ALP2 study had a median remission duration of 9 months (95% CI, 7 to 15 months), actuarial disease-free survival of 20 ± 11%, and actuarial survival after achieving remission of 24 ± 12% at 5 years. Actuarial disease-free survival was 21 ± 12% for ALP2 patients with de novo leukemia and 0% for patients with a prior preleukemic syndrome. Nine ALP2 patients survive in continuous remission, and one survives in second remission more than 7 years following relapse. Actuarial 5-year survival from induction chemotherapy for all ALP2 patients was 12% + 8%. Unlike the ALP3 results, there was no substantial difference in 5-year disease-free survival or survival related to patient age in the ALP2 study. Actuarial disease-free survival was 19 ± 17% for age less than 45 years, 18 + 23% for age 45 to 60, and 22 ± 11% for age greater than 60 years. Results were significantly improved with the ALP3 regimen compared with the ALP2 study for median remission duration (P < .01), diseasefree survival (P = .02), survival after remission (P = .01), and survival from first chemotherapy (P = .01). Of patients with a prior preleukemic syndrome who achieved remission, all seven patients on the ALP2 study relapsed or died within 1 year, but five of seven ALP3 patients remained in remission beyond 1 year and two continue without relapse over 6 years; the difference in disease-free survival and survival was significant (P < .02). The difference in disease-free survival for de novo leukemia patients on the ALP3 and ALP2 studies was of borderline significance (P = .10).
Considering patients in both the ALP3 and ALP2 studies, several prognostic factors predictive of prolonged remission or survival were identified by multivariate analysis (Table 2). Independent favorable prognostic factors for disease-free survival included the ALP3 treatment regimen (P = .04), absence of a preleukemic syndrome (P = .05), and female sex (P < .01). An additional favorable factor for survival from induction chemotherapy was younger patient age (P = .04). There was no significant difference in survival or disease-free survival in patients requiring one or two courses of induction therapy to achieve remission. Estimated relative risk (hazard ratios) are indicated in Table 2. DISCUSSION These data indicate that intensive consolidation chemotherapy using high-dose cytarabine 1009080o 70W 0
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Days Fig 4. Actuarial disease-free survival for patients with de novo leukemia or prior preleukemic syndromes for the ALP2 and ALP3 study.
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1204
CHAMPLIN ET AL
and daunorubicin has efficacy in postremission chemotherapy for AML. The ALP3 regimen involving an initial consolidation course of highdose cytarabine and daunorubicin, followed by a second course of standard-dose cytarabine and daunorubicin was relatively well tolerated and more effective than a comparably myelosuppressive consolidation regimen, ALP2, involving azacitidine and doxorubicin followed by a similar standard-dose cytarabine and daunorubicin second consolidation course. The duration of the initial complete remission and survival was significantly improved in the ALP3 study. Although the ALP2 regimen was not concurrent with the ALP3 study, patient characteristics, referral patterns, and supportive care were similar. Each study used similar induction chemotherapy and had nearly identical rates of initial complete remission. The induction regimen used cytarabine by IV bolus in ALP2 and by constant IV infusion in ALP3; this difference in schedule could theoretically have contributed to the observed difference in outcome. These data, as well as data from other centers, indicate improved disease-free and overall survival in young adults when treated with intensive consolidation chemotherapy. Five-year diseasefree survival with the ALP3 regimen was 32%. Six of 34 (18%) patients who relapsed have achieved prolonged second remissions either with high-dose cytarabine-based chemotherapy or with BMT. For patients less than 45 years of age, 5-year survival after first remission was 54%, which was comparable or superior to results typically achieved in adults with BMT.21 Up to 30% of young patients with an HLA-identical donor can be salvaged with BMT after relapse.22 Autologous,23 partially matched, and unrelated donor allogeneic transplants 24-26 may also be considered for patients after first relapse or in second remission. These data suggest that initial consolidation chemotherapy may be appropriate treatment in most adults. In both the ALP2 and ALP3 studies, superior disease-free survival occurred in females compared with males. This effect of sex has not been noted in other large trials and requires confirmation. Treatment results were less favorable in elderly patients; actuarial 5-year survival was only 16% for patients greater than 60 years of age.
There was no advantage for the ALP3 compared with the ALP2 regimen in this group. High-dose cytarabine is associated with a greater risk of neurotoxicity in older patients,27 and the results of treatment are not substantially different from less intensive regimens.28' 29 Wolff et al recently reported a somewhat more intensive program involving one or more 6-day courses of high-dose cytarabine, followed by daunorubicin as consolidation chemotherapy; 49% of patients remain in remission after 4 years. 9 In that study, patients were carefully selected so that patients with borderline remissions, early relapse, persistent infections, or toxic complications of induction treatment were excluded. Many patients were entered after achieving remissions elsewhere and some had been in remission for an extended period, biasing this study to select patients with a relatively favorable prognosis. Our study involved consecutively entered patients, in which all individuals were evaluated. A recent randomized study by the Eastern Cooperative Oncology Group reported improved remission duration with a single course of consolidation high-dose cytarabine 3 g/m 2 every 12 hours for 6 days and amsacrine 100 mg/m 2 for 3 days; actuarial event-free survival at 2 years was 32% compared with 21% for patients receiving standard maintenance chemotherapy.' 0 It is possible that our regimen involving 4 days of high-dose cytarabine and daunorubicin may be less toxic and provide comparable results to these more intensive programs. Results achieved in our study were consistent with other recent reports 30involv35 ing intensive consolidation chemotherapy. The optimal form of postremission treatment of acute myelogenous leukemia remains controversial and may vary according to age group and disease characteristics. High-dose cytarabine alone or in combination with an anthracycline, amsacrine, or mitoxantrone has been used in many effective regimens. 1,2 The optimal dose and schedule of cytarabine is unclear, and doses lower than 3 g/m 2 may be equally effective and less toxic. 36 38 Some studies involving highly myelosuppressive regimens without high-dose cytarabine have reported similar results in young patients. 32 34 Overall dose intensity may be important.
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POSTREMISSION CHEMOTHERAPY FOR ADULT AML
In conclusion, for young adults, intensive consolidation chemotherapy involving high-dose cytarabine and daunorubicin improved remission duration and survival compared with a regimen involving azacitidine and doxorubicin, with overall survival comparable to recent studies involv-
ing BMT. Advances in postremission treatment of AML in the elderly remain elusive. The efficacy of intensive chemotherapy such as the ALP3 regimen versus less intensive maintenance chemotherapy has not been established.
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mia: In EORTC leukemia cooperative group phase II study. Eur J Cancer Clin Oncol 24:1721-1725, 1988 32. Preisler HD, Raza A, Early A, et al: Intensive remission consolidation therapy in the treatment of acute nonlymphocytic leukemia. J Clin Oncol 5:722-730, 1987 33. Creutzig U, Ritter J, Riehm H, et al: Improved treatment results in childhood acute myelogenous leukemia: A report of the German Cooperative Study AML-BFM78. Blood 65:298-304, 1985 34. Machover D, Rappaport H, Schwarzenberg L, et al: Treatment of acute myeloid leukemia with a combination of intensive induction chemotherapy, early consolidation, splenectomy and long term maintenance chemotherapy. Cancer 53:1644-1650, 1984
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