Haematology and Blood Transfusion

Vol. 33

Acute Leukemias II

Edited by Buchner, Schellong, Hiddemann, Ritter

© Springer-Verlag Berlin Heidelberg 1990

Intensive Sequential Chemotherapy for Children with Acute Myelogenous Leukemia H.E. Grier, R.D. Gelber, L.A. Clavell, B.M. Camitta, M.P. Link, M.J. Delorey Garcea, and H. J. Weinstein

Acute myelogenous leukemia (AML) is a heterogeneous group of leukemias derived from cells of the myeloid lineage. Progress in therapy has increased the complete remission rate and the percentage of children achieving prolonged disease-free survival (>5 years). From 1976 to 1988 we have treated 228 consecutive patients with AML at our institutions on three consecutive protocols: VAPA, 80-035, and Hi-C DAZE. All three protocols featured intensive consolidation chemotherapy. Results of the first two protocols have been published previously [1, 2], and will be updated here. In addition a preliminary analysis of the third study, Hi-C DAZE, will be presented. Material and Methods

Patients

Sixty-one consecutive untreated children < 18 years of age with AML were treated on the VAPA protocol from 1976 to 1980. From 1980 to 1984, 64 patients were treated on the 80-035 protocol. The third protocol, Hi-C

Division of Pediatric Oncology and Biostatistics, Dana-Farber Cancer Institute; Division of Hematology/Oncology, The Children's Hospital, Boston; University of Puerto Rico, San Juan; Midwest Children's Cancer Center, Division of Hematology/Oncology, Children's Hospital of Wisconsin, Milwaukee; Division of Hematology/Oncology, Children's Hospital at Stanford.

DAZE, enrolled 103 patients from 1984 to 1988. Hi-C DAZE was modified after entry of 33 patients (group 1) because of CNS toxicity, and the subsequent 70 patients were designated as group 2. The diagnosis of AML was based on morphological examination of bone marrow and histochemical stains. Morphological subtypes of AML were determined according to the FrenchAmerican-British (FAB) method of classification [3]. Treatment

The details of the VAPA and 80-035 protocols have been published [1, 2]. Table 1 summarizes the induction regimens for VAPA, 80-035, as well as both groups of Hi-C DAZE. For all the protocols, patients not entering remission after two induction regimens were considered induction failures and taken off study. In the VAPA study, remission was induced with two courses of vincristine, Adriamycin, prednisolone, and standard-dose cytosine arabinoside (Ara-c) (Table 1). Patients entering remission were treated with 14 months of intensive sequential chemotherapy (Table 2). 80-035 differed from VAPA in that: a) daunorubicin was substituted for doxorubicin in an attempt to reduce the incidence of enterocolitis, b) the Ara-c dose during induction was doubled, and c) intrathecal Ara-c was added during induction and maintenance to decrease primary CNS relapse. 193

Table 1. Induction therapy Protocol

Drug

Dose

Route

Course 1

Course 2

VAPA

Vcr Adr Pred Ara-c

1.5 mg/m 2 30 mg/m 2 40 mg/m 2 100 mg/m 2

i.v.

dl,5 dl,2,3 dl-5 dl-7

dl dl,2 dl-5 dl-5

Dauno Ara-c IT Ara-c

45 mg/m 2 200 mg/m 2

1. v.

i.v. i. t.

dl,2,3 dl-7 dl

dl dl-5 dl

Dauno HD Ara-c

30 mg/m 2 3 g/m 2

i.v. i. v. q12 h

dl,2,3 dl-4

dl,2 dl-4

Dauno HD Ara-c VP-16 5-aza

30 mg/m 2 3 g/m 2 200 mg/m 2 150 mg/m 2

1. v.

dl,2,3 dl-4 None None

None None dl-3,6-8 d3-5,8-10

80-035

Hi-C DAZE (gpl) Hi-C DAZE (gp 2)

LV.

i.v. q12 h i.v. c. i.

i. v. q12 h i.v. i.v. c.i.

Drugs: Vcr, vincristine; Adr, doxorubicin; Pred, prednisolone; Ara-c, cytosine arabinoside; HD Ara-c, high-dose cytosine arabinoside; VP-16, etoposide; 5-aza, 5-azacytidine; d, day; c. i., continuous infusion

Table 2. Consolidation therapy VAPA

80-035

Sequence I (courses 1-4) Adr 45 i. V., dl Ara-c 200 c. i., dl-5

Sequence I (courses 1-4) Dauno 45 i. V., dl Ara-c 200 c. i., dl- 5 6 TG 200 p.o., dl-5

Sequence II (courses 5-8) Adr 30 i. V., dl 5-aza 150 c. i., dl- 5

Sequence II (courses 5 - 7) Dauno 30 i. V., dl 5-aza 150 c. i., dl-5

Sequence III (courses 9-12) Vcr 1.5 i. V., dl Pred 800 i. V., dl-5 6-MP 500 i. V., dl-5 MTX 7.5 i. V., dl-5

Sequence III (courses 8-11) Ara-c 200 c. i., dl- 5 6-TG 200 p.o., dl-5

Hi-C DAZE group 1 (alternating for six cycles)

Hi-C DAZE group 2 (alternating for six cycles)

VP-16 200 i.v., dl-3 5-aza 150 c.l., d3-5,

Dauno 30 i.v., dl,2 HD Ara-c3 g i.v., q12 h dl-3

Dauno 30 i. V., dl, 2 HD Ara-c 3 g i. V., q12h dl-3

VP-16 200 i.v., dl-3 5-aza 150 c. i., d3 - 5

Sequence IV (courses 13 -16) Ara-c 200 c. i., dl-5 CNS treatment: none

CNS treatment: CNS treatment: intermittent i. t., Ara-c intermittent i. t., Ara-c

CNX treatment: intermittent i. t., Ara-c

Drugs: Adr, Adriamycin; Ara-c, cytosine arabinoside; 5-aza, azacytidine; Vcr, vincristine; Pred, methylprednisolone; 6-mp, mercaptopurine; MTX, methotrexate; Dauno, daunorubicin; 6-TG, thioguanine; VP-16, etoposide; HD, high dose; c. i., continuous infusion; d, day; i. t., intrathecal; p.o., oral; i. V., intravenous; g, grams

194

Hi-C DAZE utilized high-dose Ara-c during induction and consolidation and paired VP16 with azacytidine. At the time we designed this protocol, high-dose Ara-c was shown to be active in patients with AML whose leukemia was refractory to standard doses, and schedules of Ara-c [4, 5] and VP-16 was most effective in patients with the M4 and M5 subtypes of AML [6-8]. The Hi-C DAZE induction regimens are outlined in Table 2. The two courses of high-dose Ara-c during induction resulted in a high incidence of cerebellar toxicity. The protocol was therefore modified to include VP-16 and 5azacytidine for the second induction course (group 2). Consolidation therapy differed conceptually from the previous protocols in that pairs of drugs were given on an alternating basis rather than in sequential blocks. Statistical Analysis

Disease-free survival (Kaplan-Meier method) was measured from the time of complete

P R 0 B A B I L I T

Y

remission [9]. Leukemic relapses and deaths in remission were both counted as failures in this analysis. Patients removed from study for bone marrow transplantation in first remission are censored at the time of transplantation. Withdrawals for other reasons were handled similarly. Statistical tests of significance were made with the log rank test [10] or the Cox model [11] when appropriate. All probability measurements were two sided. Results

VAPA and 80-035

The results for VAPA and 80-035 are shown in Table 3. The complete remission rate was 74% on VAPA and 70% on 80-035. There were no remission deaths on VAPA, but 20% of the failures on 80-035 were due to death during remission. There were fewer primary CNS relapses on 80-035 (where intrathecal drug was used) compared with VAPA, but this did not achieve statistical signif-

0.8 0.7 0.6 0.5 0.4

, '------II---. L

__

L _

- - I-

~I-

-IH

+A

Ll _ _ _+!1 ·_H F - _ n - , -.. --+ IH -IH

0.3 0.2 0.1 0.0 0

2

TRBATMENT VAPA

80-035

4

YEARS CCR

23 19

6 FAIL

22 26

8 TOTAL

45 45

10 MEDIAN

3.6 2.8

Fig. 1. Kaplan-Meier estimate for probability of disease-free survival for patients entering complete remission on VAPA (solid line) or 80-035 (dashed line). Tick marks indicate patients continuing in remission

195

Discussion

Table 3. VAPA and 80-035 results

No. No. No. No.

patients complete remission rem. deaths relapses (CNS)

VAPA

80-035

61

45 (74%)

64 45 (70%)

22 (8)

20 (3)

o

5

icance. Figure 1 shows the disease-free survival curves for VAPA and 80-035. As illustrated, both VAPA and 80-035 resulted in a 45% probability of continuous complete remission at 5 years. There were no clinical or laboratory findings that had a statistically significant effect upon the remission induction rate in VAPA and 80-035. However, by univariate analysis, the following were adverse factors for duration of remission: white blood cell count greater than 100000/mm 3 , age less than 2 years, and FAB subtypes M4 (myelomonocytic) and M5 (monocytic). By multivariate analysis white blood cell count and FAB type appeared to have independent prognostic importance. Hi-C DAZE

The remission induction results for both groups of Hi-C DAZE are shown in Table 4. The complete remission rate for group 1 was 85% and 78% for group 2. One patient was withdrawn after the first induction course because of patient preference. The original induction regimen (group 1) was modified because of CNS toxicity. Five patients developed severe cerebellar signs at the end of the second induction course. Because of the toxicity, these five patients received no Ara-c during consolidation. Table 4. Hi-C daze induction results Group 1 Group 2 Overall Total patients Induction withdrawals Entered CR (%) CNS toxicity

196

33 0 28 (85%) 5

70 1 54 (78%) 0

103 1 82 (80%) 5

The VAPA, 80-035, and Hi-C DAZE protocols were designed to improve long-term disease-free survival for children with AML. Disease-free survival on VAPA and 80-035 was 45% at 5 years. The median follow-up for both studies is greater than 5 years and relapse after 3 years in continuous complete remission has been unusual. Growth and development appeared normal in the longterm survivors. The modifications of therapy in 80-035 (intrathecal Ara-c, daunorubicin for Adriamycin and addition of thioguanine) did not result in an improvement in overall disease-free survival compared with VAPA. The results of VAPA and 80-035 were comparable or better than most other chemotherapy trials in childhood AML [12-15]. High white count and M4 and M5 FAB subtypes predicted for short duration of remission on both VAPA and 80-035. The biological basis for poorer outcome in patients with monocytic subtypes was unclear. Other investigators have not uniformly corroborated this finding [12, 13]. Monocytic leukemia tends to present and relapse in extramedullary sites [2, 16]. Perhaps better therapy to these areas could improve survival in this subgroup. However, the decreased primary eNS relapse rate on 80-035 did not improve outcome for the patients with M4 and M5 leukemic subtypes. Hi-C DAZE was designed to incorporate a new chemotherapeutic agent (VP-16) and to use Ara-c in a new and potentially more powerful way [4-8]. In addition to excellent activity against relapsed medullary disease, high-dose Ara-c has excellent CSF penetration, and might decrease leukemia in this sanctuary spot [17]. The CNS toxicity of high-dose Ara-c forced us to modify the regimen and use VP-16 and azacytidine as the second induction drugs. Remission duration results are still too early to report. By increasing the Ara-c dose we, of necessity, shortened the duration of therapy. The efficacy of Ara-c is clearly dose and time dependent [4, 18]. Hopefully, the possible gain in efficacy by the logarithmic increase in dose will be greater than any possible decreased efficacy of shortened duration. Further progress awaits other careful analysis of factors that affect duration of remission

and better application of chemotherapeutic modalities. References 1. Weinstein HJ, Mayer RJ, Rosenthal DS, et al. (1983) Chemotherapy for acute myelogenous leukemia in children and adults: VAPA update. Blood 62: 315 2. Grier HE, Gelber RD, Camitta BM, et al. (1987) Prognostic factors in childhood acute myelogenous leukemia. J Clin Oncol 5: 1026 3. Bennett JM, Catovsky D, Daniel MT, et al. (1985) Proposed revised criteria for the classification of acute myeloid leukemia. Ann Intern Med 103: 626 4. Herzig RH, Wolff SN, Lazarus HM, et al. (1983) High-dose cytosine arabinoside therapy for refractory leukemia. Blood 62: 361 5. Wells RJ, Feusner J, Devney R, et al. (1985) Sequential high-dose cytosine arabinoside-asparaginase treatment in advanced childhood leukemia. J Clin Oncol 3:998 6. Methe F, Schwarzenberg L, Pouillart P, et al. (1974) Two epipodophyllotoxin derivatives VM-26 and VP16-213 in the treatment of leukemias, hematosarcomas, and lymphomas. Cancer 34: 985 7. Chard RL, Kruit W, Bleyer WA, Hammond D (1979) Phase II study of VP-16-213 in childhood malignant disease. A CCSG report. Cancer Treat Rep 63: 1755 8. Look AT, Dahl GV, Kalwinsky D, et al. (1981) Effective remission induction of refractory childhood acute non lymphocytic leukemia by VP-16-213 plus azacitidine. Cancer Treat Rep 65:995 9. Kaplan KL, Meier P (1970) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457

10. Kalbfleisch JD, Prentice RL (1980) The statistical analysis of failure time data. Wiley, New York, pp 14-15 11. Cox DR (1972) Regression models and life tables (with discussions). J R Stat Soc 34: 187 12. Creutzig U, Ritter J, Riehm H, et al. (1985) Improved results in childhood acute myelogenous leukemia: a report of the German cooperative study AML BFM 78. Blood 65:298 13. Dahl GV, Kalwinsky DK, Murphy S, et al. (1982) Cytokinetically based induction chemotherapy and splenectomy for childhood acute nonlymphocytic leukemia. Blood 60: 856 14. Baehner RL, Kennedy A, Sather H, et al. (1981) Characteristics of children with acute non-lymphocytic leukemia in long-term continuous remission: a report for Children's Cancer Study Group. Med Pediatr Oncol 9:393 15. Kalwinsky D, Mirro J Jr, Schell M, Behm F, Mason C, Dahl GV (1989) Early intensification of chemotherapy for childhood acute nonlymphoblastic leukemia: improved remission induction with a five drug regimen including etoposide. J Clin Oncol 6: 1134 16. Pui C-H, Dahl GV, Kalwinsky DK, et al. (1985) Central nervous system leukemia in children with acute nonlymphoblastic leukemia. Blood 66: 1062 17. Slevin ML, Pial EM, Aherne GW, et al. (1983) Effect of dose and schedule on pharmacokinetics in high dose cytosine arabinoside in plasma and cerebrospinal fluid. J Clin Oneol 1: 546 18. Burke PJ, Serpick AA, Carbone PP, Tarr N (1968) A clinical evaluation of dose and schedule of administration of cytosine arabinoside (NSC 63878). Cancer Res 28: 274

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