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Current Issues in Adult AML

High-Dose Chemotherapy in the Treatment of AML

Berman spacer
Ellin Berman, MD
Associate Professor,
Memorial Sloan Kettering,
Cancer Center

In induction or consolidation treatment for acute myelogenous leukemia (AML), the impression gathered from many clinical trials is that higher doses of either the anthracycline daunorubicin (DNR) or of cytosine arabinoside (Ara-C) result in improved remission and survival rates. However, a close look at the data reveals that only a few studies have prospectively compared different doses of each agent.1-4 Even in the study that compared the two most dramatically different doses of Ara-C for induction chemotherapy-1,400 mg/m" v 24,000 mg/m"-no difference in overall rates was demonstrated.4

Response rates for induction using various doses of Ara-C
First author Median age Total Ara-C dose
(mg/m")
DNR dose
(mg/m")
No. of CR
(mg/m")
Comments
Preisler1 NS 700 over 7d v
1,000 over 10d
45 d 1,2,3
same
111/211 (53%)
123/216 (57%)
No significant difference in response rates
Dillman2 NS 700 over 7d v
1,400 over 7d
45 d 1,2,3
same
92/160 (58%)
106/166 (64%)
No significant difference in response rates
Schiller3 471,400 over 7d v 60 d 1,2,3
same
36/51 (71%) No difference in disease-free survival

48 6,000 over 6d same 37/50 (74%) Higher CR rates in patients <60 yrs (82% in each arm)
Weick4 >49*1,400 over 7d v
24,000 over 6d
45 d 1,2,3
same
(55%)
(59%)
In HD v standard group: 17% v 7% toxic death rate; neurologic toxicity
HD=high dose
*Maximum age; median not given.

The dose of Ara-C used during consolidation has been extensively explored mostly in single-arm trials. An important study from the CALGB was recently published by Mayer et al.5 This large, randomized study of 596 patients with AML in first remission is really the first to suggest a dose-response relationship with Ara-C.

Response rates for consolidation using various doses of Ara-C.5,6

Continuous remission duration
in months by cytogenetic risk group
Ara-C dose
(mg/m")
Disease-free
survival (%)
Overall
Survival (%)
Favorable* Intermediate** Unfavorable
100 by CI 21% x 5d 21% 31% 15 mo 13 mo 10 mo
400 by CI 25% x 5d 25% 35% NR 22 mo 10 mo
3,000 q 12h d 1,3,5 39% 46% NR NR 14 mo
*Favorable risk: t(8;21) (q22;q22); inv(16)(p13; q22).
**Intermediate risk: t(15;17)(q22;q12) or normal karyotype.
***Unfavorable risk: all other abnormal karyotypes.

Patients who received the 3,000 mg/m" dose appeared to have an improved disease-free and overall survival, especially if they were less than 60 years of age. An important finding of this study is that high-dose Ara-C was effective only in patients who had "favorable" or "intermediate" or normal karyotypes at presentation.

Conclusions

  • Studies to date have not conclusively demonstrated an advantage to doses of DNR higher than 45 mg/m".
  • One large study has demonstrated an advantage to high-dose Ara-C during consolidation therapy, but only for patients less than 60 years of age in "favorable" or "intermediate" risk cytogenetic subgroups.
  • Dose intense therapy appears to be a limited tool in induction or consolidation treatment of AML, and other means of manipulating the disease should be examined.

References

  1. Preisler H, Davis RB, Kirshner J, et al. Comparison of three remission induction regimens and two post induction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia Group B study. Blood. 1987;69:1441-1449.
  2. Dillman RO, Davis RB, Green MR, et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood. 1991;78:2520-2526
  3. Schiller G, Gajewski J, Nimer S, et al. A randomized study of intermediate versus conventional-dose cytarabine as intensive induction for acute myelogenous leukaemia. Br J Haematol. 1992;81:170-177.
  4. Weick J, Kopecky K, Appelbaum F, et al. A randomized investigation of high-dose (HDAC) versus standard dose (SDAC) cytosine arabinoside with daunorubicin (DNR) in patients with acute myelogenous leukemia. Proc Am Soc Clin Oncol. 1992;11:261. Abstract 856.
  5. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994;331:896- 903.
  6. Bloomfield CD, Lawrence D, Arthur DC, Berg DT, Schiffer CA, Mayer RJ. Curative impact of intensification with high-dose cytarabine (HiDAC) in acute myeloid leukemia (AML) varies by cytogenetic group. Blood. 1994;84:111a. Abstract 431.


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