Acute myeloid leukemia in patients more than 50 years of age: Special considerations in diagnosis, treatment, and prognosis

Acute Myeloid Leukemia in Patients More Than 50 Years of Age: Special Considerations in Diagnosis, Treatment; and Prognosis MICHAEL

AUERBACH,

M.D.,

Ra/timore,

Mary/and

Although most patients with acute myeloid leukemia are more than 50 years of age and age is known to be an adverse prognostic factor, relatively few studies have been conducted to determine the optimum treatment strategy for the older patient. This report suggests that, until definitive studies are conducted in this age group, intensive chemotherapy should always be considered if the older patient’s overall status and desires are consistent with this approach. Other factors, specifically cytogenetic and cell-surface marker findings, provide prognostic information, independent of age, and should also be considered during patient management.

A

cute myeloid leukemia @ML) can be characterized as a disease of older persons. Approximately 7,000 people in the United States are diagnosed with AML each year [l]. The incidence of the disease rises from 1.3 per 100,000 in persons under age 65 years, to 11.7 per 100,000 in those 65 years of age and older. The median patient age is 66 years [ll. The development of AML (also called acute nonlymphocytic leukemia, or ANLL) may be associated with prior exposure to radiation or benzene, or it may be secondary to chemotherapy for other cancers. However, the overwhelming majority of cases occur in the absence of apparent risk factors. Procarbazine and the alkylating agents, including the nitrosoureas, are probably the best-known leukemogens [2,31. The various myelodysplastic syndromes (also called oligoblastic leukemia, preleukemia, or “smoldering” leukemia) transform into AML in 10% to 75% of patients affected, depending on the syndrome present 141.

AGE AS A RISK FACTOR

From the Department of Hematology and Oncology, Franklin Square Hospital Center, Baltimore, Maryland. Requests for reprints should be addressed to Michael Auerbach, M.D., Department of Hematology and Oncology, Franklin Square Hospital Center, 9000 Franklin Square Drive, Baltimore, Maryland 21237. Manuscript submitted March 9, 1993, and accepted in revised form April 8, 1993.

180

February

1994

The American

Journal

of Medicine

Volume

Most patients with AML are more than 50 years of age, and age has been identified as one of the disease’s most potent adverse prognostic factors, as well as an essential management consideration [5,61. Although the prognosis for younger patients has improved in recent years, due to more intensive remission induction and consolidation therapies, the outlook for elderly patients has remained poor, with complete remission being notably more difficult to achieve in this population 171. Although cure is the goal of therapy, most patients of all ages ultimately die of their disease. In general, older patients die of persistent leukemia and aplasia,> whereas younger patients die of persistent leukemia. Several explanations are advanced to explain the disparity in complete remission based on age. These include the increased incidence of resistant leukemia in older persons, possibly because of the transformation of myelodysplastic syndromes into AML. This condition is more common in older people, with an overall incidence of 10% to 30%.

96

ACUTE

Older patients are also more likely to have secondary AML, which is resistant to treatment [21. Moreover, older patients are more susceptible to treatment-induced neutropenia and die more frequently of infection [7,8]. In addition, cardiotoxicity from chemotherapy is more common in patients older than 55 to 60 years [9]. However, most importantly, chromosomal abnormalities, which are associated with low-remission rates and short durations of remission, are disparately high in older patients. For example, older patients show many more abnormalities of chrbmosomes 5, 7, or 8 than do younger patients. Favorable markers, such as the translocation of chromosome 8 to 21, are much less common in older patients. Effective treatment of the older patient is also associated with a greater destruction of normal hematopoiesis. Among patients more than 50 years of age, there is variation in the suitability of the patient for intensive therapy. In general, frailty increases with age, but the relationship is complex: at our institution, we find some patients more than 60 years of age who are more robust than those aged 50 to 60 years, and some patients of advanced age (more than 70 years) who can tolerate intensive chemotherapy reasonably well. Noteworthy also is the conclusion of most recent studies that elderly patients should be treated aggressively [6,101. Overall patient status seems more predictive of survival than age alone [ill. This conclusion is borne out at our institution., in which patients more than 50 years of age are treated as aggressively as possible in accordance with the patient’s status and desires. Nonetheless, this approach remains controversial, largely because more elderly patients still fail to achieve complete remission and a good quality of life than younger patients [6,12]. Yet conservative therapy, usually meaning low doses of cytotoxic agents, yields a lower complete response rate as well as lower levels of toxicity in this age group, as would be expected [8]. This approach clearly leads to incomplete responses, and, therefore, such conservative treatment should be avoided.

PATIENT

EVALUATION

Clinical Presentation The classic signs and symptoms of AML are those associated with the failure of normal hematopoiesis, including bleeding (evidenced by petechiae and easy bruisability), pallor, and fever. The patient may also complain of bone and joint pain or experience headaches, vomiting, and irritation related to central nervous system involvement. In February

MYELOID

LEUKEMIA

/ AUERBACH

most patients, however, the presenting symptoms are nonspecific or consist of progressive weakness and lethargy, leading to the performance of routine blood tests. Preleukemic syndromes, which may escape diagnosis, are more common in the elderly

[61. Diagnosis Blood smear findings will include leukemic blast cells unless the total white blood cell count is extraordinarily low. The diagnosis should always be confirmed by bone marrow examination. Further, this allows for a more reliable estimate of chromosomal aberrations. Anemia and thrombocytopenia will be evident in most patients.

PROGNOSTIC

INDICATORS

Cytogenetics Cytogenetics may ultimately provide definitive prognostic and treatment guidance in patients with AML, independent of patient age. AML in elderly patients, in particular, often fits the FrenchAmerican-British morphologies poorly [ 131, leading researchers to seek out alternatives that might have greater clinical significance for these patients. Although morphology can be assessed at diagnosis, karyotyping requires more time, and, thus, results are normally available only after treatment has commenced. Numerous chromosomal abnormalities have been associated with AML, and the list is almost certainly incomplete. Certain chromosome arrangements are associated with more favorable outcomes than other arrangements. For example, both translocation and inversion of chromosome 16 are related to a favorable prognosis, whereas the translation and deletion of the Y chromosome are associated with an intermediate prognosis 161. The Phl (Philadelphia) chromosome in patients with AML portends an extremely poor prognosis regardless of patient age [14]. Recently, a new chromosome abnormality was discovered in two patients with AML, a deletion of chromosome 2 involving the short arm: del(2p)(p23) [15]. The significance of this is unknown. Also, trisomy 13 has been identified as the sole (and a rare) cytogenetic abnormality in patients with AML and is associated with a poor prognosis [16]. Among elderly patients, chromosomal abnormalities are more likely to be of the least favorable types, and this alone may explain their poor treatment response rate [61. To date the complexity of chromosomal abnormalities, and the difficulty in detecting them all, have prevented assignment of specific prognostic values to most karyotypes U41.

1994

The American

Journal

of Medicine

Volume

96

181

ACUTE

MYELOID

LEUKEMIA

/ AUERBACH

Cell Surface Markers Bone marrow and peripheral blood cells may express surface molecules characteristic of their lineage and maturation, and these antigenic markers can have prognostic significance [6]. Although this line of inquiry is still in its infancy, some markers have already been clearly identified. For example, a favorable prognosis has been shown to be related to the presence of the lymphoid cellassociated antigens CD2 and CD19, independent of age 1171. Interestingly, 53% of these patients also showed a normal karyotype, suggesting that these two kinds of indicators are independent. In another study of 34 patients with a median age of 56 years, with unequivocal AML (FAB criteria and/or immunophenotype), who were also expressing at least one lymphoid marker (CD7, CD2, CDlO, CD19, CD22, TdT), 6 showed llq23 rearrangement; 3 had classic Philadelphia chromosome; 15 had aberrations of the myeloid type (among them 4 with structural aberrations of 13q or trisomy 13, 3 with 7q and lq anomalies, and 2 with trisomy llq), whereas 10 showed a normal karyotype [181. In this study, no cytogenetic anomaly was found to be specifically associated with AML, and no chromosome change was found to identify a true “hybrid” leukemia, but four distinct subgroups were identified in AML with lymphoid features. Ultimately, research of this nature may explain the differential responses of patients to therapy independent of age and perhaps may reveal why age alone can have such a significant effect on patient response.

THERAPEUTIC

CONSIDERATIONS

General Observations Although absorption of chemotherapeutic agents is probably not affected by age, elimination, distribution, protein binding, renal excretion, and liver metabolism of cytotoxic drugs are known to change as individuals grow older 1191. The clinician can do little to compensate for this, except to provide excellent supportive care. Recent advances in the use of antibiotic and antiemetic agents have provided enormous assistance in this regard. For example, at our institution, the prophylactic use of ciprofloxacin when the neutrophil count falls below 500/mm3 has markedly diminished septic episodes during induction. Moreover, prophylactic administration of ondansetron has all but eliminated severe nausea and vomiting. In an attempt to reduce mortality as a result of infection or drug toxicity, some investigators have systematically reduced the dosage of chemotherapeutic drugs in patients more than 60 years of age. Such attenuated regimens have, thus far, failed to demonstrate improved survival in older patients. 182

February

1994

The American

Journal

of Medicine

Volume

For example, in a Southwest Oncology Group Phase II study, reduced dosages were administered to all patients age 50 years and older [20]. More cycles of therapy were required to achieve a complete response in these patients, and the overall complete response rate of 38% was no better than the historical results of 40% to 44% obtained in large studies of elderly patients with AML [21,22]. Indeed, it has been convincingly demonstrated that, despite its toxicity, intensive chemotherapy is superior to a “wait and see” approach, even in the elderly 15,101. The patient’s age will determine whether allogeneic or, less commonly, autologous bone marrow transplant can be considered for postremission therapy. Bone marrow transplant is rarely reported in patients over age 50 years 1231, and this procedure is nearly always considered too aggressive for elderly patients 161. However, newer agents to combat toxicity are enabling allogeneic transplants up to age 60 years, and autologous transplants as late as age 70 years. Induction With complete remission more difficult to achieve in older patients, careful consideration must be given to their induction regimen. Until recently, however, many studies have failed to report the rate of complete remission or long-term survival stratified by patient age. When data from the 1988 study of intensive maintenance by Dutcher et al 1101 were examined in this light, as of early 1993, those patients 51 to 72 years of age (n = 33) showed a median survival of 18.4 months, whereas those aged 14 to 49 years (n = 48) experienced a median survival of 27.55 months. Among the younger patients, three died in complete remission, whereas nine died in the older group free of disease (Dutcher, personal communication). Daunorubicin, an anthracycline antibiotic, has been a mainstay of AML treatment for many years 1241. In our experience, the gold standard of therapy in AML, the “3 + 7” combination of cytarabine (an antimetabolite) and an anthracycline, need not be adjusted for elderly patients. High rates of complete response have been reported using a variety of aggressive combination regimens, but age remains a significant consideration. For example, short-term therapy with cytarabine, thioguanine, and doxorubicin, in which up to six cycles are administered with as short an intercycle time period as the patient’s condition allows, can achieve complete response in 63% of patients aged 15 to 60 years. However, the best results with this intensive regimen have been reported in patients younger than 40 years of age 96

ACUTE

[25]. Because of their special vulnerability to toxicities, various strategies have been adopted to try to reduce adverse events in older patients, such as combining amsacrine with cytarabine [261. To date, such attempts have shown no advantage over the standard “3 + 7” combination. The new drug mitoxantrone, an anthraquinone, has been administered as an alternative to the daunorubicin component of the induction regimen, and it appears to be as effective as daunorubicin for this purpose [27]. It has yet to demonstrate an advantage in older patients 1241. For example, in a study of 33 patients aged 60 to 78 years using 12 mg/m2/d mitoxantrone for 3 days or 10 mg/m2/d for 5 days, plus cytarabine at 100 mg/m2 twice daily for 7 days, complete remission was achieved in 16 patients (480101,comparable to what would be expected with daunorubicin [71. Most remissions tended to be short (median: 6 months) [71. In this trial, septic deaths were unacceptably high. Another study of elderly patients using mitoxantrone, but designed to evaluate high and intermediate dosages of cytarabine (3.0 g/m2 vs 1.0 g/m2 per administration in patients under 60 years of age, 1.0 g/m2 vs 0.5 g/m2 in those 60 years of age and older), found no difference in response rate with either treatment and no improvement in response compared with conventional induction therapy 1281. Although higher doses of cytarabine did produce better antileukemic effects, the advantage failed to translate into better outcomes because of increased treatment toxicity (usually infections). Another new drug, idarubicin, has been incorporated into induction regimens and is being actively evaluated for the older patient. Idarubicin is an anthracycline analogue with the same mechanism of action as daunorubicin, but with a minor structural difference that changes the pharmacokinetics of the drug. Being more lipophilic than daunorubitin, idarubicin is taken up more rapidly by cells. Moreover, idarubicin’s metabolite is an active alcohol derivative with a longer plasma half-life than the comparable metabolite of daunorubicin, which is biologically inactive [29-321. This may explain the greater proportion of complete responses observed after only one course of therapy with idarubicin. A phase III trial recently reported by the Southeastern Cancer Study Group found idarubicin to be more effective than daunorubicin in patients regardless of age. Among those aged 51 to 60 years, 17 of 24 patients (71%) achieved complete remission with idarubicin versus 10 of 22 (45%) in the daunorubicin group. The difference was less pronounced in patients over 60 years of age, with 33 of 52 patients (63%) achieving complete remission February

MYELOID

LEUKEMIA

/ AUERBACH

with idarubicin versus 31 of 59 (53%) doing so with daunorubicin [331. Nonetheless, a 63% response rate is higher than that usually reported for patients more than 60 years of age. An earlier multicenter report of 214 patients stratified by age showed that age had a major impact on response to two chemotherapy regimens (cytarabine plus either daunorubicin or idarubitin), with patients under 60 years of age showing higher response rates under either regimen 1341. Although cytarabine plus idarubicin showed a significantly higher response rate than cytarabine plus daunorubicin in patients up to 50 years of age (p = 0.035), there was no significant difference in the response to the two treatments in patients 51 years of age and older in this study (p = 0.5418). Toxicities were equivalent overall with the two treatments [34]. Another multicenter study, this one conducted by the Italian Co-operative Group (GIMEMA) involving 255 patients aged 55 to 78 years, found no difference in the complete response rate between patients treated with daunorubicin (39%) or idarubicin (40%). These authors suggest that older patients receive reduced doses of either drug to decrease the risk of aplastic death from myelotoxicity (Mandelli). Idarubicin is unique among anthracycline agents in that it can be administered orally, although it is not available in this form in the United States. To date, five reports exist on the oral use of the drug [35]. Oral administration has proven useful in the elderly (65 to 79 years), but it is was still too toxic for outpatient use [ 11,361. Also noteworthy is the finding in a study of 120 patients that idarubicinlcytarabine appeared more cost-effective than daunorubicin/cytarabine when hospital charges to produce a complete response with the two regimens were compared 1371. Results of this study were not broken down by age, however, with the median ages of the idarubicin and daunorubicin groups being 36 and 41 years, respectively. Patients enrolled in the idarubicin arm of the study were more likely to achieve remission after one course of treatment and then tended to survive longer afterward. Consolidation and Maintenance Since bone-marrow transplant is contraindicated for most older patients, postremission therapy has usually been limited to administration of intermediate doses of the same agents used to achieve complete remission or administration of new cytotoxic drugs. No consensus exists as to which approach is best. Perhaps because complete remission is more difficult to achieve in older patients than in younger ones, and because doing so is the 1994

The American

Journal

of Medicine

Volume

96

183

ACUTE

MYELOID

LEUKEMIA

/ AUERBACH

necessary first step toward cure, most studies of patients more than 50 years of age have focused on obtaining a complete response instead of on strategies to prolong the remission [lo]. The use of high-dose cytarabine has been shown to be useful postremission in patients under 60 years of age with AML, but episodes of neurotoxicity have been found to be so common among patients over 60 years of age that at least one group has elected to exclude all older patients from such studies [38]. Further, the Cancer and Leukemia Group B (CALGB) study compared high-dose cytarabine with nonablative doses of cytarabine, making a comparative conclusion difficult. Currently, low-dose cytarabine is the most popular consolidation therapy for the older patient, but its efficacy is doubtful. Additional studies are certainly needed for this patient population, and several are in progress. The CALGB is nearing completion of a placebocontrolled, phase III study using granulocytemacrophage colony stimulating factor (GM-CSF), mitoxantrone, and cytosine arabinoside exclusively in patients 60 years of age and older. This study seeks to determine whether GMXSF can reduce the duration of neutropenia after induction without significantly stimulating the growth of leukemia cells. To explore the hypothesis that the pharmacokinetics of idarubicin make it less cardiotoxic but more antileukemic for induction in elderly patients, the University of Southern California is conducting a nonrandomized study of patients aged 55 to 75 years. The Mid-Atlantic Oncology Program has also initiated a multicenter study of postremission therapy in older patients (more than 50 years). Following induction with idarubicin and cytosine arabinoside, these patients are randomized to receive three rapid cycles of idarubicin, cytosine arabinoside, and 6-thioguanine, or 3 years of ablative therapy with 6-thioguanine and cytosine arabinoside. We expect to provide our findings from this study within the next 3 to 5 years. These regimens were selected for study because they represent a randomized comparison between the two best published series, in terms of duration of survival and acceptable toxicity, for patients more than 50 years of age. CONCLUSION Most patients with AML are more than 50 years of age. In general, these patients should be treated as aggressively as their overall status and willingness allow. To limit treatment options in older patients only because of their chronologic age, is a strategy that is no longer supported by research or 184

February

1994

The American

Journal

of Medicine

Volume

clinical experience. either administered period of time, are to offer prolonged population.

Repeated ablative measures, quickly or over a protracted still the only methods shown disease free survival for this

REFERENCES 1. Ries LAG, Hankey BF, Miller BA, et a/. Cancer statistics review 19731988. National Cancer Institute. NIH Pub. No. 91-2789, 1991. 2. Pedersen-Bjergaard J. Radiotherapy- and chemotherapy-induced myelodysplasia and acute myeloid leukemia. A review. Leuk Res 1992; 16: 61-5. 3. Mastrianni DM, Tung NM, Tenen DG. Acute myelogenous leukemia: current treatment and future directions. Am J Med 1992; 92: 286-95. 4. Cheson BD. The myelodysplasticsyndromes: current approaches to therapy. Ann Intern Med 1990; 112: 932-41. 5. Lowenberg B, Zittoun R, Kerkhofs H, et al. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase Ill study of the European organization for research and treatment of cancer leukemia group. J Clin Oncol 1989; 7: 1268-74. 6. Baker MA. The management of leukemia in the elderly. In: Hamblin TJ, editor. Bailliere’s clinical haematology: international practice and research. Vol. 1, No. 2, June 1987: 427-47. 7. MacCallum PK, Rohatiner AZS, Davis CL, et al. Mitoxantrone and cytosine arabinoside as treatment for acute myeloblastic leukemia at first recurrence. Leukemia 1993; 10: 1496-9. 8. Marie J-P, Zittoun R. Chemotherapy of acute myelogenous leukemia. In: Zittoun RA, editor. Baillere’s clinical haematology: international practice and research. Vol. 4, No. 1, January 1991: 97-l 11. 9. Champlin R, Gale RP. Acute myeologenous leukemia: recent advances in therapy. Blood 1987; 69: 1551-62. 10. Dutcher JP, Wiernik PH, Markus S, et a/. Intensive maintenance therapy improves survival in adult acute nonlymphocytic leukemia: an eight-year follow-up. Leukemia 1988; 2: 413-9. 11. Sebban C, Archimbaud E, Coiffier B, et al. Treatment of acute myeloid leukemia in elderly patients. Cancer 1988; 61: 227-31. 12. Mandelli F, Petti MC, Ardia A, et al. A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin cytarabine in the treatment of acute non-lymphoid leukemia. EurJ Cancer 1991; 27: 750-55. 13. Head DR, Downing JR. Pathology and immunology of leukemia. Curr Opin Oncol 1992; 4: 14-23. 14. Preisler HD. Determinants of response and prediction of response to chemotherapy in acute myelogenous leukemia. In: Zittoun RA, editor. Baillere’s clinical haematology: international practice and research. Vol. 4, No. 1, January 1991: 69-95. 15. Najfeld V, Scalise A, Fruchtman S, et a/. del(2)(p23): A new recurrent abnormality in acute myeloid leukemia. Cancer Genet Cytogenet 1990; 46: 185-90. 16. Dohner H, Arthur DC, Ball ED, et a/. Trisomy 13: a new recurring chromosome abnormality in acute leukemia. Blood 1990; 76: 1614-21. 17. Ball ED, Davis RB, Griffin JD, eta/. Prognosticvalueof lymphocytesurface markers in acute myeloid leukemia. Blood 1991; 77: 2242-50. 18. Cuneo A, Michaux J-L, Ferrant A, et al. Correlation of cytogenetic patterns and clinicobiological features in adult acute myeloid leukemia expressing lymphoid markers. Blood 1992; 79: 720-7. 19. Wynne H, Woodhouse KW. The disposition of cytotoxic drugs in the elderly. In: Hamblin TJ, editor. Bailliere’s clinical haematology: international practice and research. Vol. 1, No. 2, June 1987: 513-30. 20. Minutes of the Southwest Oncology Group Leukemia Committee meeting. March 1987. 21. Keating MJ, McCrede KB, Benjamin RS, et al. Treatment of patients over 50 years of age with acute myelogenous leukemia with a combination of Rubidazone and Cytosine Arabinoside, Vincristine, and Prednisone (ROAP). Blood 1981; 58: 584-91. 22. Rai KR, Holland JF, Glidewell OJ, et al. Treatment of acute myelocytic leukemia: a study by Cancer and Leukemia Group B. Blood 1981; 58: 1203-12. 23. Mills LE, Cornwell GG, Ball ED. Autologous bone marrow transplantation

96

ACUTE in the treatment of acute myeloid leukemra: the Dartmouth experience and a review of the literature. Cancer Invest 1990; 8: 181-90. 24. Schijlzel C, Putten WV, Liiwenberg B. A comparison of in vitro sensitivity of acute myeloid leukemia precursors to mitoxantrone, 4’deoxydoxorubicin, 4-demethoxydaunorbicin and daunorubicin. Leuk Res 1986; 10: 1455-9. 25. Rohatiner AZS, Gregory WM, Bassan MJ, et al. Short-term therapy for acute myelogenous leukemia. J Clin Oncol 1988; 6: 218-26. 26. Harousseau JL, Reiffers J, Hurteloup P, et al. Treatment of relapsed acute myeloid leukemia with idarubicrn and intermediate-dose cytarabine. J Clin Oncol 1989; 7: 45-9. 27. Wiernik PH. New agents in the treatment of acute myeloid leukemia. Semin Hematol 1991; 28: 95-8. 28. Hiddemann W, Aul C, Maschmeyer G, et a/. High-dose versus intermediate dose cytarabine combined with mitoxantrone for the treatment of relapsed and refractory acute myeloid leukemia: results of an age-adjusted randomized comparison. Semin Hematol 1991; 28: 35-8. 29. Daghestani A, Arlin ZA, Leyland JB, et al. Phase I and II clinical and pharmacological study of 4-demethoxydaunorubicin (rdarubicin) in adult patients with acute leukemia. Cancer Res 1985; 45: 1408-12. 30. Berman E, et a/. Results of a randomized trial comparing idarubicin and cytosine arabinoside wrth daunorubicin and cytosine arabinosrde in adult patients with newly diagnosed acute myelogenous leukemia. Blood 1991; 77: 1666-76. 31. Supino A, Necco A, Dasdia T, et al. Relationship between effects on

February

MYELOID

LEUKEMIA

/ AUERBACH

nucleic acid synthesis in cell cultures and cytotoxicity of 4-demethoxy derivatives of daunorubicin and adriamycin. Cancer Res 1977; 37: 4523-8. 32. Speth PAJ, Van de Loo FAJ, Linssen PCM, et al. Plasma and human leukemiccell pharmacokineticsof oral and intravenous 4-demethoxydaunomycm. Clin Pharmacol

Ther 1986;

40: 643.

33. Vogler WR, Velez-Garcia E, Weiner RS, et al. A Phase Ill trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group study. J Clin Oncoi 1992; 10: 1103-11. 34. Wiernik PH, Banks PLC, Case DC, et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 1992; 79: 313-9. 35. Cersosimo RJ. Idarubicin: an anthracycline antineoplastic agent. Clin Pharm 1992; 11: 152-7. 36. Harousseau JL, RigaCHuguet F, Hurteloup H, et al. Treatment of acute myeloid leukemia in elderly patient with oral idarubicin as a single agent, Eur J Haematol 1989; 42: 182-5. 37. Pashko S, Jacobs J, Santorsa J. The cost-effectiveness cytosine arabinoside versus daunorubicin/cytosin arabrnoside

of idarubicin/ in the treatment

of adults with acute myeloid leukemia. Clin Ther 1991; 13: 353-60. 38. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Sarno E, Frei E Ill. Intensive post-remrssion therapy with ARA-C in adults with acute myeloid leukemia: initial results of a CALGB phase Ill trial. Leukemia

1994

The American

Journal

of Medicine

1992;

6: Suppl 2: 66-7.

Volume

96

185