Induction chemotherapy for acute myelogenous leukemia (AML) in the elderly usually combines standard doses of cytarabine with an anthracycline (daunorubicin or idarubicin) 1–3 or anthracycline derivative (mitoxantrone). 4–6 Any of these combinations reproducibly results in remission rates of approximately 50%. Despite remission, however, survival is brief and cure is unlikely. 7,8
Several prospective, randomized trials demonstrate that adding hematopoietic growth factors to standard, anthracycline-containing chemotherapy shortens the period of severe neutropenia 2,9,10 and may reduce infectious morbidity and mortality. 3 Remission rates and survival, however, have not consistently improved with the addition of growth factors. Importantly, there is also no evidence from the randomized studies that growth factors increase the incidence or accelerate the onset of relapse.
Mitoxantrone is an anthracenedione with excellent activity against AML. 11 In prospective trials, the combination of cytarabine and mitoxantrone appears to have activity at least equivalent to combinations of cytarabine and an anthracycline when given as initial induction chemotherapy. 12,13 Some studies also suggest that mitoxantrone may incur less toxicity than the anthracyclines. 14,15 The combination of mitoxantrone and cytarabine followed by a hematopoietic growth factor may reduce morbidity further without compromising therapeutic efficacy. We designed a clinical trial to test this hypothesis.
MATERIALS AND METHODS
All patients were at least 55 years of age. All patients had morphologic proof of AML as defined by the French–American–British classification system. 16 All patients were untreated except with hydroxyurea to control leukocytosis. Patients with antecedent hematologic disorders were not excluded. Patients were not excluded for abnormal renal function, liver function, or performance status. Cardiac function tests were not required before treatment, and the results of such tests did not affect eligibility. All patients gave informed consent and were treated in a Cleveland Clinic Foundation Institutional Review Board approved clinical trial.
All patients were treated with standard supportive care measures as previously described. 17 Cytarabine 100 mg/m2 was infused as a continuous infusion daily for 7 days. Intravenous bolus mitoxantrone 12 mg/m2 was given daily for the first 3 days of cytarabine. Ten days after cytarabine was started, a bone marrow aspirate and biopsy were obtained. If the marrow was hypocellular with less than 5% blasts, granulocyte-macrophage colony-stimulating factor (GM-CSF; yeast-derived granulocyte-macrophage colony-stimulating factor, Immunex Corp., Seattle, WA, U.S.A.) 250 μg/m2 was given subcutaneously daily until either the neutrophil count rose above 1,000/μl on 2 consecutive days or evidence of progressive disease developed. If the marrow contained more than 5% blasts, chemotherapy was restarted on day 14 of treatment with the same doses, but the duration of cytarabine was reduced to 5 days and mitoxantrone was only given for 2 days.
If a second induction cycle of chemotherapy was necessary, another marrow aspirate and biopsy were obtained on the tenth day of treatment. If the marrow was hypocellular with less than 5% blasts, GM-CSF 250 μg/m2 was given subcutaneously daily until either the neutrophil count rose above 1,000/μl on 2 consecutive days or evidence of progressive disease developed. If the marrow contained more than 5% blasts, the patient was removed from the study and treated at the physician’s discretion.
For patients achieving a complete remission with either one or two cycles of induction chemotherapy, two cycles of cytarabine 400 mg/m2 daily as a continuous infusion for 5 days were planned, each with GM-CSF 250 μg/m2 starting the day after cytarabine was complete. Treatment was usually started in the outpatient area with admission reserved for episodes of fever in the setting of neutropenia. In addition to other standard supportive care measures, dexamethasone eyedrops were given every 6 hours during the consolidative cytarabine infusions.
Remission was defined according to standard definitions. Complete remission required normocellular bone marrow with less than 5% blasts as well as a neutrophil count greater than 1,500/μl, hemoglobin more than 11 mg/dl, and platelet count greater than 100,000/μl for a minimum of 4 weeks. Once remission status was documented, further routine marrow aspirates and biopsies were not required. Marrow samples were performed for alterations in peripheral blood counts or symptoms consistent with relapse. Relapse was defined as any marrow sample demonstrating more than 5% blasts, any circulating blasts, or any evidence of extramedullary leukemia. Toxicity was defined according to National Cancer Institute common toxicity criteria.
Survival, duration of complete remission (CR), and time to neutrophil recovery were summarized using the method of Kaplan and Meier. The log-rank test was used to compare groups of patients with respect to survival, and Fisher’s exact test was used to compare CR rates.
From December 1994 to July 1998, 30 patients were enrolled in this clinical trial. In general, patients not eligible for other clinical trials (usually because of preexisting hematologic disorders) were enrolled in this one. All 30 patients are evaluable for response and toxicity. The characteristics of the patients are listed in Table 1. The one patient with good-risk cytogenetics had acute promyelocytic leukemia. French-American-British classification is omitted because this information lacks prognostic significance. Of the seven patients with secondary leukemia, four transformed from preexisting myelodysplasia and three had previously been treated with chemotherapy.
Of the 30 patients, 19 (63%) achieved CR. Of these 19 patients, 12 (63%) achieved remission with one cycle of chemotherapy. Of the 14 patients treated with a second cycle of induction chemotherapy, 7 (50%) achieved CR. Induction chemotherapy failed to eradicate leukemia in 11 patients, all of whom subsequently died of neutropenic sepsis or refractory leukemia.
Marrow aplasia was achieved with 1 or 2 cycles of chemotherapy in 23 patients, all of whom subsequently were treated with GM-CSF. Of these, 16 (70%) patients completed GM-CSF therapy according to protocol. GM-CSF was stopped early in seven patients. The reasons for early termination of GM-CSF included progressive disease or circulating blasts in five patients, rash in one patient, and fever in one patient. In two cases, the circulating blasts resolved when GM-CSF was discontinued, and both patients achieved complete remission.
The median time to neutrophil recovery from the first day of chemotherapy was 25 days in patients treated with GM-CSF after 1 cycle of induction chemotherapy. Neutrophil recovery occurred in 28 days in patients who received a second course of induction.
Nonhematologic toxicity during induction was no more than expected. Grade III-IV toxicity was mostly hepatic and reversible (Table 2). One patient died of an intracerebral hemorrhage from thrombocytopenia and platelet transfusion alloimmunization. Another patient with a history of coronary artery disease died of a myocardial infarction during his neutropenic nadir. Two patients developed reversible and compensated atrial fibrillation and one patient had a moderately severe, but reversible, ileus. Fatal septicemia occurred in eight patients during their neutropenic nadir. All of these eight patients died after they were removed from the treatment protocol. Four patients were never treated with GM-CSF because they never achieved marrow aplasia. The other four died after GM-CSF was stopped because of progressive leukemia.
Of the 19 patients who achieved CR, 9 were treated with postremission chemotherapy as outlined in the protocol. Two patients only received one cycle because of either life-threatening sepsis during the first cycle or failure to recover adequate platelet counts before the second cycle. Two patients were treated with intermediate-dose cytarabine, but without GM-CSF because of fever or rash that was attributed to GM-CSF during induction chemotherapy. Three patients were treated with other chemotherapies because of vertigo either attributed to cytarabine with the first cycle or concern for worsening by intermediate-dose cytarabine with consolidation. Three patients received no additional chemotherapy because of either uncontrolled infection (n = 2) or early relapse (n = 1).
The last patient was enrolled in this treatment protocol in July 1998. The median overall survival of the 30 evaluable patients is 7 months, with 10% alive after a median of 15 months of follow-up. For patients who achieved CR, median disease-free survival is 8.1 months. All patients have relapsed.
There was no statistically significant difference in either remission or survival rates between patients presenting with good or intermediate risk cytogenetics compared with those presenting with poor-risk cytogenetics. For patients with a good- or intermediate-risk karyotype, the CR rate was 67% compared with 56% (p = 0.71) in those with a poor-risk karyotype. Patients with good- or intermediate-risk cytogenetics achieved remission with 1 cycle of induction chemotherapy more frequently than patients with poor-risk cytogenetics (75 versus 33%). However, the number of patients in each group is relatively small and the difference is not statistically significant (p = 0.33). Similar results were observed with respect to survival. That is, median survival of patients with good- or intermediate-risk cytogenetics was 7.7 months compared with 3.6 months for patients with poor-risk cytogenetics (p = 0.93).
Mitoxantrone combined with cytarabine is a known, effective induction chemotherapy regimen in both young and elderly patients with AML. 12–15 The addition of hematopoietic growth factors to induction chemotherapeutic regimens that use daunorubicin consistently shortens the duration of neutropenia without accelerating the onset of relapse in prospective, randomized studies. 2,3,9,10,18 Our study demonstrates that mitoxantrone can be substituted for daunorubicin when GM-CSF is used to accelerate neutrophil recovery with similar efficacy and acceptable, if not reduced, toxicity.
The complete remission rate of 63% (95% confidence interval: 44–80%) for our patients treated with mitoxantrone compares favorably with the remission rates achieved in the growth factor treatment arms of the published, randomized studies using a similar treatment schedule with daunorubicin (Table 3). In fact, a preliminary analysis of a prospective, randomized trial comparing 3 days of either daunorubicin (45 mg/m2), idarubicin (12 mg/m2), or mitoxantrone (12 mg/m2) in combination with cytarabine as induction therapy for AML in the elderly 19 suggests no difference in either complete remission rates or survival according to assigned treatment. There also was no difference in CR rate or survival between patients randomized to either idarubicin (8 mg/m2) or mitoxantrone (7 mg/m2) combined with cytarabine and etoposide in another recently reported study. 20 Our data also suggest no significant disadvantage for mitoxantrone in the treatment of elderly patients with poor-risk cytogenetics. Any differences between daunorubicin, idarubicin, and mitoxantrone given at standard doses appear to result from differences in toxicity profile rather than differences in efficacy.
The toxicity encountered from induction chemotherapy for AML may be hematologic or nonhematologic. Hematologic toxicity is universal because the goal of treatment is bone marrow aplasia. A direct result of the hematologic toxicity of chemotherapy is an increased risk of neutropenic sepsis. All patients in our study developed fevers in the setting of neutropenia. Eight patients died of infectious complications, but none were still being treated on our treatment protocol. Patients who failed to achieve a remission with two cycles of induction chemotherapy were declared treatment failures and were treated at their physician’s discretion. All of these patients (n = 11, 37%) died of either infectious complications or progressive leukemia.
Although our regimen appears efficacious and reasonably well tolerated, elderly patients should be selected for treatment based on their predicted ability to withstand the significant toxicity of any chemotherapy regimen designed to induce remission of AML. One may argue that ours was a selected population of elderly patients because not every patient who was eligible for this treatment in the 4 years it was offered was enrolled in this protocol. However, the fact that most of our patients were older than 65 years and were not excluded for abnormal renal, hepatic, or cardiac dysfunction suggests the contrary. Additionally, some patients were offered this protocol because they were not considered fit candidates for more intensive treatment protocols for this population of patients.
Nonhematologic toxicity in our study was acceptable and similar to that which would be expected with a daunorubicin- or idarubicin-containing regimen. These toxicities are not explored in detail in the randomized growth factor trials. Other studies, however, have compared the toxicity of daunorubicin to idarubicin without the addition of growth factors. 1,21–23 The study that most closely matches ours in terms of patient population and drug doses is the one reported by Vogler et al. 23 Although Vogler’s study included younger patients, only 50% were older than 60 years. The cytarabine dose and schedule they used is identical to ours, but they compared 3 days of idarubicin (12 mg/m2) to daunorubicin (45 mg/m2). Table 2 compares the nonhematologic toxicity encountered in that study with the toxicities noted in ours. In general, the treatment was well tolerated with reversible grade I-II toxicity. The apparent increased incidence of reversible cardiac and hepatic toxicity is more likely related to the older patient population in the current study than to a specific increased risk of these toxicities with this particular treatment regimen.
No specific toxicity could be attributed to the use of either mitoxantrone or GM-CSF, although GM-CSF was withheld in two patients because of the possibility of toxicity. Side effects are often erroneously attributed to hematopoietic growth factors in general, and GM-CSF in particular. In the prospective, randomized trials, there was no significant difference in the incidence of nonhematologic toxicities in patients randomized to growth factors compared with placebo. 2,3,9,10,18
There is no standard postremission therapy for elderly patients with AML. In a randomized study reported by Mayer et al., four cycles of cytarabine administered at a standard dose of 100 mg/m2/d for 5 days resulted in similar relapse-free and overall survival compared with higher doses of cytarabine with less toxicity. 24 Adding mitoxantrone in remission also appears to be of no benefit. 25 There is also evidence that similar survival is possible in the absence of any postremission therapy in this patient population. 6 Although many patients in our study did not receive or complete the planned postremission therapy, the median relapse-free survival of 8.1 months is not inferior to other reported therapy schedules (Table 4). Given the toxicity incurred by postremission chemotherapy, and the questionable benefit, one could reasonably make the argument that postremission chemotherapy in the elderly patient with AML is not routinely indicated.
Remission rates for elderly patients with AML are generally lower that those achieved in younger patients, reflecting the different biology of AML in these two patient populations. 26,27 Efforts to improve these results with growth factors has largely failed. 28 Increasing chemotherapy dose intensity has also been unsuccessful in the elderly patient population. New, innovative treatment approaches are needed, such as modulation of multidrug resistance. 29,30 Until such approaches are fully evaluated, however, the standard induction chemotherapy for AML in the elderly remains a 7-day infusion of a standard dose of cytarabine combined with 3 days of an anthracycline or anthracycline derivative such as mitoxantrone. Hematopoietic growth factors, although not standard therapy, are recommended because they shorten the duration of neutropenia without significant adverse effects, and it is difficult to conceive how that would be undesirable.
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