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1 Department of Internal Medicine I, Division of Hematology & Hemostaseology, 2 Institute of Medical Biology, and 3 Institute of Medical and Laboratory Medicine, Medical University of Vienna, Vienna, Austria
ABSTRACT
Purpose: High-dose intermittent cytarabine is an effective postremission treatment for patients with acute myeloid leukemia (AML). This regimen is a safe approach in patients < 60 years but produced severe neurotoxicity in the elderly.
Experimental Design: We have established a dose-reduced age-adapted consolidation using intermediate dose (IDAC; 2 x 1 g/m2 i.v., days 1, 3, and 5) for AML patients 
60 years. Forty-seven de novo AML patients in complete remission (CR; median age, 70 years) were scheduled to receive four consolidation cycles of IDAC.
Results: In 25 of 47 patients (53%), all four cycles were administered: 9 (19%) received three cycles; 7 (15%) received two cycles; and 6 patients (12%) one cycle. Treatment was well tolerated without neurotoxicity. The median number of days with severe neutropenia (absolute neutrophil count < 500/µl) was 9. Neutropenic fever occurred in 22 of 47 patients (49%) during the first cycle, in 24 of 41 (60%) during the second, in 15 of 34 (44%) during the third, and in 18 of 25 (72%) during the fourth cycle. Only 1 patient died during consolidation (cardiac failure). The median overall survival, disease-free survival, and continuous CR were 10.6, 15.5, and 15.9 months, respectively. The probability of overall survival, disease-free survival, and continuous CR at 5 years were 18, 22, and 30%, respectively.
Conclusions: IDAC is a safe and effective postremission therapy for elderly patients with AML.
INTRODUCTION
The incidence of acute myeloid leukemia (AML) increases with age. In fact, >50% of all AML patients are >60 years at diagnosis (1, 2, 3, 4, 5) . Whereas for younger patients treatment strategies are well established, therapy in the elderly deserves special consideration (6, 7, 8) . Thus, in many of these patients, the poor performance status and/or comorbidity prohibit intensive myelosuppressive therapy (9, 10, 11) . For induction treatment, most chemotherapy regimens used in elderly AML patients have been the same (some of them dose reduced) as that applied in younger adults (5, 6, 7, 8, 9, 10, 11) . However, the outcome in the elderly is less favorable compared with younger patients. This appears to be due to a relatively high rate of treatment-related death, as well as to poor prognostic features (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16) . Still, however, the long-term survival in elderly AML patients receiving remission induction polychemotherapy is superior compared with those who are considered for palliative treatment with hydroxyurea or low-dose cytarabine (ARA-C; Ref. 5, 6, 7, 8, 9, 10, 11 ).
It is generally appreciated that intensive postremission therapy with repetitive cycles of chemotherapy is important to maintain remission in patients with AML (17, 18, 19)
. In younger patients, intensive consolidation treatment (high-dose chemotherapy or stem cell transplantation) is the established approach (20, 21, 22)
. Beyond the age of 60 years, however, no generally accepted treatment strategy has become available thus far. In most series, consolidation treatment consisted of one to two cycles of chemotherapy, using the same agents that were used for induction treatment (3
, 6, 7, 8
, 12
, 15)
. The overall survival at 5 years that was achieved using such regimens amounted to 
10% (12
, 15
, 23, 24, 25, 26, 27, 28, 29, 30)
. Thus, only a small group of elderly patients with AML are cured using these regimens. In a more recent study, intermediate doses of ARA-C (500 mg twice daily on days 1–3) together with mitoxantrone were applied to elderly AML patients for postremission treatment with slightly superior effects on leukemia-free and overall survival (31)
.
In 1994, the Cancer and Leukemia Group B study group introduced the high-dose intermittent ARA-C regimen (HiDAC; 2 x 3 g/m2 on days 1, 3, and 5) as an effective consolidation treatment for patients with de novo AML (32)
. In the vast majority of patients <60 years, this regimen was well tolerated (32)
. However, in a significant number of elderly patients (60 years) receiving this regimen, severe neurotoxicity occurred (32)
. Therefore, the administration of HiDAC was recommended only for patients < 60 years.
In the present study, we have dose modified the original HiDAC protocol by using ARA-C at 2 x 1 g/m2 on days 1, 3, and 5 and applied this regimen to a cohort of consecutive AML patients > 60 years. This regimen was found to be an effective and well-tolerated consolidation therapy for these patients.
PATIENTS AND METHODS
Patients’ Characteristics.
Between October 1994 and September 2001, a total number of 144 elderly patients (60 years) with de novo AML (AML M3 excluded) were admitted to our department (University Hospital of Vienna). Patients were followed up until April 2003. Of the 144 patients, 93 patients (63%) were eligible to receive induction chemotherapy. Fourteen patients were included in a study trial using PEG-rHuMGDF (33)
and therefore were excluded. Seventy-nine patients received standard induction therapy (see below) and, after receiving complete remission (CR), were scheduled to undergo consolidation with intermediate dose ARA-C (IDAC). These 79 patients were included in our analyses. The median age was 70 years (range, 60–89 years). Diagnoses were established according to French-American-British criteria (34, 35, 36)
. The patients’ characteristics are depicted in Table 1
. Table 2
shows the patients’ karyotype. Chromosome analyses were performed using banding and fluorescence in situ hybridization techniques. The karyotypes were described according to guidelines of the International System for Human Cytogenetic Nomenclature (37)
. Cytogenetic risk categories were defined by Southwest Oncology Group criteria (38)
. Written informed consent was obtained from all patients before chemotherapy.
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Pretreatment and Follow-Up Examinations.
Before each chemotherapy cycle, patients underwent physical examination and laboratory assessments, including liver and renal function tests, C-reactive protein, and coagulation parameters. In addition, patients had a X-ray of the chest before chemotherapy. Bone marrow examinations were performed before induction treatment and before the first cycle of consolidation in all patients. During consolidation, routine laboratory parameters and blood counts were serially determined. After completion of therapy, all patients were seen in follow-up examinations (including complete blood and differential counts) in 1–3-month intervals.
Response Criteria and Evaluation of Toxicity.
According to established criteria (40)
, CR was defined as a blast cell count of <5% in bone marrow smears and evidence of trilineage regeneration. Resistant disease was defined as blast cell persistence (>5% in bone marrow smears) after two cycles of induction chemotherapy. Induction death was defined as death occurring within 28 days after start of an induction chemotherapy cycle. Relapse was defined as a blast cell count of >5% in bone marrow smears in patients who were previously in CR. Treatment-associated hematological toxicity was examined by analyzing the duration of neutropenia (ANC < 500 cells/µl), numbers of red cell and platelet concentrates, and days of neutropenic fever/cycle. Nonhematological and hematological toxicities were evaluated using WHO criteria.
Statistical Analysis.
Patients had to have received at least one cycle of chemotherapy to be included in statistical analyses. The product limit method of Kaplan and Meier was applied to analyze the probability of survival, disease-free survival (DFS), and continuous CR (CCR). To calculate the significance of differences between cytogenetic risk groups, the log-rank test was applied. Differences were considered to be significant when the P was <0.05.
RESULTS
Response to Induction Treatment.
CR was obtained in 49 of 79 patients (62%). The majority of these patients (n = 41, 84%) entered CR after the first induction cycle, whereas in 8 patients (16%), a second course of induction therapy was required. Thirty of the 79 patients (38%) did not enter CR. In 24 (80%) of these patients, blast cell persistence was found [no remission (NR)], whereas 6 (20%) died from treatment-related complications (severe infections, bleeding) within 28 days after start of therapy (induction death).
Toxicity of Consolidation Treatment with IDAC.
Forty-seven of the 49 patients who had entered a CR received IDAC for consolidation. Two patients were not eligible for additional chemotherapy because of uncontrolled infection. All four courses of IDAC could be administered in 25 of 47 patients (53%). Nine patients (19%) received three cycles and 7 patients (15%) two cycles of IDAC. In 6 patients (13%), treatment had to be discontinued after the first IDAC cycle. Severe infection was the major cause (32%) to discontinue consolidation therapy. Five patients (23%) had an early relapse occurring during the consolidation phase (Table 3)
.
|
. The median duration of neutropenia was 9 days (range, 1–17 days). Neutropenic fever (>38°C) occurred in 22 patients (49%) during the first IDAC cycle, 24 patients (60%) during the second IDAC cycle, 15 patients (44%) during the third IDAC cycle, and 18 patients (72%) during the fourth IDAC cycle. No patient died from infections. G-CSF was not given routinely. However, in 60 of the 145 IDAC cycles (41.4%), patients received G-CSF because of infection and grade IV neutropenia (31 of 60 = 51.7%) or because severe infections had occurred during one of the preceding chemotherapy cycles (prophylactic use in 29 of 60 patients = 48.3%).
|
CCR and DFS.
At a median follow-up of 24.4 months, the estimated probability to remain free from recurrent leukemia (DFS) was 22% at 5 years. The median DFS was 15.5 months. The median CCR was 15.9 months with a probability of CCR of 30% at 5 years (Fig. 1A)
. When analyzing different cytogenetic risk groups, it was found that the CCR rate was superior in patients with favorable or intermediate karyotypes compared with poor risk karyotypes (P < 0.05; Fig. 1B
).
|
. The median overall survival in patients who achieved a CR and were treated with IDAC (n = 47) was found to be 31.8 months. The probability to be alive at 5 years was 34% (Fig. 2B)
. The most important prognostic factor for overall survival was the karyotype. In fact, patients with intermediate or favorable cytogenetics had a significantly longer median overall survival (16.6 months) compared with patients presenting with an unfavorable karyotype (5.0 months; P < 0.05; Fig. 3A
). Another important survival-related factor was age. In fact, when comparing patients ages 60–74 years with those ages 75 years, it was found that the median overall survival was shorter in older patients (P < 0.05; Fig. 3B
).
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Repetitive cycles of HiDAC (3 g/m2 ARA-C twice a day on days 1, 3, 5) were introduced as an effective consolidation regimen for AML patients by the Cancer and Leukemia Group B study group in 1994 (32)
. In patients <60 years, this protocol produced a high rate of CCR (32)
. In patients >60, however, a high rate of neurotoxicity was reported using this regimen (32)
. In the current study, we have dose modified this protocol by using IDAC (1 g/m2 ARA-C twice a day on days 1, 3, 5) and applied this regimen to a group of elderly patients (60 years) with de novo AML. This protocol (IDAC) was found to be an effective and well-tolerated consolidation regimen for this group of patients.
The general outcome of therapy in elderly patients with AML is poor compared with younger adults (5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16)
. This appears to be due to a lower CR rate (unfavorable prognostic factors), as well as to a higher number of patients who cannot tolerate aggressive (postremission) treatment (5, 6, 7, 8, 9, 10, 11)
. In addition, many of these patients have secondary AML, which has a worse prognosis. The CR rate in our group of patients with de novo AML 60 years was 62%. This CR rate is similar to that in other studies analyzing older patients with AML (8
, 12
, 25
, 27, 28, 29, 30, 31)
and clearly inferior when compared with the outcome reported for younger adults (4
, 5
, 16
, 41)
However, the DFS and CCR in our elderly patients who had entered CR and received postremission treatment were relatively high and may be in a similar range when comparing to DFS and CCR rates reported for younger adults (5, 6, 7, 8, 9, 10, 11)
. All in all, these data point to the high efficacy of IDAC as consolidation therapy.
The relatively favorable overall survival, DFS, and CCR at 5 years obtained in our patients may have several explanations. First, we have used higher doses of ARA-C than had been used for elderly AML patients in most previous trials (8 , 14 , 24 , 28) . Second, up to four cycles of ARA-C were intended to be administered, and the vast majority of our patients (> 70%) indeed received three or four cycles of consolidation. Thus, the intensity of the consolidation program may have contributed to the relatively favorable DFS and CCR in our patients. The possibility that the patients analyzed were selected for good-risk cases has to be considered as well. In fact, only 69% of patients > 60 years admitted to our department underwent induction therapy. However, the rate of treated patients and the degree of selection in our trial seems to be comparable with other reported treatment studies in elderly patients with AML (8 , 14 , 24 , 28) . Therefore, we believe that our patients were not overselected compared with other trials.
In AML, age and cytogenetics are well-known risk factors concerning (leukemia-free) survival (13 , 15) . In this study, the prognostic significance of these variables could be reconfirmed for our AML patients >60 years. In fact, when comparing overall survival and CCR, a longer survival was found for patients 60–74 years compared with those >75 years. Similarly, the karyotype was found to be a significant prognostic factor for overall survival.
Our data obtained in elderly AML patients using IDAC are superior when compared with reported consolidation regimens using lower doses of ARA-C (5 , 10 , 14 , 26, 27, 28, 29, 30) . In one recent study, however, relatively high doses, i.e., 500 mg/m2 ARA-C, were applied in combination with mitoxantrone (31) . In this particular study, the median DFS was 10 months and thus inferior compared with our results (median DFS, 15.5 months; Ref. 31 ). This may be because of the higher doses of ARA-C or the increased number of cycles administered in our study. All in all, these data point to a significant effect of higher doses of ARA-C for consolidation of elderly patients with AML. In fact, it may be desirable to increase ARA-C doses for consolidation in elderly patients as much as possible, and our trial may be a useful contribution to AML therapy in this regard.
Chemotherapy-related toxicity is a major dose-limiting factor in the treatment of older patients with AML (5, 6, 7, 8, 9, 10, 11 , 14 , 30) . Therefore, it was important to look carefully for potential side effects. The nonhematological toxicity observed in our consolidation protocol was mild. Especially, no major neurological toxicity was noted, and only 1 patient died (cardiac failure). This is of particular importance because a high rate of severe neurotoxicity was reported in elderly patients in the original Cancer and Leukemia Group B protocol, which resulted in the recommendation to restrict HiDAC to patients <60 years (32) . Our data now show that IDAC can be administered to elderly AML patients as a safe approach. Other cytarabine-related side effects, including fever and exanthema, were also tolerable, and no consolidation cycle had to be interrupted because of drug-related nonhematological toxicity.
Treatment-associated hematological toxicity was determined by analyzing the duration of neutropenia (ANC < 500 cells/µl), days of neutropenic fever/cycle, and number of red cell and platelet concentrates. Chemotherapy-induced aplasia was observed in all patients receiving IDAC and required support with blood products in a way similar to patients treated with HiDAC. The duration of IDAC-induced severe neutropenia (ANC < 500 cells/µl) was moderate with a median of 9 days, which is a shorter compared with the neutropenic phase in other protocols.
Neutropenic fever and/or infections occurred in 55.2% of all consolidation cycles and thus represented the major toxicity observed during consolidation therapy with IDAC. However, none of our patients died from severe infection during postremission treatment. This is of particular interest because elderly patients are often considered to be more susceptible to life-threatening infections when treated with aggressive chemotherapy (5, 6, 7, 8, 9, 10) . Several possibilities for the relatively mild course of infections have to be considered. One possible reason may be the relatively late onset of neutropenia. Second, all patients received antibiotic prophylaxis, and in case of a history of severe infections during one of the preceding chemotherapy cycles, they also received prophylactic antimycotics. Third, patients with neutropenic fever and prolonged aplasia, as well as those who had a severe infection in one of their preceding chemotherapy cycles, received G-CSF. In this regard, it has to be taken into account that the use of G-CSF is likely of having influenced the duration of neutropenia.
Thus far, it remains unknown how many consolidation cycles are required to maintain long-term CR in patients with AML. In the original HiDAC protocol, a maximum of four cycles of consolidation were applied (32) . In the current study, the primary intention was also to give a total number of four IDAC consolidation cycles. In fact, we attempted to give all four cycles independent of the age of the patient. Indeed, the majority (53%) received all four cycles and another 19% received three cycles of IDAC. It is of interest that in the group of patients receiving three cycles, we were able to identify several patients who showed long-term DFS. Therefore, one could speculate that a reduction of the number of IDAC consolidation cycles to three may by equally effective compared with four cycles.
All in all, IDAC seems to be an effective and safe consolidation regimen for elderly patients with AML. Randomized studies are now required to further evaluate this new treatment strategy and to clarify the ideal number of courses to be applied.
FOOTNOTES
Grant support: Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich Grant P-14031.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Wolfgang R. Sperr, Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria. Phone: 43-1-40400-6085; Fax: 43-1-402-69-30; E-Mail: wolfgang.r.sperr{at}univie.ac.at
Received 1/30/04; revised 2/20/04; accepted 2/25/04.
REFERENCES
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  M.-T. Krauth, S. Florian, A. Bohm, K. Sonneck, H. Agis, P. Samorapoompichit, A. W. Hauswirth, W. R. Sperr, and P. Valent Immunological Characterization and Antibacterial Function of Persisting Granulocytes in Leukemic Patients Receiving Pulse Cytosine Arabinoside-Consolidation Chemotherapy on Days 1, 3, and 5 J. Immunol., February 1, 2006; 176(3): 1759 - 1768. [Abstract] [Full Text] [PDF]
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