Japanese Journal of Clinical Oncology Advance Access originally published online on September 19, 2005
Japanese Journal of Clinical Oncology 2005 35(10):612-616; doi:10.1093/jjco/hyi149
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© 2005 Foundation for Promotion of Cancer Research
Phase II Trial of Amsacrine Plus Intermediate-dose Ara-C (IDAC) with or without Etoposide as Salvage Therapy for Refractory or Relapsed Acute Leukemia
1 Department of Hematology/Oncology, 2 Stem Cell Transplantation Center, Kyungpook National University Hospital, Daegu, Korea
For reprints and all correspondence: Sang Kyun Sohn, Department of Hematology/Oncology, Kyungpook National University Hospital, 50 Samduk 2-ga, Jung-gu, Daegu 700-721, Korea. E-mail: sksohn{at}knu.ac.kr
Received May 12, 2005; accepted July 24, 2005
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Abstract |
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Objective: The current trial attempted to evaluate the efficacy and toxicity of a salvage therapy consisting of amsacrine plus intermediate-dose Ara-C (IDAC) with or without etoposide for acute leukemia patients in refractory or relapsed states.
Methods: A total of 51 patients with refractory or relapsed acute leukemia were included in the current trial. Twenty-nine patients with acute myeloid leukemia (AML) received a salvage therapy of amsacrine plus IDAC and etoposide, while 22 patients with acute lymphoblastic leukemia (ALL) received amsacrine plus IDAC.
Results: The overall complete remission rate was 55% (45% for AML, 68% for ALL) and the median duration of overall survival was 144 days (95% confidence interval = 101–186 days). Grade 3, 4 infectious toxicities were observed in 43 patients (87%), while treatment-related toxicity, excluding infectious causes, included heart failure from myocarditis (n = 1) and central nervous system toxicity (n = 1).
Conclusion: A salvage therapy consisting of amsacrine plus IDAC with or without etoposide appears to be safe and an effective bridge therapy into a stem cell transplantation programme for patients with refractory or relapsed acute leukemia.
Key Words: acute leukemia • salvage therapy • amsacrine • intermediate-dose Ara-C • etoposide
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Although the treatment outcome for patients with acute leukemia has substantially improved over the past decade, therapeutic failure or relapse remains a major concern. Patients with refractory or relapsed acute leukemia have a poor prognosis; however, a minority can be salvaged with secondary-line treatment or stem cell transplantation (SCT). As such, number of chemotherapeutic regimens have already been investigated for refractory or relapsed acute leukemia, and in patients with refractory or relapsed acute myeloid leukemia (AML) these regimens have resulted in complete remission (CR) rates ranging from 47 to 56% and median CR durations of 3–6 months (1,2), while in patients with refractory or relapsed acute lymphoblastic leukemia (ALL) they have produced CR rates ranging from 21 to 83% and median CR durations of 2–7 months (3–5). Therefore, despite a treatment response, the response duration is generally brief and the overall results unsatisfactory.
Accordingly, the current trial attempted to evaluate the efficacy and toxicity of amsacrine plus intermediate-dose Ara-C (IDAC) with or without etoposide in 51 patients with refractory and relapsed acute leukemia. The primary end point was the efficacy of the regimen, i.e. CR rate, and the secondary end points were the toxicity and survival of the patients.
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PATIENTS AND METHODS |
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PATIENTS
Between June 1998 and March 2003, 51 consecutive acute leukemic patients, 29 with AML and 22 with ALL, were enrolled on the current trial at the Hematology/Oncology Unit of Kyungpook National University Hospital. Among these patients, 11 (22%) were in primary refractory states after a remission induction regimen that consisted of a standard induction cycle, including idarubicin (12 mg/m2/day for 3 days) and cytarabine (100 mg/m2/day for 7 days) for AML, and adriamycin (45 mg/m2/day for 2 days), vincristine (2 mg/day on days 1 and 8) and prednisone (60 mg/m2/day for 21 days) for ALL. The remaining 40 patients (78%) were in relapsing states during the maintenance of CR, among which five had relapsed after SCT (allogeneic, 2; autologous, 3). Cytogenetic analyses of the marrow were performed at presentation, as previously described (6). The criteria used to describe a cytogenetic clone and karyotype followed the recommendations of the International System for Human Cytogenetic Nomenclature (7). The current study was approved by the Institutional Research Board of Kyungpook National University Hospital and each patient gave written informed consent.
SALVAGE THERAPY
The salvage therapy for AML consisted of amsacrine 100 mg/m2/day intravenously as a short infusion over 3 days (days 1–3), plus Ara-C 1 g/m2/12 h intravenously as a short infusion over 3 days (days 1–3) with etoposide 100 mg/m2/day intravenously as a short infusion over 5 days (days 1–5). Meanwhile, the salvage therapy for ALL consisted of amsacrine 150 mg/m2/day intravenously as a short infusion over 3 days (days 1–3) and Ara-C 2 g/m2/day intravenously as a short infusion over 5 days (days 1–5).
DEFINITIONS AND EVALUATION OF THERAPY
CR was defined as a normal peripheral blood count with <5% blast cells in the marrow for at least 1 month (8). Treatment failure was classified as a non-response, which included all patients with proven blastic regrowth after chemotherapy, even if they died before a blood count recovery, and other failure, corresponding to patients who presumably died of chemotherapy-related toxicity (9). Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v3.0 on a scale of 1–4 (10). The cytogenetic risk was classified according to the Medical Research Council 10 criteria (11).
STATISTICAL ANALYSIS
The basic statistical data were obtained using the SPSS software package (SPSS 10.0, Inc., Chicago, IL, USA). The duration of overall survival (OS) was calculated from the initiation of the salvage treatment until death from any cause. Disease-free survival (DFS) was calculated from date of CR until the end of follow-up, relapse or death while in CR. Patients who enrolled into a SCT programme in a CR state after the salvage therapy were counted as a censored case at the time of transplantation as regards DFS. The OS and DFS rates were estimated using the method of Kaplan and Meier. Statistical significance is represented by two-tailed P-values. A cut-off value of 0.05 was adopted for all statistical analyses.
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RESULTS |
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PATIENT CHARACTERISTICS
The characteristics of the 51 patients are summarized in Table 1. The study group consisted of 27 males and 24 females with a median age of 35 years (range 15–65 years). According to a cytogenetic classification of the 29 AML patients, 10 (34%) were classified as a favorable-risk group, 11 (38%) as an intermediate-risk group and 8 (28%) as an adverse-risk group. The Philadelphia chromosome was detected in five cases (23%) out of the 22 ALL patients. All patients were evaluable for the response and toxicity.
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RESPONSE RATE
Forty-two patients (82%) received a full dose of the salvage regimen, while nine patients (18%) received a 33% reduction of the original dosage due to old age (>55 years; n = 8) or chronic hepatitis B (n = 1). CR was achieved in 28 patients (13 AML and 15 ALL patients; Table 2). After achieving CR (n = 28), a consolidation schedule was administered based on the same schedule as the salvage regimen (n = 15) or SCT performed (n = 11; allogeneic, 9; autologous, 2).
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The median duration of DFS and OS was 1.5 months [95% confidence interval (CI) = 24–66 days] and 5 months (95% CI = 101–186 days), respectively. When last assessed, 11 patients who had achieved CR with the salvage therapy had relapsed. Only three patients survived long-term (months 14, 14 and 34; Fig. 1).
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Out of 11 patients receiving consecutive SCT after the salvage regimen, the transplant outcomes of the allogeneic SCT recipients (n = 9) are alive in CR (n = 1), deaths due to recurrence (n = 3), treatment-related mortality (TRM) (n = 2) and death due to opportunistic infection (n = 3), while that of the autologous SCT recipients (n = 2) are alive in recurrence (n = 1) and death due to recurrence (n = 1).
TOXICITY
The toxicities are summarized in Table 3. Grade 4 hematologic toxicity was observed in all patients. The median recovery time for the WBC (
1 x 109/l), neutrophils (0.5 x 109/l) and platelets (50 x 109/l) was 21 days (range 11–72 days), 21 days (range 12–72 days), and 25 days (range 15–90 days), respectively.
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Grade 3, 4 infectious toxicity was observed in 43 (87%) patients, among whom six died of infections related with neutropenia. Life-threatening toxicity was only observed in two patients: one of whom died from cardiac failure and the other from a hemorrhage. Other serious complications included Grade 4 myocarditis (n = 1) and Grade 4 confusion due to Ara-C-induced central nervous system toxicity (n = 1). In summary, eight patients (16%) suffered from treatment-related deaths from neutropenic infection (n = 6), cardiac failure (n = 1) and from hemorrhage (n = 1).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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This current study examined the efficacy and toxicity profile of amsacrine plus Ara-C with or without etoposide as a salvage therapy for acute leukemia patients in refractory/relapsed states. Overcoming drug resistance remains unsatisfactory in adult refractory or relapsed acute leukemia, even though allogeneic SCT can provide a chance to cure the disease. Therefore, the main purpose of a salvage therapy for acute leukemia is not only the achievement of CR but also bridging patients into an SCT programme without increasing organ toxicity.
Amsacrine [4'-(9-acridinylamino) methnanesulfon-m-anisidine] is an acridine derivative that was originally synthesized by Cain et al. (12) and found to have a potent antitumor activity against leukemic cells based on a mechanism of intercalation. Several phase- studies with amsacrine monotherapy have reported CR rates of 15–28% in refractory AML patients (13,14). Furthermore, amsacrine has been related to a lower incidence of cardiac events than anthracycline analogs (15), meaning that amsacrine would appear to be safe as regards cardiac toxicity in a salvage setting.
The introduction of high-dose Ara-C with amsacrine has been reported to increase the CR rate up to 75% in refractory or relapsed ALL patients according to a study by Arlin et al. (16). However, another report found that increasing the dose of cytarabine did not significantly improve the survival of patients when compared with high-dose Ara-C arm (3 g/m2 twice a day for 4 days, total 24 g/m2) followed by standard-dose Ara-C arm (100 mg/m2 for 5 days, total 500 mg/m2) in a consolidation setting, because of the profound toxicity of high-dose Ara-C arm (17). Meanwhile, Dekker et al. (18) reported a low toxicity for amsacrine plus IDAC therapy in refractory AML patients, and a CR rate of 67% and mild complications. As such, the current regimen, amsacrine plus IDAC with or without etoposide, was designed to reduce the regimen-related toxicity that can hinder a consecutive SCT, while maintaining the CR rate.
Mehta et al. (19) reported that a combination regimen consisting of idarubicin, high-dose Ara-C and etoposide was highly effective in newly diagnosed and relapsed AML. The addition of etoposide to anthracycline analogs (i.e. daunorubicin or mitoxantrone) and Ara-C has also improved the CR rates for AML (20).
In the present study, the CR rate (55%) was comparable to those in previous trials with other salvage regimens (21,22). The patients also exhibited a good tolerance and the toxicity profiles were generally acceptable and reversible. In addition, a relatively lower TRM was noted compared with other studies using high-dose Ara-C-based chemotherapy (23,24). The lower TRM than with a high-dose Ara-C-based regimen can be explained as follows: (i) Refractory or relapsed patients are relatively heavily treated cases, thus IDAC may prevent serious organ dysfunctions, such as hepatotoxicity or renal failure. (ii) The addition of amsacrine instead of anthracycline-derivatives may lower the cardiac toxicity of the patients. Thus, further development of this regimen including amsacrine plus IDAC needs to be investigated, such as the introduction of a granulocyte-colony stimulating factor into the regimen.
Although salvage therapies for acute leukemia may not be a definite treatment modality to eradicate remnant leukemic blasts, they can act as a bridge treatment to introduce patients to a transplantation programme in a CR state. Thus, when deciding a salvage therapy regimen, the safety profile should not be neglected in favor of the CR rate. Out of the current cohort, 11 patients underwent autologous or allogeneic SCT and none exhibited any serious clinical cardiac dysfunction based on an echocardiographic evaluation before transplantation. Even though these observations should be interpreted with caution, since objective cardiac functional evaluations were only conducted on patients with overt clinical manifestations of heart failure during the post-transplant period, the current regimen showed a similar CR rate and relatively lower TRM compared with previous trials adopting a higher dose of Ara-C (24). As such, the current regimen including amsacrine and IDAC appeared to be a suitable choice for SCT programme candidates.
In conclusion, a salvage regimen consisting of amsacrine plus IDAC with or without etoposide seemed to be a safe and effective regimen for patients with refractory or relapsed acute leukemia, and especially for SCT candidates, and the regimen may be valuable as regards organ dysfunction and TRM.
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Acknowledgments |
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The great work of our nursing staff is gratefully acknowledged.
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References |
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