the Nagoya University Graduate School of Medicine, Nagoya
    Nihon University School of Medicine, Tokyo
    Toyohashi Municipal Hospital, Toyohashi
    Tokyo Metropolitan Komagome Hospital and Jikei University School of Medicine, Tokyo
    Saitama Medical School, Saitama
    Mie University Graduate School of Medicine, Tsu
    Kurashiki Central Hospital, Kurashiki
    Minami-Okayama Medical Center, Okayama
    Saiseikai Maebashi Hospital, Maebashi
    Kanagawa Cancer Center, Yokohama
    Nagasaki University Graduate School of Biomedical Sciences, Nagasaki
    Kanazawa University Graduate School of Medicine, Kanazawa
    Aichi Cancer Center, Nagoya, Japan

    ABSTRACT

    PURPOSE: A novel therapeutic approach is urgently needed for BCR-ABL–positive acute lymphoblastic leukemia (ALL). In this study, we assessed the efficacy and feasibility of chemotherapy combined with imatinib.

    PATIENTS AND METHODS: A phase II study of imatinib-combined chemotherapy was conducted for newly diagnosed BCR-ABL–positive ALL in adults. Eighty patients were entered into the trial between September 2002 and January 2005.

    RESULTS: Remission induction therapy resulted in complete remission (CR) in 77 patients (96.2%), resistant disease in one patient, and early death in two patients, as well as polymerase chain reaction negativity of bone marrow in 71.3%. The profile and incidence of severe toxicity were not different from those associated with our historic chemotherapy-alone regimen. Relapse occurred in 20 patients after median CR duration of 5.2 months. Allogeneic hematopoietic stem-cell transplantation (HSCT) was performed for 49 patients, 39 of whom underwent transplantation during their first CR. The 1-year event-free and overall survival (OS) rates were estimated to be 60.0%, and 76.1%, respectively, which were significantly better than those for our historic controls treated with chemotherapy alone (P < .0001 for both). Among the current trial patients, the probability for OS at 1 year was 73.3% for those who underwent allogeneic HSCT, and 84.8% for those who did not.

    CONCLUSION: Our results demonstrated that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL–positive ALL. Despite a relatively short period of observation, a major potential of this treatment is recognized. Longer follow-up is required to determine its overall effect on survival.

    INTRODUCTION

    Philadelphia chromosome (Ph) is a translocation abnormality leading to the formation of the BCR-ABL gene rearrangement.1-5 The product of this fusion gene is a constitutively active protein tyrosine kinase, which plays a critical role in leukemogenesis. This genetic abnormality occurs in up to 30% of adult acute lymphoblastic leukemia (ALL), and its presence is known to be the most adverse prognostic factor for ALL.5-14 Because long-term survival cannot be achieved by conventional chemotherapy alone, there is a clear medical need for alternative treatment approaches.

    Imatinib is a potent selective inhibitor of the BCR-ABL protein kinase, and it has been reported that single-agent imatinib induced response in a substantial proportion of Ph-positive ALL (Ph+ALL) patients, but that the response was not durable.15,16 Several groups are currently exploring the effects of combining imatinib and chemotherapy.17-20 We recently reported our preliminary results for 24 patients with newly-diagnosed BCR-ABL–positive ALL treated with imatinib-combined regimen,18 which showed that the treatment was well-tolerated, that complete remission (CR) was achieved in 96% of the subjects, and that 78% of patients achieved polymerase chain reaction (PCR) negativity in bone marrow. This was followed by the recruitment of 80 preplanned patients for the study reported here. In this article, we present the results of our phase II study designed to assess the clinical effect of imatinib-combined regimen on newly-diagnosed BCR-ABL–positive ALL, and compare these results with those of our historic controls treated with chemotherapy alone.

    PATIENTS AND METHODS

    Patients

    This study was conducted with patients aged between 15 and 64 years with newly diagnosed BCR-ABL–positive ALL. Eligibility criteria included adequate functioning of the liver (serum bilirubin level < 34.2 μmol/L [2.0 mg/dL]), kidneys (serum creatinine level < 152.50 μmol/L [2.0 mg/dL]), and heart (left ventricular ejection fraction > 50% and no severe abnormalities detected on ECGs and echocardiographs) and an Eastern Cooperative Oncology Group performance status between 0 and 3. Written informed consent was obtained from all patients before registration.

    Study Design and Treatments

    The design of the Japan Adult Leukemia Study Group (JALSG) ALL202 study has previously been described in detail.18 Following registration, pretreatment bone marrow (BM) was subjected to the multiplex reverse transcription (RT) -PCR test, and patients were treated differently according to age and the BCR-ABL diagnosis results. All patients positive for BCR-ABL were treated with the Ph regimen as presented in Table 1. For remission induction therapy, imatinib was administered from day 8 to day 63 in combination with other anticancer agents. Consolidation therapy consisted of an odd course (C1) comprising high-dose methotrexate (MTX) and high-dose cytarabine (Ara-C) and an even course (C2) with single-agent imatinib for 28 days. C1 and C2 were alternated for four cycles each. For the initiation of the first consolidation course, neutrophil counts of 1,500/μL and platelet counts of 100,000/μL were required, as were neutrophil counts of 1,000/μL and platelet counts of at 80,000/μL for the initiation of the subsequent courses. After the completion of the consolidation therapy, patients received maintenance therapy consisting of vincristine, prednisolone, and imatinib up to 2 years from the date they had attained CR. The daily dose of imatinib used in this study was 600 mg. Dose modification was generally based on the following conditions. During remission induction courses, for grades 3 or 4 nonhematologic toxicity, administration was interrupted until recovery to grade 1 or better, and then resumed at 600 mg/d. If grades 3 or 4 toxicity recurred after resuming, dose reduction was implemented. For hematologic toxicity, dose modification was not essentially considered, but was allowed when grade 4 neutropenia persisting longer than 3 weeks occurred. During consolidation or maintenance courses, for grades 3 or 4 neutropenia and thrombocytopenia, administration was interrupted until recovery to grade 2 or better, and then resumed at 600 mg/d, and for nonhematologic toxicity, the procedure similar to that for remission induction courses was used. CNS prophylaxis was attained by means of intrathecal (IT) injection of MTX, Ara-C, and dexamethasone during the remission induction course and each consolidation course (nine times in total). Patients with symptomatic or cytologic evidence of CNS leukemia received additional IT injections with or without whole cranial irradiation. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended if a human leucocyte antigen (HLA)-identical sibling donor was available and was allowed from an alternative donor. The protocol was reviewed and approved by the institutional review board of each of the participating centers and was conducted in accordance with the Declaration of Helsinki.

    Quantitation of BCR-ABL Transcripts

    The numbers of BCR-ABL copies in BM samples was assessed with the real-time quantitative RT-PCR (RQ-PCR) test at diagnosis, on days 28 and 63 of the remission induction course, after the first and third cycles of C1 and C2, after 1 year of treatment, and at the end of the entire therapy course at a central laboratory. Total RNA was extracted from mononuclear cells and transcribed to cDNA according to the manufacturer's instructions. The RQ-PCR assay was performed with the aid of TaqMan technology (PE Biosystems, Foster City, CA). The primers and the detection probes were described in a previous paper.18 The number of transcript copies was normalized by means of glyceraldehyde 3-phosphate dehydrogenase, and converted into molecules/μg RNA. The threshold for quantification was 50 copies/μg RNA, which corresponded to a sensitivity of 10–5. The levels below the threshold were differentiated into not detected and detected but not quantifiable, and PCR negativity was categorized as the former.

    Evaluation of Patients

    CR was defined as the presence of all of the following: less than 5% of blasts in BM, no leukemic blasts in peripheral blood (PB), recovery of PB values to neutrophil counts of at least 1,500/μL and platelet counts of at least 100,000/μL, and no evidence of extramedullary leukemia. Relapse was defined as the presence of at least one of the following: recurrence of more than 10% leukemic cells in BM or any leukemic cells in PB or extramedullary sites. Toxicity evaluation was based on the National Cancer Institute Common Toxicity Criteria Version 2.0.

    Statistical Analysis

    The primary end point of this study was the CR rate. We used Simon's optimal two-stage design21 to calculate the sample size. Regarding that the CR rate was 51% for Ph+ALL patients treated with chemotherapy alone in the JALSG ALL93 study,13 which had employed the eligibility criteria similar to that of the current study, we set an expected CR rate of 60% and a threshold CR rate of 45%, and estimated that 77 patients would be needed under conditions of two-tailed  = .05 and one-tailed  = .80. If the number of patients who achieved CR exceeded 12 among the first 24, recruitment was continued as originally planned, and the treatment was considered effective if 42 or more patients achieved CR among 77 patients. Toxicity, response duration, and survival were the secondary end points.

    Event-free survival (EFS) was defined as the time from the first day of therapy to induction failure, relapse, death, or last visit, and overall survival (OS) as the time from the first day of therapy to death or last visit. Kaplan-Meier survival analysis was performed to estimate the probabilities of EFS and OS. Differences between the curves were compared by means of the log-rank test. The results for Ph+ALL patients in the JALSG ALL93 study13 were used as historic controls. Comparisons of baseline characteristics of the two groups were made with the 2 or Fisher's exact tests for categoric variables, and with the Mann-Whitney U test for continuous variables. StatView 5.0 (SAS Institute Inc, Cary, NC) was used for all statistical analyses.

    RESULTS

    Patient Characteristics

    Between September 2002 and January 2005, 80 patients with newly diagnosed BCR-ABL–positive ALL were entered onto the trial. The characteristics of the patients are listed in Table 2. There were 49 males and 31 females with a median age of 48 years (range, 15 to 63 years). Three patients had CNS leukemia at diagnosis. As for the transcript types, two patients who expressed major and minor BCR-ABLs, concurrently, were considered to be positive for major BCR-ABL in the subsequent analysis. Of the remaining 78 patients, 21 patients were positive for major BCR-ABL and 56 for minor BCR-ABL, while the type of one patient could not be determined because fluorescent in situ hybridization analysis was used instead of the PCR test. Patients with minor BCR-ABL tended to have a higher percentage of PB blasts (P = .0021) and a higher level of BCR-ABL transcripts (P < .0001). Median follow-up was 13.1 months (range, 2.2 to 35.3 months) for surviving patients, and 12.0 months (range, 0.3 to 35.3 months) for the patients overall.

    Response to Therapy

    CR was achieved in 77 of 80 patients (96.2%; Table 3). The median time to CR was 28 days (range, 19 to 69 days). Two early deaths occurred during the remission induction course, and one patient, for whom imatinib had to be discontinued because of ileus, did not reach CR after completing the remission induction therapy. The CR rate for our trial group was significantly higher than the 51% achieved for 51 patients treated with chemotherapy alone in the JALSG ALL93 study (P < .0001).13 The results of RQ-PCR are summarized in Table 3. PCR negativity was confirmed for 18 of 68 samples (26.4%) on day 28, and for 33 of 66 samples (50.0%) on day 63.

    Toxicity

    Severe toxicity associated with the remission induction therapy was not different from that observed with conventional chemotherapy. For patients who attained CR, the median time of neutrophil recovery to at least 1,000/μL from the start of treatment was 17 days (range, 9 to 54 days), and the median time of platelet recovery to at least 100,000/μL was 22.5 days (range, 13 to 38 days). The profile and incidence of grades 3 to 4 nonhematologic toxicity are presented in Table 4. Two early deaths occurred during the induction course. One patient (32 years old) died of pulmonary bleeding on day 10, and the other patient (44 years old) died of pneumonia on day 31. Including these two patients, 21 patients (26.2%) required interruption of imatinib during the remission induction course, because of liver dysfunction (n = 6), nausea (n = 4), multiple organ failure secondary to life-threatening infection (n = 3), persistent neutropenia (n = 2), ileus (n = 2), pulmonary bleeding (n = 1), pancreatitis (n = 1), fluid retention (n = 1), and skin rash (n = 1). The median duration of interruption was 9.5 days (range, 6 to 18 days) for liver dysfunction, and 10 days (range, 5 to 26 days) for nausea. Both of the patients who discontinued imatinib because of neutropenia resumed the drug after 13 and 14 days of interruption, respectively. None of the patients had to withdraw from the study at any time because of these adverse events.

    Survival

    EFS and OS at 1 year were estimated to be 60.0% with an SE of 6.1%, and 76.1% with an SE of 5.5%, respectively. Allogeneic HSCT had been performed for 49 patients (18 from a sibling donor, one from a related donor other than a sibling, 21 from an unrelated donor, and nine from unrelated cord blood), 39 of whom (48.8%) underwent transplantation during first CR with the median duration from achieving CR to transplantation of 3.9 months (range, 1.2 to 18.0 months). Two patients received allogeneic HSCT during second CR, and the remaining eight patients did so with active disease. The probability for OS at 1 year was 73.3% with an SE of 6.9% for those who underwent allogeneic HSCT and 84.8% with and SE of 7.1% for those who did not (P = .9416). Of the 20 patients who experienced relapse, 17 were nontransplant patients at the time of relapse. Median CR duration for the 17 patients was 4.0 months (range, 2.8 to 12.4 months). Twenty-three patients died because of disease progression (n = 6), complications during remission induction therapy (n = 2), transplant-related causes (n = 13), external causes (n = 2; melanoma and suicide). No significant effect of age, initial WBC counts, or type of BCR-ABL transcripts on survival duration was shown. During the follow-up period, 57 patients (71.3%) demonstrated PCR negativity at least at one time point without HSCT, and 39 patients (48.8%) at least at two consecutive points. Among the 57 patients who achieved PCR negativity, 17 patients experienced recurrence of detection thereafter. Of them, seven patients had a relapse, six patients proceeded to allogeneic HSCT during first CR, and four patients remained disease-free without transplantation. When the four patients had a recurrence, the transcript levels were detected but not quantifiable in three patients and 87 copies/μg RNA in one patient, without successive positive results. Of 39 patients who had at least two consecutive PCR negative results, relapse occurred in eight patients.

    Next, the outcomes for the trial group were compared with those for historic control patients from the JALSG ALL93 study.13 Kaplan-Meier curves for EFS and OS are shown in Figure 1. Superiority of trial cases over controls was statistically significant for both outcomes (P < .0001 for both). Separate analyses of those who underwent allogeneic HSCT and those who did not were performed and the results are shown in Figures 2 and 3. For the comparison of allogeneic HSCT, only those who had received transplantation during first CR were considered. The probability of OS was almost identical (P = .4820) in patients who underwent allogeneic HSCT with/without imatinib, but differed significantly for those who did not receive allogeneic HSCT (P = .0006).

    DISCUSSION

    Recent studies have indicated that children with Ph+ALL can be cured by chemotherapy alone, if they have low WBC counts at diagnosis or good initial response to treatment.22,23 There is a general agreement, however, that allogeneic HSCT is the only curative form of treatment available for adults with this disease. An additional and important consideration is that outcomes after allogeneic HSCT are strongly affected by disease status at the time of transplantation, and results remain poor for refractory or relapsing disease.24-27 This points out the urgent need for an effective therapy to provide a transition to subsequent allogeneic HSCT. In addition, the fact that a substantial proportion of patients do not qualify for allogeneic HSCT because of a lack of a suitable donor, advanced age, or underlying medical conditions, proves that a nontransplant therapy with curative potential is also warranted. As a novel agent for the treatment of this disease, imatinib has been the subject of eager anticipation because of its unique mechanism of action as well as acceptable toxicity profile and antileukemic activity demonstrated in the phase I and phase II single-agent studies.15,16 Findings that single-agent treatment induced response in more than 50% of patients, but that the response was not durable,15,16 prompted us to plan a phase II study to assess the efficacy and feasibility of imatinib-combined regimen for newly-diagnosed BCR-ABL–positive ALL. Response to treatment was excellent with CR and PCR negativity achieving rates of 96.2% and 71.3%, respectively. These results have confirmed our preliminary observations.18 Some chemotherapy-alone studies reported high CR rates up to 90% for Ph+ALL,8,10,14,28 however, when compared with our own historic patients, the CR rate achieved in this study was significantly higher. It should be noted that other groups, such as the M.D. Anderson Cancer Center (Houston, TX)29 and the German Multicenter ALL Study Group19 also reported CR rates exceeding 90% and PCR negativity rates around 50% by imatinib-combined chemotherapy.

    By contrast, imatinib-combined regimen was not found to exert any synergistic action with respect to adverse effects. Hematopoietic recovery was not delayed, and adverse events thought to be caused by imatinib such as liver dysfunction, fluid retention, skin rash, and nausea could be managed with supportive care or temporary interruption of the drug. Thus, clinical feasibility of the treatment was also confirmed in this study.

    For survival, imatinib-combined regimen appears to be superior to conventional chemotherapy, a superiority that may be attributed not only to the higher response rate but also to the lower incidence of relapse. In fact, 39 patients could receive allogeneic HSCT during their CR1, currently, the best option for long-term survival. Although comparison with historic controls showed no significant differences in OS for those who underwent allogeneic HSCT, patients treated with imatinib-combined regimen had an advantage in that transplant candidates had a better chance to receive allogeneic HSCT. Furthermore, advantages also appear to exist for those who are not candidates for transplantation. Among those who did not undergo allogeneic HSCT, patients treated with the combination therapy had significantly better survival than those treated with chemotherapy alone. When interpreting the results regarding survival, we should be cautious because of a relatively short observation period, which is a major limitation of this study. However, our findings indicate that the effect of this treatment is, at least in the short-term, comparable with that of allogeneic HSCT. Although longer follow-up is required to determine its effect on survival, this treatment clearly has a major potential to improve the treatment of Ph+ALL, one of the most therapeutically challenging hematologic diseases for which an effective treatment is yet to be developed.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Masamitsu Yanada, Jin Takeuchi, Noriko Usui, Fumiharu Yagasaki, Shuichi Miyawaki, Shigeki Ohtake, Itsuro Jinnai, Keitaro Matsuo, Ryuzo Ohno

    Administrative support: Masamitsu Yanada, Nobuhiko Emi, Tomoki Naoe

    Provision of study materials or patients: Jin Takeuchi, Isamu Sugiura, Hideki Akiyama, Noriko Usui, Fumiharu Yagasaki, Tohru Kobayashi, Yasunori Ueda, Makoto Takeuchi, Shuichi Miyawaki, Atsuo Maruta, Yasushi Miyazaki, Shigeki Ohtake

    Collection and assembly of data: Masamitsu Yanada, Isamu Sugiura, Hideki Akiyama, Noriko Usui, Fumiharu Yagasaki, Tohru Kobayashi, Yasunori Ueda, Makoto Takeuchi, Shuichi Miyawaki, Atsuo Maruta, Yasushi Miyazaki, Shigeki Ohtake

    Data analysis and interpretation: Masamitsu Yanada, Keitaro Matsuo, Ryuzo Ohno

    Manuscript writing: Masamitsu Yanada, Tomoki Naoe, Ryuzo Ohno

    Final approval of manuscript: Masamitsu Yanada, Jin Takeuchi, Isamu Sugiura, Hideki Akiyama, Noriko Usui, Fumiharu Yagasaki, Tohru Kobayashi, Yasunori Ueda, Makoto Takeuchi, Shuichi Miyawaki, Atsuo Maruta, Nobuhiko Emi, Yasushi Miyazaki, Shigeki Ohtake, Itsuro Jinnai, Keitaro Matsuo, Tomoki Naoe, Ryuzo Ohno

    Acknowledgment

    We thank Masayuki Towatari, MD and all physicians and staff at the participating centers. We also thank Yukie Konishi, Hideko Noguchi, and Yuko Makino for their secretarial assistance. Imatinib used in this study was kindly provided by Novartis Pharmaceuticals (Basel, Switzerland).

    NOTES

    Supported by the Grants for cancer from Ministry of Health, Welfare, and Labor and by the Grant for cancer Translational Research Project from Ministry of Education, Culture, Sports, Science, and Technology, Government of Japan.

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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