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© 2002 American Society for Clinical Oncology Phase I Evaluation of Prolonged-Infusion Gemcitabine With Mitoxantrone for Relapsed or Refractory Acute LeukemiaByFrom the Division of Medical Oncology and Transplantation, Duke University Medical Center, and Duke Oncology Consortium, Durham, NC. Address reprint requests to David A. Rizzieri, MD, Division of Medical Oncology and Transplantation, Duke University Medical Center, Box 3961, Durham, NC 27710; email: rizzi003{at}mc.duke.edu
PURPOSE: To ascertain the maximum tolerated duration of infusion of gemcitabine at 10 mg/m2/min in combination with mitoxantrone at 12 mg/m2 daily for 3 days in the treatment of acute leukemia. PATIENTS AND METHODS: Thirty-four patients were enrolled. Stratum I consisted of 26 patients, median age 50 years (range, 25 to 71 years), with relapsed or refractory leukemia. Stratum II contained eight patients, median age 62.5 years (range, 38 to 83 years), who had received fewer than three cycles of myelotoxic therapy for chronic myeloid leukemia or myelodysplasia that had evolved into leukemia. Patients received mitoxantrone at 12 mg/m2 daily for 3 days. After the first mitoxantrone dose, gemcitabine was provided intravenously at 10 mg/m2/min with the duration adjusted by following a continuous reassessment model. RESULTS: Severe myelosuppression, and stomatitis or esophagitis were the most common hematologic and nonhematologic dose-limiting toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours (7,200 mg/m2). The mean steady-state concentration of gemcitabine was 24.72 µmol/L and varied over a fivefold range among patients. Overall response rates in this phase I trial for strata I and II were 42% and 63%, respectively. CONCLUSION: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m2/min for 12 hours with 12 mg/m2/d mitoxantrone for 3 days is a tolerable induction regimen and achieves plasma concentrations sufficient for maximal intracellular activation. Stomatitis or esophagitis should be anticipated; however, this regimen may induce significant responses in patients with difficult-to-treat leukemias.
ALTHOUGH CURRENT regimens for adult acute leukemias induce initial remissions in a majority of patients, most relapse and die as a result of disease.1,2 The potential for new drug combinations to provide better outcomes needs to be explored. Gemcitabine (2'2'-difluorodeoxyctidine) is a deoxycytidine analog shown to have activity in a range of solid tumors.3-8 The drug’s multiple mechanisms of action, particularly its so-called masked termination, make it attractive for investigation for hematologic malignancies as well.9-12 Various concentrations and dosing strategies have been evaluated in efforts to maximize activity. Incorporation into DNA has been found to increase in a dose-dependent manner as extracellular gemcitabine concentrations are increased to 15 to 20 µmol/L, where maximal accumulation occurs.11,13,14 Infusion rates of 10 mg/m2/min have been shown to produce this target extracellular concentration, which suggests that this dose rate may optimize antitumor efficacy.11,12 In mice with tumor xenografts, a 24-hour continuous intravenous infusion of gemcitabine showed higher efficacy than frequent discrete injections. In vitro studies demonstrate the benefit of longer exposure to gemcitabine as well.13 These studies suggest that a prolonged infusion of gemcitabine targeting the serum concentration that will maximize incorporation into DNA (15 to 20 µmol/L) might bring about a better antitumoral effect and support the approach taken in this trial. This phase I study investigated the toxicity and pharmacokinetics of a prolonged infusion of fixed-dose-rate gemcitabine in combination with mitoxantrone in patients with relapsed or refractory acute myelogenous leukemia (AML) or acute lymphocytic leukemia.
Patient Eligibility Adult patients were enrolled onto one of two strata that were escalated separately. Stratum I included patients with AML or acute lymphocytic leukemia whose cancer had failed to respond to at least one cycle of induction chemotherapy and who had more than 5% blasts in the bone marrow or peripheral blood. All patients in stratum I had received cytarabine before enrollment onto this trial. Stratum II included less heavily pretreated patients with chronic myelogenous leukemia (CML) in blast phase or those with myelodysplastic syndrome (MDS) that had progressed to leukemia. Patients in stratum II must have received two or fewer cycles of myelotoxic therapy or they were entered in stratum I. Other eligibility requirements included the following: liver function tests less than three times the upper limit of normal, unless related to the leukemia; estimated creatinine clearance more than 40 mg/mL; and Cancer and Leukemia Group B performance status of 0 to 3. Patients could not have received any other chemotherapy for a minimum of 1 week before initiation of therapy. Before starting chemotherapy, patients must have had adequately recovered from all prior chemotherapy-related toxicity. This typically resulted in patients not having been exposed to myelotoxic chemotherapy for at least 1 month before enrollment. All patients were required to provide written informed consent, and the protocol was approved by the local institutional review board.
Treatment
Statistical Analysis Toxicities were graded according to the National Cancer Institute Common Toxicity criteria, version 2. After every two patients had recovered from therapy, interim data were evaluated for occurrence of DLT to determine the estimated MTD. This determination guided the decision whether to increase or decrease the infusion duration of the next cohort. Duration modification was restricted to one level at a time. Use of this method typically results in a high proportion of patients treated near the MTD rather than an equal numbers at extremely high and extremely low durations. Further details of the proper use of this technique are referenced above. Initially, DLT required grade 4 nonhematologic toxicity lasting more than 7 days. However, our initial experience established that severe stomatitis or esophagitis lasting this long was not tolerable. Following established precedent,18 the trial was then amended in October 1998 so DLT included nonhematologic grade 4 toxicity lasting more than 3 days or grade 3 toxicity lasting more than 6 days. Patients treated before this were reevaluated using this new definition.
Patient Monitoring and Toxicity Assessment During therapy, patients were examined daily and complete blood counts were assessed daily until ANC was more than 500 x 106 cells/L and platelets were more than 10 x 109 cells/L on 3 consecutive days. After that, samples were taken a minimum of twice a week until platelets reached more than 20 x 109 cells/L for 1 week; then samples were taken weekly. Serum creatinine and liver function studies were observed daily while the patients were receiving chemotherapy and at least three times a week until recovery from therapy. Platelets were to be maintained at a minimum of 10 x 109 cells/L and the hematocrit kept above 25%. Bone marrow aspirate and biopsy with histologic and cytogenetic evaluation were repeated at days 11 to 14, and again when the ANC count recovered to more than 1,000 x 106 cells/L to assess whether an antileukemic effect was present.
Patient response was evaluated by examination of marrow and peripheral blood smears following the guidelines published by the National Cancer Institute.19 Complete response (CR) was defined as the absence of all leukemia on the basis of laboratory and bone marrow examinations performed at the time of myeloid (ANC > 1,500 x 106 cells/L) and platelet recovery (
Pharmacokinetic Evaluation Plasma concentrations of gemcitabine were determined by modification and validation of a previously published high-performance liquid chromatography method.20 Briefly, 35-µL samples of plasma were directly injected into a high-performance liquid chromatography system consisting of a Bondapack C-18 analytic column (Waters Associates, Milford, MA); 0.5 µmol/L ammonium acetate, isocratic mobile phase; and an ultraviolet detector set at 275 nm. The lower limit of quantitation for this technique was 9.6 µmol/L; the working linear range was 9.6 to 192 µmol/L. Intra- and interassay variabilities were 5.1% and 2.7%, respectively. Noncompartmental methods were used to estimate the systemic clearance of gemcitabine by a standard two-stage approach.
Patient Characteristics Characteristics of the 34 patients who entered this trial are summarized in Table 1. Patients were divided into two strata: those with de novo relapsed or refractory acute leukemia, and those with leukemia with a history of CML or MDS who had two or fewer cycles of myelotoxic therapy. Among the 26 patients with acute leukemia in stratum I, the median age was 49 years (range, 25 to 71 years). Stratum I contained 15 men and 11 women, and there were three African Americans. This group averaged 2.3 prior regimens (range, one to five regimens) and 4.2 prior cycles (range, two to nine cycles), and had all received cytarabine previously. Eight patients had undergone bone marrow transplantation (five autologous and three allogeneic). The average duration of first remission for this group was 7 months (range, 0 to 48 months); four of these patients had never attained remission previously. Among the eight patients in the less heavily pretreated stratum II, the median age was higher: 62.5 years (range, 38 to 83 years). Four of the eight patients had received prior therapy, and the average patient had previously received one myelotoxic regimen (range, zero to three regimens) and two cycles (range, zero to eight cycles) of therapy. Stratum II had equal numbers of men and women, and one patient was African American.
Toxicity Because of the possibility that patients in the more heavily pretreated stratum I would be less able to tolerate higher doses of therapy, the two strata were escalated separately. Myelosuppression occurred in nearly all patients, and patients who responded took an average of 4 weeks to recover normal peripheral blood counts. Five patients (19%) in stratum I developed culture-positive febrile neutropenia (two Staphylococcus, one Enterococcus, one Clostridium difficile, and one Stenotrophomonas), and one developed sepsis (Escherichia coli). Stratum II had two cases of documented infections (one streptococcus, one Staphylococcus) (25%). Severe stomatitis or esophagitis was the most common nonhematologic adverse event and was the primary cause of DLT (Table 2). Fifteen patients (58%) in stratum I had grade 2 to 4 stomatitis or esophagitis. In stratum II, two patients (25%) had grade 3 toxicity, and none had grade 4 stomatitis or esophagitis (Table 3). These effects all resolved within 2 weeks. Overall, the rates of stomatitis or esophagitis did not vary with hours of gemcitabine infusion (Table 4). When both strata are pooled, there was a significant increase in the rate of grade 2 to 4 esophagitis or stomatitis (67% v 31%) among those with four or more prior cycles of treatment (P = .04,  2 = 4.50).
Several gastrointestinal adverse effects were also common. These included elevated bilirubin levels, nausea, vomiting, and diarrhea (Table 3). In stratum I, 10 patients (38%) developed nausea, vomiting, or diarrhea. Another three patients (12%) had bilirubin elevated up to three times normal. In stratum II, there were two instances each (25%) of elevated bilirubin and nausea or vomiting. Several less common events were also noted. In stratum I, there was one episode each of anorexia not requiring parenteral support, elevated liver enzymes less than five times normal, pruritic rash covering less than 50% body surface, and dyspnea with normal activity. Among those in stratum II, there was one episode each of rash and dyspnea with significant exertion. The rashes were transient, and we were unable to determine their precise nature, given the patients’ multiple drug exposures. Five patients (15%) died during the course of treatment. In stratum I, two of the three patients treated with a 21-hour infusion died as a result of infections. One patient in the 6-hour cohort died as a result of an exacerbation of veno-occlusive disease after achieving a CR. This patient had a history of alcohol abuse and had developed veno-occlusive disease (clinically diagnosed and confirmed by biopsy) after a prior autologous bone marrow transplant. Another patient, treated with 18 hours of infusion, died from progression of disease before recovery from chemotherapy. A 70-year-old woman in stratum II who had received two prior cycles of therapy died as a result of pulmonary hemorrhage after treatment with 12 hours of gemcitabine (Table 4). Given the similar rates of DLT in the two strata, our group considers the 12-hour gemcitabine infusion to be the MTD for both groups of patients when given with a 3-day course of mitoxantrone. On the basis of the continuous reassessment method, for patients in stratum I, the estimated risk of developing DLT with 12 hours of gemcitabine was 34.1% (90% prediction interval, 15.3% to 56.0%). Because of the small rate of DLT in stratum II, insufficient information existed to estimate risks for these patients.
Pharmacokinetic Data
Antileukemic Activity Forty-two percent of patients in stratum I and 63% of those in stratum II experienced a clinical response, as demonstrated by a CR or partial response (Table 2). In those with prior CML or MDS, five of eight demonstrated responses, and one patient died. A total of 16 patients were treated with 12 hours of gemcitabine; CR was produced in five (31%; 95% confidence interval, 11% to 59%). Among the nine patients who achieved a CR, seven had previously received myelotoxic therapy. However, only three of these nine patients had previously achieved a CR lasting more than 4 months. Patients who obtained a CR required 3 to 4 weeks after chemotherapy for count recovery. All responders were offered consolidative therapy; therefore, the duration of response to this one cycle of therapy cannot be determined.
Traditional induction regimens for leukemia, such as combination therapy of cytarabine and an anthracycline, consistently lead to CR; however, relapse is common. Only 25% to 45% of patients younger than 60 years remain in CR at 4 years.21,22 Patients who develop AML out of preexisting MDS have even worse responses.23 New approaches are needed to address this problem. This trial demonstrates that in patients with acute leukemia receiving three daily 30-minute intravenous doses of mitoxantrone at 12 mg/m2, a 12-hour infusion of gemcitabine given at 10 mg/m2/min (7,200 mg/m2) is the maximum recommended duration of infusion. This regimen was associated primarily with gastrointestinal and integument toxicities. Myelosuppression and febrile neutropenia were common, although they generally resolved within 3 to 4 weeks. The most significant nonhematologic toxicity was stomatitis or esophagitis, which occurred in 58% and 25% of strata I and II, respectively. Patients typically experienced onset of this adverse event within 1 week of completing chemotherapy, and they resolved within 2 weeks. This reaction was more common in those who underwent more than five cycles of prior therapy. Newer agents in development to minimize chemotherapy-induced mucosal damage may help improve the toxicity of this regimen. Other significant toxicities included nausea, vomiting, and diarrhea. These generally subsided within 2 weeks, and only three patients required intravenous fluids. Several patients experienced transient elevations of bilirubin and liver enzymes. No patients suffered any of the neurologic complications that have been described in patients receiving high-dose cytarabine.18 Pharmacokinetic studies showed that this infusion schedule provided patients with a mean plasma gemcitabine concentration of 25 µmol/L; however, a high degree of variability was observed, consistent with that found on other studies.24 Approximately 70% of patients had concentrations above the target of 15 to 20 µmol/L. Larger investigations with the same duration can further evaluate the affect variable steady-state levels may have on toxicity or efficacy. Because the maximally tolerated infusion duration is 12 hours and the analytic technique used here relatively simple and efficient, it is possible to perform dose individualization with this regimen if further investigation notes potential for improved outcome by assuring that the target steady-state values are attained. Although this is a phase I study, the clinical responses are highly encouraging. In stratum II, five (63%) of eight patients responded, and four of these experienced a CR. Eleven (42%) of 26 responded in stratum I, and five of the 11 responders experienced a CR. Mitoxantrone monotherapy has been shown to have varying responses in patients with refractory AML or who have experienced relapse. Moore and Olsen25 showed an overall 29% CR rate in 38 patients with relapsed AML treated with mitoxantrone. The responses seen in this trial are likely due to the additive effects of these agents that can be demonstrated with in vitro analyses (D.J. Adams and D.A. Rizzieri, unpublished data). The toxicity of this regimen is acceptable, and the regimen is worthy of further clinical study.
Supported in part by Eli Lilly and Co, Indianapolis, IN, and Immunex, Seattle, WA.
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Miller AA, Lilenbaum RC, Lynch TJ, et al: Treatment related fatal sepsis from topotecan/cisplatin and topotecan/paclitaxel. J Clin Oncol 14: 1964-1969, 1996 19. Cheson BD, Cassileth PA, Head DR, et al: Report of the National Cancer Institute–sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8: 813-819, 1990[Abstract] 20. Abbruzzese JL, Grunewald R, Weeks EA, et al: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 9: 491-498, 1991[Abstract] 21. Mayer RJ, Davis RB, Schiffer CA, et al: Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 331: 14896-14903, 1994 22. Bennett JM, Young ML, Anderson JW, et al: Long term survival in acute myeloid leukemia. Cancer 80: 2205-2209, 1997[CrossRef][Medline] 23. Economopoulos T, Papageorgiou E, Stathakis N, et al: Treatment of high risk myelodysplastic syndromes with idarubicin and cytosine arabinoside supported by granulocyte colony stimulating factor (GM-CSF). Leuk Res 20: 385-390, 1996[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
100 x 109 cells/L). These criteria require the marrow to have more than 20% cellularity and all lines maturing, no Auer rods detected, less than 5% blasts in the bone marrow, and no abnormal blasts in the peripheral blood for at least 1 month after myeloid recovery. A partial response was defined as less than 25% blasts on bone marrow examination performed at the time of myeloid recovery, but with an insufficient decrease for the response to be classified as a CR. 
