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Phase I Evaluation of Prolonged-Infusion Gemcitabine With Irinotecan for Relapsed or Refractory Leukemia or Lymphoma

From the Division of Medical Oncology and Transplantation, Duke University Medical Center, and the 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

	ABSTRACT

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PURPOSE: To estimate the maximum-tolerated duration of infusion of gemcitabine at 10 mg/m²/min in combination with irinotecan at 40 mg/m² daily for 3 days in the treatment of relapsed or refractory acute leukemia or lymphoma.

PATIENTS AND METHODS: Patients with leukemia or lymphoma were escalated in separate strata. Stratum I consisted of 11 patients, median age of 47 years (range, 18 to 68 years), with relapsed or refractory leukemia. Stratum II contained nine patients, median age of 48 years (range, 39 to 68 years), who had refractory non-Hodgkin’s lymphoma. Patients received irinotecan at 40 mg/m² daily for 3 days, beginning just before the first dose of gemcitabine. Gemcitabine was given at 10 mg/m²/min, with the total duration adjusted following a modified continuous reassessment model.

RESULTS: Severe myelosuppression and stomatitis/esophagitis were the most serious hematologic and nonhematologic toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours delivered at 10 mg/m²/min (7,200 mg/m²). The overall response rate for one cycle of this therapy in this phase I trial for patients with leukemia was 18% (95% confidence interval, 8% to 45%), and for those with lymphoma, 33% (95% confidence interval, 17% to 66%).

CONCLUSION: A prolonged infusion of gemcitabine at 10 mg/m²/min for 12 hours with 3 days of irinotecan at 40 mg/m²/d is a tolerable induction regimen for patients with acute leukemia or lymphoma. Stomatitis/esophagitis should be anticipated; however, this regimen may induce responses in patients with difficult-to-treat hematologic malignancies.

	INTRODUCTION

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CURRENT TREATMENT OF relapsed or refractory hematologic malignancies induces some responses but creates few long-term remissions without using high-dose therapy requiring hematopoietic support.^1,2 New combinations should be explored to improve the long-term outlook for patients.

Gemcitabine (2'2'-defluorodeoxycytidine) is a novel deoxycytidine analog shown to have activity in a range of solid tumors.^3-8 Gemcitabine has been traditionally administered in 30-minute infusions. However, several studies have suggested that prolonged infusions may increase the efficacy of treatment.^9,10 Other investigators have explored the unique and attractive properties of using a prolonged infusion of gemcitabine in the treatment of leukemia (V. Ghandi, personal communication, July 2001). Experience using the prolonged infusion at a constant dose rate demonstrates that significantly more drug is tolerated and there is a prolonged effect in the patient, relating to increased opportunities to induce cell damage. Our group has completed further in vitro work with combinations of gemcitabine with other agents in the treatment of hematologic malignancies (D.J.A., unpublished data). Additive or synergistic activity can be noted with various other drugs, including the camptothecin derivative irinotecan, a topoisomerase I inhibitor.

Few reports are available assessing irinotecan’s single-agent activity for patients with hematologic malignancies, but one phase II study has shown 33% and 25% response rates in less heavily pretreated patients with relapsed lymphoma and acute leukemia, respectively.¹¹ Continued work from the investigators from this original phase II study has shown similar results.^12,13 This phase I study investigates the toxicity and feasibility of administering a prolonged infusion of a fixed dose rate of gemcitabine in combination with irinotecan in patients with relapsed or refractory acute leukemia (acute myeloid leukemia or acute lymphocytic leukemia) or non-Hodgkin’s lymphoma (NHL).

	PATIENTS AND METHODS

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Patient Eligibility
Adult patients with relapsed or refractory leukemia or NHL were eligible for this study. The duration of gemcitabine infusion was escalated independently in these two groups. Stratum I included patients with histologically confirmed acute leukemia who had failed at least one cycle of induction chemotherapy and had more than 5% blasts in the bone marrow or peripheral blood unrelated to recovery of normal hematopoiesis from prior chemotherapy. Stratum II included patients with relapsed or refractory NHL who at the time of enrollment were not considered good candidates for alternative curative therapy such as high-dose therapy with autologous support.

Other eligibility requirements included the following: AST, ALT, alkaline phosphatase, and total bilirubin levels less than three times the upper limit of normal, unless related to the leukemia; estimated creatinine clearance more than 40 mg/mL; Cancer and Leukemia Group B performance status of 0 to 2; and estimated life expectancy 5 weeks. Peripheral cell counts of WBCs 2,000 x 10⁹/L, platelets 80,000 x 10⁹/L, and hematocrit 25% were required, unless it was documented by the treating team that the low counts were because of bone marrow involvement or the disease process. Those with known Gilbert’s disease were excluded because they are prone to excessive irinotecan-induced toxicity. Patients with active CNS involvement with disease were eligible if they met all other criteria. Adequate methods to prevent pregnancy were mandated, and female patients were required to have a negative serum beta human chorionic gonadotropin test before entry. Patients were not allowed to be taking phenytoin, carbamazepine, or phenobarbital while receiving chemotherapy. Those with other psychiatric or medical illnesses that would have prevented them from complying with the protocol were excluded. Patients could not have received other chemotherapy for 1 week before initiation of therapy. Before starting chemotherapy, patients must have adequately recovered from prior therapy, as judged by the treating physician. The protocol was approved by the Duke University Institutional Review Board and Cancer Center Protocol Committee, and all patients were required to provide written informed consent before initiating therapy.

Treatment
On entry, all patients received hydration and were given allopurinol at the discretion of the treating physician. Prophylactic antiemetics were given to all patients, although prochlorperazine was not given on any day of irinotecan administration because of its association with akathisia. Irinotecan (US Pharmacia, Peapack, NJ) was administered intravenously at 40 mg/m² over 60 minutes daily for 3 days. Intravenous gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) at 10 mg/m²/min was begun immediately after the first dose of irinotecan. The first leukemia patient received a 9-hour gemcitabine infusion (3,600 mg/m²), and the first lymphoma patient received a 12-hour infusion (2,400 mg/m²). Subsequent patients received longer or shorter infusion durations as directed using the modified continuous reassessment model (mCRM). Patients with leukemia were given granulocyte colony-stimulating factor (G-CSF) (Neupogen; Amgen, Inc, Thousand Oaks, CA) subcutaneously at 5 µg/kg/d beginning on days 11 to 14. G-CSF was continued until the absolute neutrophil count (ANC) was greater than 1,500 x 10⁶ cells/L for at least 2 days, and it could then be stopped at the discretion of the treating physician. Patients in the NHL stratum received G-CSF at 5 µg/kg/d beginning 24 hours after the completion of all chemotherapy. All patients were instructed to begin taking loperamide at the earliest signs of diarrhea and/or abdominal cramping occurring more than 8 hours after receiving irinotecan. Lacrimation, diaphoresis, abdominal cramping, diarrhea, or other symptoms of early cholinergic syndrome that occurred during or within 1 hour after receiving irinotecan could be treated with intravenous atropine (0.25 to 1 mg intravenously or as indicated). Fungal and viral prophylaxis could be given at the discretion of the treating physician. Patients showing evidence of response as outlined below were permitted to receive a second cycle at the same dose and duration of infusion if the maximum-tolerated duration (MTD) of gemcitabine infusion had not been exceeded.

Statistics
This study determined patient dosing using an mCRM.¹⁴ The end point of the study was the estimate of the MTD of gemcitabine infusion given as a prolonged infusion at the fixed dose rate of 10 mg/m²/min in combination with irinotecan daily for 3 days. The MTD was defined as the duration of gemcitabine that caused a dose-limiting toxicity (DLT) in one third of patients. The logistic function with fixed intercept equal to 3 approximated the underlying dose-toxicity curve. Patients were escalated in 3-hour increments for the duration of infusion. After each patient was treated and toxicity was assessed, the model determined whether the subsequent patient was to be treated at the same dose or at a dose higher or lower than the last patient. Duration modification was restricted to one level (3-hour differences in duration) at a time. Thus, with this model, a minimum of one patient per cohort needed to be treated before switching dose levels. A minimum of six patients were to be treated at the MTD. The maximum possible doses included in the trial were a 27-hour infusion for acute leukemia and a 21-hour infusion for lymphoma. Included in the initial dose-toxicity curves for those with lymphoma or leukemia were predictions of the risk of DLT at different treatment durations made by estimates of three oncology specialists. These estimates were averaged and used as initial assumptions of the relationship between gemcitabine infusion duration and the risk of toxicity in the logistic function log_e[p/(1 - p)], where p is DLT risk. The prior probabilities of DLT for leukemia patients treated with 9, 12, and 15 hours of gemcitabine were .07, .12, and .28, respectively. The predicted probabilities for lymphoma patients were .22, .48, and .80, respectively. The mCRM used the patient data to calculate the probability of a given dose being the MTD. No preset probability was required to label a given dose the MTD.

DLT was defined differently for those with leukemia versus those with lymphoma, given different degrees of toxicity considered acceptable by most treating physicians for these refractory illnesses. This was the primary reason these two groups were escalated separately. Hematologic DLT for the leukemia stratum was defined as neutropenia (ANC < 1,000 x 10⁶ cells/L) lasting longer than 28 days with less than 5% blasts in the marrow. Prolonged neutropenia because of persistent disease was not considered a DLT. Toxicities were graded according to the National Cancer Institute common toxicity criteria, version II. On the basis of the severity of the implications of refractory leukemia, other toxicities were not considered dose-limiting unless there was nonhematologic grade 4 toxicity lasting 3 days or longer or grade 3 toxicity lasting 7 days or longer. For those with lymphoma, hematologic DLT was defined as neutropenia (ANC < 1,000) lasting longer than 10 days. Nonhematologic toxicities were considered dose-limiting if there was grade 4 toxicity lasting 2 days or longer or grade 3 toxicity lasting 5 days or longer. Febrile neutropenia, nausea, and alopecia were assessed but were not considered in the evaluation of DLT for either stratum.

Patient Monitoring and Toxicity Assessment
Within 3 weeks of starting therapy, each patient underwent assessment, including physical examination; recording of weight, height, and body-surface area; evaluation of prior treatment toxicity; and Cancer and Leukemia Group B performance status. All patients underwent the following tests at initiation: complete blood count with differential, AST, ALT, alkaline phosphatase, total bilirubin, creatinine, sodium, potassium, uric acid, chloride, carbon dioxide, calcium, phosphorous, magnesium, total protein, and albumin. Bone marrow examination with aspirate and biopsy was obtained on all patients and cytogenetic evaluation was performed for all leukemia patients. Patients with NHL were also evaluated by measuring lactate dehydrogenase levels and by computed tomographic scans of the chest, abdomen, and pelvis. Gallium scans were also obtained if these had not previously been obtained or were positive in the past.

During therapy, physical examination was assessed daily until discharge and then again on each outpatient visit. Complete blood counts were taken daily until the ANC was more than 500 x 10⁶ cells/L and the platelet count was more than 10 x 10⁹ cells/L. After that time, these measurements were taken a minimum of twice per week until the platelet count was more than 20 x 10⁹ cells/L for 1 week and were then checked as needed at the treating physician’s discretion. Serum creatinine, sodium, potassium, chloride, bicarbonate, blood urea nitrogen, glucose, and liver function studies were followed no less than two times per week until the patient had recovered from side effects of the therapy. Other electrolytes were followed as clinically indicated while patients were hospitalized. Chemotherapy was to be discontinued if liver enzymes increased to 10 times baseline values or if the creatinine increased to five times baseline. Platelets were to be maintained at a minimum of 10 x 10⁹ cells/L and the hematocrit kept above 25%. Higher hematologic parameters were allowed at the treating team’s discretion.

For patients with acute leukemia, patient response was evaluated by examination of marrow and peripheral blood smears. If there was evidence of response on the basis of peripheral blood differentials, bone marrow examination was repeated at days 11 to 14, and again when the ANC recovered to more than 1,000 x 10⁶ cells/L to assess degree of clearance of leukemic blasts from the marrow and peripheral blood. If the patient did not have evidence of a response, such as a decrease in percentage of peripheral blood blasts, the follow-up marrow examinations were not required. If neutropenia ensued, time to myeloid recovery, ANC more than 1,000 x 10⁶ cells/L, was monitored. Complete response (CR) was defined as the absence of all leukemia for a minimum of 4 weeks on the basis of laboratory evaluation and bone marrow examination performed at the time of myeloid recovery (ANC > 1,000 x 10⁶ cells/L). Absence of leukemia entailed the following: platelet recovery to 100 x 10⁹ cells/L, less than 5% blasts in the bone marrow, and no abnormal blasts in the peripheral blood for at least 1 month. A partial response (PR) entailed 50% decrease in blasts seen on bone marrow examination but an insufficient decrease for a CR. Peripheral counts were not used in this determination. Stable disease was defined as the lack of an increase in percentage of blasts in peripheral blood and bone marrow. Patients were considered to be on study at the initiation of protocol chemotherapy and were followed until progression or death.

Patients with NHL did not have bone marrow examinations repeated until the time of blood count recovery to ANC more than 1,000 x 10⁶ cells/L, and then only if the marrow was involved before chemotherapy. Four to 6 weeks after completing therapy, lymphoma patients were restaged with computed tomographic and gallium scans of previously involved sites (gallium was only used if previous scans had been positive). Complete response for those with lymphoma required all tests of disease before therapy to have resolved (radiographs and functional studies, and a negative marrow examination if this was involved before chemotherapy initiation). For those with residual masses that may have represented scar tissue rather than active disease, the residual tissue must have had a negative functional study (gallium or positron emission tomography) and must not have increased in size for at least 4 weeks to have been considered remission with residual mass.

	RESULTS

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Patient Characteristics
Characteristics of the patients who entered this trial are listed in Table 1. Overall, there were 20 patients, with 12 males, eight females, and two African-Americans. This group of patients with difficult-to-treat hematologic malignancies was divided into two strata: those with leukemia and those with NHL. Among the 11 acute leukemia patients in stratum I, the median age was 47 years (range, 18 to 68 years). The median number of prior regimens was two (range, one to seven regimens), with a median of four prior cycles (range, two to nine cycles) of therapy. Seven leukemia patients had achieved prior CR, lasting a median of 3 months (range, 1 to 8 months), and four of the 11 never attained a prior remission. Three of the leukemia patients had lymphocytic, and eight had myeloid leukemia. Among the nine patients in the NHL group, stratum II, the median age was 48 years (range, 39 to 68 years). The median number of prior regimens was four (range, two to 13 regimens), with 13 cycles (range, six to 45 cycles) of therapy. Three of these patients had received prior bone marrow transplantations. All the lymphoma patients had refractory disease, and only one had previously achieved a CR.

Overall, four patients in each stratum developed DLT. Severe stomatitis/esophagitis was the most severe nonhematologic adverse event and was the primary cause of DLT. In stratum I, two patients had dose-limiting esophagitis/stomatitis. A third had dose-limiting esophagitis/stomatitis in addition to dose-limiting elevated bilirubin and obtundation likely secondary to this chemotherapy given in addition to intrathecal therapy given during recovery. The fourth leukemia patient to develop DLT had lethal hypotension and disseminated intravascular coagulation. In stratum II, three patients had dose-limiting esophagitis/stomatitis, including one patient who died from this toxicity. The fourth patient to suffer DLT had dose-limiting anorexia.

Table 4 shows that a total of seven patients developed grade 2 or higher stomatitis/esophagitis. Six of these seven events were dose-limiting. The five patients with the most severe toxicity were all treated with 12 hours of gemcitabine. Among patients in stratum I, these events resolved in an average of 10 days (range, 5 to 15 days). In stratum II, all three episodes of grade 2 or higher stomatitis/esophagitis were dose-limiting. The two surviving patients had their toxicity resolve in 4 and 10 days.

Two patients died during the course of treatment, one patient in each stratum. The leukemia patient who died was treated with 12 hours of gemcitabine. This patient had evidence of disseminated intravascular coagulation at the initiation of therapy, and this condition progressed with chemotherapy. The lymphoma patient who died during treatment was also treated with 12 hours of gemcitabine. This patient developed severe stomatitis and fungemia.

Tumor Response
Eighteen percent (95% confidence interval, 8% to 47%) of patients (two of 11) with leukemia and 33% (95% confidence interval, 17% to 66%) of patients (three of nine) with NHL had a clinical response, as demonstrated by a CR or PR (Table 2). In the relapsed/refractory acute leukemia patients, one patient achieved a CR and another achieved a PR. The patient to achieve CR had relapsed after a prior 3-month CR and had not received other therapy after the relapse. The patient with a PR had disease that was refractory to prior treatment. Both were treated with 12 hours of gemcitabine. Thus, of the seven patients treated at the MTD, two (28%) had clinical responses. Three of the six lymphoma (50%) patients treated at the MTD of 12 hours of gemcitabine had a PR, including one patient who later died because of toxicity. All three patients had refractory disease.

	DISCUSSION

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Treatment of relapsed hematologic malignancies usually requires aggressive therapies with significant side effects, yet ultimately results in progression of the underlying illness.^2,15,16 This report describes a combination of the nucleoside analog gemcitabine delivered as a prolonged infusion and the camptothecin irinotecan as a salvage regimen for acute leukemia or NHL.

Gemcitabine has most often been studied for use in solid tumors by being administered as weekly 30-minute infusions. Phase I studies have showed that 30-minute infusions of gemcitabine did allow the MTD of drug. However, gemcitabine has a short (17 minutes) half-life even though active metabolites may last longer.¹⁷ As has been suggested by in vitro work, a longer duration of infusion may increase the activity despite the lower dose.^9,10,18 A 24-hour prolonged infusion of gemcitabine was reported in patients with inoperable non–small-cell lung cancer and was generally well tolerated.¹⁹ Gemcitabine may prove to be an effective part of combination therapy in hematologic malignancies. Our group has also shown promising results in acute leukemia with a combination of prolonged-infusion gemcitabine with the anthracycline mitoxantrone (D.A.R., unpublished data).

The in vitro combination of gemcitabine and camptothecins seems to have at least additive cytotoxicity when used in many combination concentrations. Irinotecan has been shown to have single-agent activity against both acute leukemia and lymphoma. In lymphoma, irinotecan infusions of 40 mg/m² when given either daily for 5 days every 3 to 4 weeks or daily for 3 days every week demonstrated a 33% response rate in primarily sensitive relapsed patients.¹¹ In acute leukemia, administration of irinotecan at 20 mg/m² bid for 7 days every 3 to 4 weeks led to a 25% response rate. Irinotecan has been studied in combination with gemcitabine for other tumors. Combinations of the two agents showed synergistic growth inhibition of breast and lung cancer cell lines.²⁰ Early encouraging results have been shown in a phase I study of a weekly 30-minute infusion of gemcitabine in combination with irinotecan for patients with non–small-cell lung cancer.²¹ The primary nonhematologic toxicities in this study were gastrointestinal, including nausea, vomiting, and diarrhea.

The trial reported here demonstrates that, in heavily pretreated patients with refractory leukemia or lymphoma receiving three daily 60-minute intravenous doses of irinotecan at 10 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, given our definition of DLTs. This regimen was associated with both hematologic and gastrointestinal/integument toxicity. The primary cause of DLT was stomatitis/esophagitis. Grade 2 or higher stomatitis/esophagitis occurred in 36% of leukemia and 33% of lymphoma patients.

Gastrointestinal events were also common. In stratum I, 45% had toxicity from nausea, vomiting, or anorexia. Such toxicity occurred in 67% of those in stratum II. Several patients also developed elevated bilirubin or liver function tests. Given the myelotoxicity of this regimen, febrile neutropenia and infection were also seen. Seventy percent of patients developed febrile neutropenia.

Although this is a phase I study, the clinical responses are notable, given the refractory nature of the group. Overall, 18% of acute leukemia patients and 33% of lymphoma patients had responses. However, among those treated at the MTD, the response rates were 28% and 50%, respectively. These responses are encouraging, given that all the patients treated with lymphoma had refractory disease and those with leukemia were heavily pretreated as well. The responses seen in this trial are likely because of the additive effects of these agents and the prolonged infusion of gemcitabine, as demonstrated by prior in vitro work from our group. This regimen has acceptable toxicity, and future combination with newer mucoprotectants may make it more tolerable. Further clinical study of this combination is warranted.

	ACKNOWLEDGMENTS

 
Supported in part by Eli Lilly and Company, Indianapolis, IN, and US Pharmacia, Peapack, NJ.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted August 27, 2001; accepted March 27, 2002.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bass, A. J. Articles by Rizzieri, D. A. Search for Related Content PubMed PubMed Citation Articles by Bass, A. J. Articles by Rizzieri, D. A. Social Bookmarking                            What's this?