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Gemcitabine as a Single Agent in the Treatment of Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

From the Westdeutsches Tumorzentrum, Essen, Germany; Istituto Clinico Humanitas, Rozzano-Milano, Italy; Medizinische Klinik III, Klinikum Großhadern, München, Germany; Universitätskliniken des Saarlandes, Homburg-Saar, Germany; Sädtisches Krankenhaus Leverkusen, Germany; Eli-Lilly, Bad Homburg, Germany, and Florence, Italy; and Istituto Nazionale Tumori, Milano, Italy.

Address reprint requests to A. Fosså, MD, PhD, Department of Immunology, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway; email alexanfo{at}labmed.uio.no

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: A multicenter phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL).

PATIENTS AND METHODS: Thirty-one patients with B-cell intermediate or high-grade NHL (Working Formulation) were enrolled onto the study. The median age was 61 years, with a Karnofsky performance status of 80% in 65% of patients. Forty-eight percent had stage III or IV (Ann Arbor Classification) at study entry. Pretreatment consisted of one, two, or three chemotherapeutic regimens in nine, 11, and 11 patients, respectively. Gemcitabine 1,250 mg/m² was administered intravenously over 30 minutes on days 1, 8, and 15 of a 28-day schedule.

RESULTS: Thirty patients were assessable for efficacy, and 31 were assessable for toxicity. No complete responses were observed, but six patients showed a partial response, 11 stable disease, and 13 progressive disease. The overall response rate was 20% (95% confidence interval, 8% to 39%) for assessable patients and 19% (95% confidence interval, 8% to 34%) for the intent-to-treat analysis. The median duration of partial response was 6 months (range, 3.7 to 15+ months). Nonhematologic World Health Organization grade 3 toxicity included hepatic toxicity in four patients and infection in two. Hematologic toxicity was observed as grade 3 anemia in three patients, grade 3 leukopenia in two patients, grade 3/4 neutropenia in two patients, and grade 3/4 thrombocytopenia in six patients.

CONCLUSION: The present schedule of gemcitabine displays modest efficacy and mild toxicity in pretreated aggressive NHL.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
AGGRESSIVE non-Hodgkin's lymphomas (NHLs) are commonly treated with anthracycline-containing combination chemotherapy regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or derivatives thereof.^1,2 Despite the fact that NHL tumors are considered chemosensitive, the prognosis is disappointing for those 50% to 60% of patients who experience primary treatment failure or relapse after an initial response. Over the past 15 years, two main strategies have been pursued to improve treatment outcome with chemotherapy for aggressive NHL. One strategy under investigation is dose-intensification of active drugs with or without autologous stem-cell transplantation.^3,4 A second line of research has been aimed at identifying novel chemotherapeutic agents with activity against aggressive NHL to improve existing combination regimens.

Gemcitabine (2',2'-difluorodeoxycytidine) is a pyrimidine antimetabolite with structural similarities to cytarabine. However, its pharmacology and mechanism of action differ from other pyrimidine analogs in several aspects.^5,6 Gemcitabine serves as a better transport substrate for uptake into the cells, is phosphorylated more efficiently to the active gemcitabine triphosphate, and is eliminated more slowly. Gemcitabine triphosphate inhibits DNA chain elongation through a mechanism termed "masked chain termination" and competitively inhibits ribonucleotidyl reductase. The result is impaired DNA synthesis and induction of apoptosis.^5-7

Gemcitabine has been shown to have clinical activity against several solid tumors, including pancreatic,⁸ ovarian,⁹ breast,¹⁰ bladder,¹¹ and both small-cell¹² and non—small-cell lung¹³ cancer. In patients with solid tumors, gemcitabine has a favorable toxicity profile compared with many other cytotoxic agents with regard to alopecia, nausea, and myelosuppression,^14,15 and has been incorporated into combination regimens.^10,16,17 In hematologic malignancies, in vitro studies have demonstrated activity of gemcitabine against cell lines and primary cultures from patients with leukemia and lymphoma.^18,19

The objective of the present study was to evaluate the efficacy and safety of gemcitabine in the treatment of patients with relapsed or refractory aggressive NHL.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Design
This open-label, nonrandomized multicenter phase II trial was conducted in four centers in Germany and one in Italy. The study was performed according to the Guidelines for Good Clinical Practice and approved by local ethic committees in both countries. Patients were enrolled in a two-stage sequential fashion to allow for early discontinuation of the study if less than two (ie, none or one) of the first 19 patients showed a response. This procedure tests the null hypothesis (H₀) that the true response rate is 5% versus the alternative hypothesis (H_A) that the true response rate is at least 25% at a significance level of .05 and power of .95. All patients gave written informed consent.

Patients with a histologic diagnosis of intermediate- or high-grade NHL (other than lymphoblastic lymphoma) according to the Working Formulation (categories D to J except I) were eligible.²⁰ Patients were included if they had documented evidence of refractory or relapsed lymphoma, had received up to three prior chemotherapeutic regimens, were considered unlikely to experience long-term remission with any other conventional or high-dose chemotherapy, had received no anticancer treatment for at least 3 weeks before enrollment, and had bidimensionally measurable disease, a life expectancy of at least 12 weeks, a Karnofsky performance status (KPS) of 60% , and adequate bone marrow reserves. Patients were excluded if they had received high-dose chemotherapy with autologous stem-cell transplantation and had active infections (including human immunodeficiency virus—positive patients), bone lesions as the only evidence of disease, central nervous disease manifestations, inadequate liver or renal function, hypercalcemia, were pregnant or breast feeding, or had a second malignancy or other serious concomitant medical disorders.

Therapy
Gemcitabine 1,250 mg/m² was administered as a 30-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. This 4-week period was defined as a cycle of therapy. The dosing schedule remained fixed, and any dose of gemcitabine that could not be given on time was omitted. Patients who had not experienced any hematologic or nonhematologic toxicity of World Health Organization (WHO) grade 1 or worse after one complete cycle of therapy were permitted to have subsequent doses increased by 20%, ie, from 1,250 mg/m² to 1,500 mg/m² on an optional basis. No other chemotherapy, immunotherapy, hormonal therapy (excluding replacement corticosteroids), growth factors, or cytokines were given during the entire period of gemcitabine therapy.

Dose reductions were based on blood counts and nonhematologic toxicity before infusion. Doses were reduced by the following percentages if patients had blood counts within the specified ranges: 0% for leukocyte count 2 x 10⁹/L, granulocyte count 1.5 x 10⁹/L, or platelet count 100 x 10⁹/L; 25% for leukocyte count less than 2.0 x 10⁹/L and 1.0 x 10⁹/L, granulocyte count less than 1.5 x 10⁹/L and 1.0 x 10⁹/L, or platelet count less than 100 x 10⁹/L and 50 x 10⁹/L. Doses were omitted for leukocyte count less than 1.0 x 10⁹/L, granulocyte count less than 1.0 x 10⁹/L, or platelet count < 50 x 10⁹/L. Doses were reduced by 25% when a nonhematologic toxicity of WHO grade 3 occurred in the previous cycle and were reduced by 50% or omitted after a previous nonhematologic toxicity of WHO grade 4.

Patient Monitoring and Toxicity Assessment
No more than 1 week before entering the study, each patient was assessed by medical history, including evaluation of "B" symptoms and KPS; weight, height, blood pressure, and pulse rate; and measurement of palpable or visual tumor lesions. Full blood counts, including a differential count and platelet count; blood chemistries (creatinine, blood urea nitrogen, bilirubin, alkaline phosphatase, alanine and aspartate transaminase, glucose, electrolytes, calcium, total protein, and uric acid); coagulation tests; urine analyses; and ECG were performed in all patients. During therapy, KPS, weight, blood pressure, pulse rate, and full blood counts were obtained before each drug infusion. In addition, a complete medical history, including assessment of subjective (nonlaboratory assessments) and objective (laboratory assessments) toxicity according to WHO toxicity criteria, were obtained before the start of each new cycle.

Disease Monitoring
No more than 3 weeks before enrollment, each patient was assessed by clinical examination of palpable or visual tumor lesions and by at least one appropriate radiologic tests for evaluation of suspected tumor spread and tumor measurement. Disease stage was classified according to the Ann Arbor criteria. Tumor manifestations were reassessed after every second cycle of treatment using the same baseline imaging technique throughout the study. Bidimensional tumor measurement and evaluation of response were performed using standard WHO criteria. Responses were confirmed on two separate measurements at least 4 weeks apart. Time to best response and time to progression were measured from the start of gemcitabine treatment to time of documentation of response or tumor progression. Survival was calculated from the start of treatment to death of any cause.

Statistics
The 95% confidence intervals for overall response rates were calculated using the exact binomial distribution. The ² and Mann-Whitney U tests were used to compare different groups of patients for categoric and continuous variables, respectively. The medians for time to best response, time to progression, and survival were determined using the Kaplan-Meier method. The log-rank test was used to compare curves for survival between different groups of patients. Statistical analysis was performed using SPSS 8.0 for Windows (SPSS Inc, Chicago, IL).

	RESULTS

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Patient Characteristics
Thirty-one pretreated patients (77% men) with a median age of 61 years were enrolled onto the study between February 1995 and July 1997 (Table 1). Most patients (68%) had a performance status 80% and diffuse large-cell histology (65%). Based on immunohistochemical findings, all patients had B-cell tumors. Forty-eight percent of patients had stage III or IV disease at the start of gemcitabine treatment. Pretreatment consisted of one, two, or three chemotherapeutic regimens in nine, 11, and 11 patients, respectively. Thirty patients had received CHOP¹ or a CHOP-like regimen (CHOP, n = 20; prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, and vincristine [ProMACECytaBOM],¹ n = 2; CHOP with etoposide,²¹ n = 4; cyclophosphamide, doxorubicin, bleomycin, vincristine, procarbazine, and prednisone,²² n = 4). First-line treatment consisted of cyclophosphamide, vincristine, methotrexate, and prednisone in one patient. Twenty-two patients had received various second-line treatments with ProMACECytaBOM (n = 5); vincristine, ifosfamide, and methotrexate²² (n = 8); other etoposide-containing combination regimens (n = 7); and other agents (n = 2). Third-line chemotherapy consisted of etoposide- or tenoposide-containing combinations (n = 4), carboplatinum or cisplatinum with cytarabine (n = 2), CHOP (n = 1), and other agents (n = 5). Before study entry, patients had received a median of eight different cytotoxic drugs (range, four to 12), including corticosteroids. Eighteen patients (58%) had received additional radiotherapy. Seventeen patients had chemosensitive disease, defined as a relapse after a complete or partial response from the last chemotherapeutic regimen before study entry. Fourteen patients were classified as having chemoresistant disease because they showed no response to their last prior therapy.

Dose Administration
Details of the administered therapy are listed in Table 2. A total of 98 cycles was administered, with a median of two cycles per patient (range, one to nine). A total of 286 infusions of gemcitabine was scheduled, and the mean dose delivered per infusion was 1,042 mg/m². Of the 286 infusions, 188 (66%) were given at the assigned dose of 1,250 mg/m², and nine (3%) were given at a dose level of 1,500 mg/m². Five patients were able to receive infusions with escalated doses (three patients received one and two patients received three escalated doses each). Dose reductions occurred in 55 infusions (19%), principally because of thrombocytopenia and leukopenia. Thirty infusions (11%) were omitted, mostly for myelosuppression, and four infusions (1%) were delayed.

Efficacy
One patient was excluded from the efficacy analysis because of violation of entry criteria. Thus 30 of the 31 patients were assessable for efficacy.

Response data from the assessable and intent-to-treat efficacy analyses are listed in Table 3. No complete response was observed, but six patients achieved a partial response, resulting in an overall response rate of 20% (95% confidence interval, 8% to 39%) for assessable patients. In the intent-totreat analysis, the overall response rate was 19% (95% confidence interval, 8% to 34%). Eleven patients had stable disease, and 13 patients had progressive disease, four of whom experienced disease progression before completion of the first cycle.

The median time to best response for the six responders was 1.9 months (range, 1.0 to 2.9 months). The median time to progression for responders was 6 months (range, 3.7 to 15+ months) and for nonresponders, including patients with stable disease and progressive disease, was 2.2 months (range, 1.0 to 14.9 months). At the end of the follow-up period, 12 of 30 assessable patients had died, and the median survival time had not been reached. The 75% probability of survival for responders was reached at 6.3 months (range, 3.8 to 15.0+ months) and for nonresponders at 2.8 months (range, 0.5 to 18.6+ months; P = .52).

Details of the history and disease manifestations of the six responding patients are listed in Table 4. All patients who responded had a histologic diagnosis of diffuse large-cell lymphoma (category G), whereas no patient with a diagnosis of intermediate- or high-grade lymphoma other than diffuse large-cell lymphoma showed a response. No statistically significant association with response rates was found for the following parameters: time from initial diagnosis, age, stage at relapse (I or II v III or IV), performance status (KPS 80% v > 80%), number of prior chemotherapy regimens, or response to last chemotherapy (chemosensitive v chemoresistant disease). Notably, three patients with a complete response and three patients with no response after the last combination chemotherapy responded to gemcitabine.

Toxicity
Toxicity was recorded in all 31 patients during the treatment period and included events with probable or unknown relation to the study drug (Table 5). WHO grade 1 toxicities were observed in one patient (3%) each for alopecia, diarrhea, oral mucositis, pericarditis, and peripheral neurotoxicity. One patient (3%) each reported the following WHO grade 3 subjective toxicities: fever, cardiac function, pulmonary toxicity (dyspnea at rest with normal chest radiograph), and pain (related to a leg with lymphedema), respectively. Two patients (7%) suffered from WHO grade 3 infections, and four patients with transient elevations of liver enzymes or bilirubin level had biochemical evidence for hepatic toxicity. Hematologic toxicity was more common than nonhematologic toxicity, with grade 3 anemia in three patients (11%), grade 3 leukocytopenia in two patients (7%), grade 3/4 neutropenia in two patients (9%), and grade 3/4 thrombocytopenia in six patients (22%). Sixteen patients required one or more RBC transfusions with a median of four units per patient (range, two to nine). Five patients required platelet transfusions with a median of one platelet unit per patient (range, one to five).

Delayed drug toxicity after the end of the treatment period was not assessed in this study. However, one patient in partial remission died of fungal pneumonia and fungal septicemia 7 weeks after the last infusion of gemcitabine. At the time of symptomatic infection, he had fully recovered and maintained normal blood counts for 5 weeks, including a normal differential blood count.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study represents the first trial intended to evaluate the efficacy and safety of gemcitabine in aggressive lymphoma. Previous experience with this antimetabolite in aggressive lymphoma is limited to a report of three patients but has shown promising activity.²³ A preliminary report on the results of the present study at the time of 22 enrolled patients showed two patients with documented partial response, but several of the enrolled patients were still on treatment, and one of the 22 subsequently achieved a partial response.²⁴ Thus, of the last nine patients entered onto this trial, three showed a response to gemcitabine.

All of the patients included in the present study had relapsed or refractory disease after up to three regimens of prior chemotherapy. All patients but one had received anthracycline-containing combination regimens. In addition, these patients were relatively older compared with patients in other published studies on salvage chemotherapy. The older age group was expected because young patients with relapsed or refractory disease are usually treated with high-dose chemotherapy and autologous stem-cell transplantation. Only patients who were not considered candidates or were too old for more intensive chemotherapy were included in this trial. Patients who had a relapse after high-dose chemotherapy were excluded.

The present study demonstrates moderate efficacy of gemcitabine in the setting of relapsed or refractory aggressive lymphoma. The overall response rate was 20% in assessable patients and 19% in the intent-to-treat analysis. Only partial responses were observed and lasted a median of 6 months. It is difficult to compare these response rates to results reported in phase II trials using other drugs as single agents in patients with relapsed or refractory NHL.²⁵ The difficulties arise from differences in study design, especially among older studies, the generally low number of patients in most studies, and the heterogeneity of patient cohorts in terms of histologic entities or extent of prior treatment. Furthermore, independent confirmatory studies evaluating the same drug are frequently missing. Considering these difficulties, the observed efficacy and toxicity of gemcitabine compare well with results of studies using single agents that are frequently incorporated in combination chemotherapy regimens for treatment of aggressive NHL, such as etoposide,²⁶ mitoxantrone,^27,28 or cisplatinum.²⁹ The results also seem interesting when compared with other novel chemotherapeutic agents under investigation in NHL, such as paclitaxel³⁰ or the topoisomerase I inhibitors CPT-11³¹ or AC-9.³²

The toxicity associated with the chosen schedule of gemcitabine was generally mild. Transient elevations of liver enzymes or bilirubin level were observed in four of 31 patients. Toxicity generally associated with most chemotherapeutic agents, such as nausea, vomiting, alopecia, and mucositis, were rare or mild. The most common toxicity was myelosuppression, with grade 3 anemia reported in 11% of patients, and grade 3/4 neutropenia and thrombocytopenia reported in 9% and 22% of patients, respectively. Thrombocytopenia and granulocytopenia constituted the main reasons for dose reduction and omissions of scheduled infusions. However, there were no serious bleeding episodes, and only two patients suffered from grade 3 infections during the treatment period. Although the number of patients in the present study is limited, thrombocytopenia seems to be more pronounced in this study than in other studies using gemcitabine. In an analysis of safety data from a large number of clinical trials across a range of solid tumors with dose regimens from 800 to 1,250 mg/m², grades 3 and 4 hematologic toxicities were recorded in 6.4% and 0.9% of patients for hemoglobin, in 18.7% and 5.7% of patients for neutrophils, and in 3.7% and 1.0% of patients for platelets, respectively.¹⁴ The higher incidence of thrombocytopenia in the present study may have resulted from the extensive prior chemotherapy and radiotherapy among the enrolled patients. There may also be biologic differences between patients with lymphomas and solid tumors.

The modest efficacy demonstrated in the present trial and the low incidence of significant hematologic toxicity raise the question of whether the antitumor effect of gemcitabine can be improved by increasing dose-intensity or by alternative schedules. The present study used gemcitabine as a weekly short-time infusion for 3 weeks followed by 1 week of rest. This schedule is based on phase I and II studies in solid tumors, giving the highest dose-intensities with acceptable tolerability.^15,33 Dose increments in the present study were optional, and only five patients received a low number of infusions at increased doses. In view of the modest toxicity observed in the present cohort of patients, higher dose-intensities may be feasible, especially in less heavily pretreated patients. In chemotherapy-naive patients with lung cancer, the apparent maximum-tolerated dose was found to be 2,200 mg/m² given weekly for 3 weeks followed by 1 week of rest, ie, a dose-intensity considerably higher than the one used in the present trial.³⁴ Furthermore, recent data from animal and human studies indicate that the activity of gemcitabine is dependent on the chosen schedule.^35-39 Whether different schedules, such as prolonged infusion time, result in clinically relevant differences in efficacy or tolerability remains to be demonstrated. Further studies with single-agent gemcitabine aimed at testing different doses and schedules may therefore be warranted to evaluate further its potential role in chemotherapy of aggressive NHL.

	ACKNOWLEDGMENTS

 
Supported by Eli-Lilly, Bad Homburg, Germany, and Florence, Italy.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med328:1002-1006, 1993[Abstract/Free Full Text]

2. Martelli M, De Sanctis V, Avvisati G, et al: Current guidelines for the management of aggressive non-Hodgkin's lymphoma. Drugs53:957-972, 1997[Medline]

3. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med333:1540-1545, 1995[Abstract/Free Full Text]

4. Gisselbrecht C: Autologous stem cell transplantation in aggressive non-Hodgkin's lymphoma. Recent Results Cancer Res144:15-26, 1998[Medline]

5. Plunkett W, Huang P, Searcy CE, et al: Gemcitabine: Preclinical pharmacology and mechanisms of action. Semin Oncol23:3-15, 1996[Medline]

6. Plunkett W, Huang P, Xu YZ et al: Gemcitabine: Metabolism, mechanisms of action, and self-potentiation. Semin Oncol22:3-10, 1995[Medline]

7. Bouffard DY, Momparler RL: Comparison of the induction of apoptosis in human leukemic cell lines by 2',2'-difluorodeoxycytidine (gemcitabine) and cytosine arabinoside. Leuk Res19:849-856, 1995[Medline]

8. Moore M: Activity of gemcitabine in patients with advanced pancreatic carcinoma: A review. Cancer78:633-638, 1996[Medline]

9. Kaufmann M, von Minckwitz G: Gemcitabine in ovarian cancer: An overview of safety and efficacy. Eur J Cancer 33:S31-33, 1997 (suppl 1)

10. Lüftner D Flath B, Akrivakis C, et al: Gemcitabine for palliative treatment in metastatic breast cancer. J Cancer Res Clin Oncol124:527-531, 1998[Medline]

11. Stadler WM, Kuzel TM, Raghavan D, et al: Metastatic bladder cancer: Advances in treatment. Eur J Cancer 33:S23-26, 1997 (suppl 1)

12. Murray N: New drugs for small-cell lung cancer. Oncology (Huntingt)11:38-42, 1997

13. Carney DN: New agents in the management of advanced non-small cell lung cancer. Semin Oncol25:83-88, 1998[Medline]

14. Green MR: Gemcitabine safety overview. Semin Oncol23:32-35, 1996

15. Abbruzzese JL: Phase I studies with the novel nucleoside analog gemcitabine. Semin Oncol23:25-31, 1996

16. Steward WP: Combination studies with gemcitabine in the treatment of non-small-cell lung cancer. Br J Cancer78:15-19, 1998 (suppl 3)

17. Fagbemi SO, Stadler WM: New chemotherapy regimens for advanced bladder cancer. Semin Urol Oncol16:23-29, 1998[Medline]

18. Bouffard DY, Momparler LF, Momparler RL: Comparison of antineoplastic activity of 2',2'-difluorodeoxycytidine and cytosine arabinoside against human myeloid and lymphoid leukemic cells. Anticancer Drugs2:49-55, 1991[Medline]

19. Csoka K, Liliemark J, Larsson R, et al: Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors. Semin Oncol22:47-53, 1995

20. Robb-Smith AH: U.S. National Cancer Institute working formulation of non-Hodgkin's lymphomas for clinical use. Lancet2:432-434, 1982[Medline]

21. Köppler H Pflüger KH, Eschenbach I, et al: Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin's lymphomas: Treatment results and prognostic factor analysis in a multi-centre trial. Ann Oncol5:49-55, 1994[Abstract/Free Full Text]

22. Nowrousian MR, Meier CR, Schoetensack B, et al: Sequential combination chemotherapy (CABOPP/VIM) for the treatment of high-grade malignant non-Hodgkin lymphoma. Acta Oncol28:495-500, 1989[Medline]

23. Bernell P, Ohm L: Promising activity of gemcitabine in refractory high-grade non-Hodgkin's lymphoma. Br J Haematol101:203-204, 1998[Medline]

24. Santoro A, Devizzi L, Bonfante V, et al: Phase II study with gemcitabine in pretreated patients with Hodgkin's (HD) and non-Hodgkin's lymphomas (NHL): Results of a multicenter study. Proc Natl Acad Sci U S A16:21, 1997 (abstr)

25. Preti A, Cabanillas F: Management of recurrent or refractory lymphomas, Magrath IT (ed): The Non-Hodgkin's Lymphomas (ed 2)715-722London, England, Arnold, 1997

26. O'Reilly SE Klimo P, Connors JM: The evolving role of etoposide in the management of lymphomas and Hodgkin's disease. Cancer67:271-280, 1991[Medline]

27. Gams RA, Bryan S, Dukart G, et al: Mitoxantrone in malignant lymphoma. Invest New Drugs3:219-222, 1985[Medline]

28. Chisesi T: The rationale of therapy with mitoxantrone in non-Hodgkin's lymphoma: The Non-Hodgkin's Lymphoma Co-operative Study Group (NHLCSG) Italy. Leuk Lymphoma9:63-69, 1993[Medline]

29. Cavalli F, Jungi WF, Nissen NI, et al: Phase II trial of cis-dichlorodiammineplatinum (II) in advanced malignant lymphoma: A study of the cancer and acute leukemia group B. Cancer48:1927-1930, 1981[Medline]

30. Press OW, LeBlanc M, O'Rourke TJ et al: Phase II trial of paclitaxel by 24-hour continuous infusion for relapsed non-Hodgkin's lymphomas: Southwest Oncology Group trial 9246. J Clin Oncol16:574-578, 1998[Abstract]

31. Ohno R, Okada K, Masaoka T, et al: An early phase II study of CPT-11: A new derivative of camptothecin, for the treatment of leukemia and lymphoma. J Clin Oncol8:1907-1912, 1990[Abstract]

32. Wilson WH, Little R, Pearson D, et al: Phase II and dose-escalation with or without granulocyte colony-stimulating factor study of 9-aminocamptothecin in relapsed and refractory lymphomas. J Clin Oncol16:2345-2351, 1998[Abstract]

33. Storniolo AM, Allerheiligen SR, Pearce HL: Preclinical, pharmacologic, and phase I studies of gemcitabine. Semin Oncol 24:S7-2-S7-7, 1997 (suppl 7)

34. Fossella FV, Lippman SM, Shin DM, et al: Maximum-tolerated dose defined for single-agent gemcitabine: A phase I dose-escalation study in chemotherapy-naive patients with advanced non—small-cell lung cancer. J Clin Oncol15:310-316, 1997[Abstract/Free Full Text]

35. Touroutoglou N, Gravel D, Raber MN, et al: Clinical results of a pharmacodynamically-based strategy for higher dosing of gemcitabine in patients with solid tumors. Ann Oncol9:1003-1008, 1998[Abstract/Free Full Text]

36. Pollera CF, Ceribelli A, Crecco M, et al: Prolonged infusion gemcitabine: A clinical phase I study at low- (300 mg/m²) and high-dose (875 mg/m²) levels. Invest New Drugs15:115-121, 1997[Medline]

37. Anderson H, Thatcher N, Walling J, et al: A phase I study of a 24 hour infusion of gemcitabine in previously untreated patients with inoperable non-small-cell lung cancer. Br J Cancer74:460-462, 1996[Medline]

38. Veerman G, Ruiz van Haperen VW Vermorken JB, et al: Antitumor activity of prolonged as compared with bolus administration of 2',2'-difluorodeoxycytidine in vivo against murine colon tumors. Cancer Chemother Pharmacol38:335-342, 1996[Medline]

39. Braakhuis BJ, Ruiz van Haperen VW Boven E, et al: Schedule-dependent antitumor effect of gemcitabine in in vivo model system. Semin Oncol22:42-46, 1995[Medline]

Submitted March 29, 1999; accepted July 22, 1999.

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				M. Pless, K. Belhadj, H. D. Menssen, W. Kern, B. Coiffier, J. Wolf, R. Herrmann, E. Thiel, D. Bootle, I. Sklenar, et al. Clinical Efficacy, Tolerability, and Safety of SAM486A, a Novel Polyamine Biosynthesis Inhibitor, in Patients with Relapsed or Refractory Non-Hodgkin's Lymphoma: Results from a Phase II Multicenter Study Clin. Cancer Res., February 15, 2004; 10(4): 1299 - 1305. [Abstract] [Full Text] [PDF]

				T. Baetz, A. Belch, S. Couban, K. Imrie, J. Yau, R. Myers, K. Ding, N. Paul, L. Shepherd, J. Iglesias, et al. Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin's disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group Ann. Onc., December 1, 2003; 14(12): 1762 - 1767. [Abstract] [Full Text] [PDF]

				H. Kantarjian, V. Gandhi, J. Cortes, S. Verstovsek, M. Du, G. Garcia-Manero, F. Giles, S. Faderl, S. O'Brien, S. Jeha, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia Blood, October 1, 2003; 102(7): 2379 - 2386. [Abstract] [Full Text] [PDF]

				H. M. Kantarjian, V. Gandhi, P. Kozuch, S. Faderl, F. Giles, J. Cortes, S. O'Brien, N. Ibrahim, F. Khuri, M. Du, et al. Phase I Clinical and Pharmacology Study of Clofarabine in Patients With Solid and Hematologic Cancers J. Clin. Oncol., March 15, 2003; 21(6): 1167 - 1173. [Abstract] [Full Text] [PDF]

				E. Weidmann, S.-Z. Kim, A. Rost, H. Schuppert, G. Seipelt, D. Hoelzer, and P. S. Mitrou Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma Ann. Onc., August 1, 2002; 13(8): 1285 - 1289. [Abstract] [Full Text] [PDF]

				M. J. Egorin, E. G. Zuhowski, C. M. McCully, S. M. Blaney, J. Z. Kerr, S. L. Berg, and F. M. Balis Pharmacokinetics of Intrathecal Gemcitabine in Nonhuman Primates Clin. Cancer Res., July 1, 2002; 8(7): 2437 - 2442. [Abstract] [Full Text] [PDF]

				A. Santoro, H. Bredenfeld, L. Devizzi, H. Tesch, V. Bonfante, S. Viviani, F. Fiedler, H. S. Parra, C. Benoehr, M. Pacini, et al. Gemcitabine in the Treatment of Refractory Hodgkin's Disease: Results of a Multicenter Phase II Study J. Clin. Oncol., July 1, 2000; 18(13): 2615 - 2619. [Abstract] [Full Text] [PDF]

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