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Randomized Phase III Study of Fludarabine Phosphate Versus Cyclophosphamide, Vincristine, and Prednisone in Patients With Recurrent Low-Grade Non-Hodgkin’s Lymphoma Previously Treated With an Alkylating Agent or Alkylator-Containing Regimen

From the Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia; Hamilton Regional Cancer Center, Hamilton, London Regional Cancer Centre, London, and St Catherine’s Clinic, St Catherine’s, Ontario; McGill Oncology Group, Hopital Saint-Luc, and Berlex Canada, Montreal, Quebec; Toronto-Sunnybrook Regional Cancer Centre, Toronto; Saskatoon Cancer Centre, Saskatoon, Saskatchewan; and Cancercare Manitoba, Winnipeg, Manitoba, Canada.

Address reprint requests to Richard Klasa, MDCM, FRCPC, Division of Medical Oncology, British Columbia Cancer Agency, 600 W 10th Ave, Vancouver, British Columbia V5Z 4E6, Canada; email: rklasa{at}bccancer.bc.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To compare in a phase III study the safety and efficacy of fludarabine to that of cyclophosphamide, vincristine, and prednisone (CVP) in recurrent, low-grade, non-Hodgkin’s lymphoma after previous response to systemic treatment.

PATIENTS AND METHODS: Patients were randomized to fludarabine (25 mg/m² intravenously on days 1 to 5, every 28 days) or CVP (cyclophosphamide 750 mg/m² and vincristine 1.2 mg/m² both intravenously on day 1 and prednisone 40 mg/m² orally on days 1 to 5, every 21 days). The primary outcome assessed was progression-free survival (PFS); secondary outcomes included treatment-free survival (TFS), overall survival (OS), treatment-related toxicity, and quality of life (QoL) according to the European Organization for Research and Treatment of Cancer’s Quality of Life Questionnaire C-30 version 1.0 instrument.

RESULTS: Ninety-one patients were randomized, 47 to fludarabine and 44 to CVP. There was no difference in response rates, with 64% (complete response [CR], 9%) for fludarabine versus 52% (CR, 7%) for CVP (P = .72). With a median follow-up of 42 months, median PFS (11 months v 9.1 months; P = .03) and TFS (15 months v 11 months; P = .02) were superior in patients receiving fludarabine. No difference in median overall survival was detected (57 months for fludarabine v 44 months for CVP; P = .95). Three patients receiving fludarabine died of treatment-related toxicity compared with none of the patients receiving CVP. Peripheral neuropathy and alopecia were more common with CVP. Patients receiving fludarabine had higher scores for social function (P = .008); no other differences in QoL were detected.

CONCLUSION: In recurrent low-grade lymphoma, fludarabine improves PFS, TFS, and social function scores in comparison with CVP but does not improve OS.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
LOW-GRADE NON-Hodgkin’s lymphomas (NHLs) are a group of B-cell malignancies characterized by advanced stage at presentation, lack of symptoms associated with the disease, and indolent behavior in terms of time to symptomatic disease accumulation.^1,2 In asymptomatic patients without threatening nodal or extranodal involvement, no difference in survival has been seen for alkylator-based treatment initiated at diagnosis versus at symptomatic progression.³ When therapy is indicated, a common option is the use of a regimen containing cyclophosphamide, vincristine, and prednisone, such as CVP or COP.^4-6 The addition of an anthracycline such as doxorubicin to these agents, CHOP, has not been associated with any prolongation of overall survival.⁷ The addition of interferon alfa has also not consistently altered survival,^8-12 and no randomized study has yet reported on the use of high-dose chemotherapy and autologous stem-cell transplantation in comparison with a standard-dose outpatient regimen.¹³ All initial therapies are associated with high overall response rates (50% to 90%), with median durations of response ranging from 18 to 36 months. The disease inevitably relapses, with no treatment strategies associated with curative potential and median survival in the range of 8 to 10 years. Patients will require multiple courses of chemotherapy for systemic relapse with symptomatic progression of disease and radiotherapy for more localized relapses. Subsequent responses to previously used therapies are common, with repetitive use of the same regimen therefore a frequent option. Transformation to a higher-grade histologic type of NHL will occur in approximately half the patients that bear the disease for a decade and will require treatment with an anthracycline-containing regimen. The relapsing and remitting nature of the disease thus requires multiple interventions over the lifespan of the patient, making the judicious use of available treatments and careful integration of new agents fertile areas for clinical investigation.

Fludarabine phosphate is a purine analog that has been extensively studied in low-grade lymphoma and chronic lymphocytic leukemia.¹⁴ A large number of phase II studies in selected populations of patients with previously treated or refractory low-grade lymphoma have reported overall response rates ranging from 27% to 65%, with response durations of 10 to 12 months.^15-18 Fludarabine was generally well tolerated, with myelosuppression, lymphopenia, and opportunistic infection seen as major toxicities. Given these promising phase II data, the current study was undertaken to compare the safety and efficacy of fludarabine as a single agent to a CVP combination in a larger, defined patient population with relapsed low-grade lymphoma, earlier in the history of their disease.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This industry-sponsored, prospective, open-label, randomized, phase III clinical trial was conducted at 19 centers in Canada between October 1993 and December 1996. The study was performed in accordance with the Canadian Health Protection Branch guidelines on the Conduct of Clinical Investigations (1989), Good Clinical Research Practices (1993), and the Declaration of Helsinki (Hong Kong Amendment, 1989). The institutional review boards of the study centers approved the study protocol and amendments. Patients were required to give witnessed, written, informed consent for participation.

Patient Population
The inclusion criteria required that patients have one of the following histologically confirmed diagnoses, according to the International Working Formulation, with a number of additional categories then also in common use: small lymphocytic, follicular small cleaved-cell, follicular mixed small cleaved-cell, and large-cell, marginal zone, or monocytoid B-cell lymphoma.^19,20 Diagnostic lymph node biopsy specimens were centrally reviewed after enrollment but this was not an inclusion criterion. Patients must have demonstrated response to and subsequent relapse (from a complete response) or progression (from less than a complete response) of disease after each of at least one but no more than four prior courses of therapy. A course was defined as any single chemotherapeutic agent or combination of two or more agents administered for at least 3 consecutive months. Resumption of the same agents after a treatment-free interval of over 3 months was considered a new course. Responsive disease was thus operationally defined as any objective shrinkage of lesions that had led to the discontinuation of treatment for at least 3 months. Allowable prior therapy included any single agent or combination chemotherapy (CVP and CHOP included) that did not incorporate a purine analog. Patients had to have presented with advanced-stage disease at diagnosis, defined as Ann Arbor stage III or IV, or stage II with B symptoms or bulk more than 10 cm in maximum diameter at any individual tumor site. All patients were at least 18 years of age, but with no upper limit, and had a World Health Organization (WHO) performance status of 2 or better.

The study excluded patients who had not demonstrated a response to each course of prior therapy, as defined above, or who had exposure to purine analogs (eg, fludarabine, cladribine, or pentostatin). Also excluded were patients with significant renal (serum creatinine > two times normal) or hepatic (bilirubin > two times normal) insufficiency, absolute neutrophil count less than 1.5 x 10⁹/L, platelet count less than 100 x 10⁹/L, active systemic infection, any malignancy other than nonmelanoma skin cancers or carcinoma-in-situ of the cervix within 5 years of enrollment, pregnancy or lactation, a history of autoimmune hemolytic anemia, or any clinical or histologic evidence of transformation to a higher-grade NHL.

Treatment
Eligible patients were randomly assigned, by contacting a randomization center, to receive either fludarabine 25 mg/m² intravenously on days 1 to 5 every 28 days or CVP consisting of cyclophosphamide 750 mg/m² and vincristine 1.2 mg/m² both intravenously on day 1, and prednisone 40 mg/m² orally on days 1 to 5, every 21 days. Patients were stratified by the number of prior courses of chemotherapy (one or two v three or four), age (younger than 60 years v 60 years or older), and type of prior chemotherapy regimen (any anthracycline v no anthracycline).

Full doses of fludarabine or cyclophosphamide were given on time as long as the treatment-day absolute neutrophil count was greater than 1.5 x 10⁹/L and the platelet count was greater than 100 x 10⁹/L. Treatment-day counts below this level resulted in a 1-week delay and resumption of full-dose treatment if recovery to or above these levels had occurred. Treatment was discontinued and patients went off study if they did not achieve a partial response or complete response after three cycles of assigned therapy. Responding patients received two cycles of treatment beyond their best response, with a minimum of four and a maximum of 10 cycles.

Evaluations
Patients underwent full clinical examinations before the initiation of therapy, before each cycle of therapy, and throughout the follow-up period. Tests for complete blood counts, electrolytes, blood urea nitrogen, creatinine, bilirubin, AST, lactate dehydrogenase, alkaline phosphatase, uric acid, serum protein electrophoresis, and urinalysis were carried out at each visit. Diagnostic imaging studies including chest x-ray and either ultrasound or computed tomography scans of the abdomen and pelvis were performed before initiation of therapy, every two or three cycles while on therapy, depending on the need to determine response status, and at follow-up as detailed below. Quality of life (QoL) and social function score were assessed using the European Organization for Research and Treatment of Cancer’s Quality of Life C-30 version 1.0 questionnaire before treatment, every three cycles during treatment, at treatment completion, and at all follow-up visits.²¹

Patients were then followed up for at least 3 years or until death, at 3-month intervals for the first year and at 6-month intervals for the subsequent 2 years, to determine response, toxicity, date of progression, date of next treatment, and overall survival. Follow-up visits included clinical examination, complete blood count, and biochemistry as above, with imaging studies and any other tests dictated by clinical status at the discretion of the investigator. Ultrasound or computed tomography imaging of the abdomen and pelvis was performed at least yearly, even in asymptomatic patients.

Outcomes
Responses were defined as being complete (CR) if all symptoms resolved and there was no clinical, histologic, or radiologic evidence of disease at complete restaging after treatment. A partial response (PR) was defined as 50% reduction in the sum of the products of diameters in marker tumors with no evidence of new disease at any site. Progressive disease (PD) was defined as an increase of more than 25% in any marker tumor or the appearance of any new lesions, whereas stable disease was defined as any state between PR and PD. Although response evaluations were conducted before each cycle of therapy, only the final, posttreatment evaluation was accepted for analysis. Progression-free survival (PFS) was defined as the number of days from the initiation of study treatment until the day of documented PD. Treatment-free survival (TFS) was the duration in days from initiation of study therapy until the day of further chemotherapy, radiotherapy, or bone marrow transplantation. Overall survival was measured from the initiation of study therapy until the death of the patient.

All adverse events were recorded and classified according to WHO toxicity grading (grade 0 = no toxicity; grade 4 = life-threatening toxicity).^22,23 The investigator determined the relationship between each adverse event and the study treatment using standardized definitions (from "no relation to study therapy" to "definitely related to study therapy").

Statistical Analysis
The original planned sample size was calculated to detect a 20% difference in the proportion of patients remaining free from disease progression at 18 months, in favor of the fludarabine group. This was determined, by consensus among the participating investigators, to be a clinically relevant improvement in outcome. Accordingly, with alpha = 0.05 and beta = 0.2, 90 patients were required in each group (total study sample of 180), with a plan to accrue over a period of 3 years. Statistical analyses of categorical data were conducted using ² or Fisher’s exact tests and continuous variables were analyzed with Student’s t test or Wilcoxon’s test. Actuarial survival data were analyzed according to the method of Kaplan and Meier²⁴ and compared using the log-rank test.²⁵

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
A total of 91 patients from 18 institutions were enrolled onto the study between October 1993 and December 1996. Accrual was slower than expected, but analysis after longer follow-up suggested that a sufficient number of events had occurred to allow assessment of PFS. The characteristics of the two patient populations are listed in Table 1. The two groups were similar with respect to age, sex distribution, performance status, and stage of relapsed/progressive disease at enrollment. Seventy-eight percent of patients had a follicular lymphoma, 87% had received one or two prior chemotherapy regimens, and 40% in both groups had received an anthracycline-containing regimen, usually CHOP. The median time from diagnosis to enrollment was 2.5 years for the fludarabine group versus 3.7 years for the CVP group, and median time from last treatment was 10.7 months for the fludarabine group versus 15.5 months for the CVP group, with wide ranges and no statistical significance to these differences. Ninety-three percent of patients had stage III or IV disease documented at enrollment. There was no statistically significant difference in any of the baseline characteristics of the two groups of patients.

Patients were followed for a median period of 42 months. Median PFS was superior in the fludarabine group at 11 months compared with 9.2 months for the CVP group (P = .03) (Fig 1). At 2 years, the progression-free rates were 30% in the fludarabine arm compared with 13% in the CVP arm. Among responding patients, the 2-year PFS rates were 48% for the fludarabine group and 23% for the CVP group (P = .02). At the time of study analysis, four patients remained free from disease progression; all four were on the fludarabine arm and had been followed for 36, 43, 49, and 69 months.

View larger version (28K): [in this window] [in a new window]   Fig 1. Kaplan-Meier analysis of PFS (n = 91). Median PFS: fludarabine (FLU; solid line), 10.9 months (95% confidence interval [CI], 8.8-19.3); CVP (dashed line), 9.2 months (95% CI, 7.1-13.3); P = .03.

View larger version (27K): [in this window] [in a new window]   Fig 2. Kaplan-Meier analysis of TFS (n = 91). Median TFS: FLU (solid line), 15.3 months (95% CI, 11.1-28.6); CVP (dashed line), 11.2 months (95% CI, 8.6-16.6); P = .02.

View larger version (26K): [in this window] [in a new window]   Fig 3. Kaplan-Meier analysis of overall survival (n = 91). Median overall survival: FLU (solid line), 57.1 months; CVP (dashed line), 43.6 months; P = .95.

Toxicity
The median number of cycles of treatment delivered was equal on both arms of the study at six in responding patients and four in nonresponders. Dose reductions because of hematologic or other toxicity were necessary in 10% to 20% of any patient treatment cycle, after the first, and were comparable in each group.

The toxicity profiles were essentially similar for both groups of patients in most categories, with differences detailed below. In the fludarabine group, 18% to 30% of patients experienced nausea or vomiting requiring antiemetic treatment or prophylaxis at any given cycle during the first six cycles of treatment. In comparison, antiemetic measures were required for 83% to 95% of CVP patient cycles. The incidence of any degree of neurotoxicity was significantly lower in the fludarabine group than in the CVP group (36% v 75%; P = .0005), but the primary difference was the high incidence of grade 1 and 2 paresthesias observed with CVP caused by vincristine (54% v 11%). The incidence of WHO grade 3 or 4 neurotoxicity was identical in both at 2%. The hematologic toxicity (Table 2) was similar for both groups except for lower absolute lymphocyte counts, resulting in significantly lower total leukocyte counts, with fludarabine, as expected for treatment with a purine analog. There was also a trend that did not reach statistical significance toward more thrombocytopenia with fludarabine.

At the end of the study, a total of 46 patients (23 in each group) had died. With the exception of seven deaths (four in the fludarabine group and three in the CVP group), disease progression was the established cause of death. Three deaths considered caused by toxicity were seen in the study population and are described below; all occurred in patients receiving fludarabine. A 70-year-old woman who had received two cycles of fludarabine without disease response was admitted to the hospital 3 weeks after the second cycle with fever, neutropenia, and abdominal pain because of an enlarged spleen; gastrointestinal candidiasis and aspergillosis of the trachea and lung were documented at autopsy. A second patient had persistent mucositis after achieving a partial remission with fludarabine; 5 months after the last course of treatment, he developed Stevens-Johnson syndrome with severe skin desquamation and subsequently died. A third patient demonstrated disease progression during the first course of fludarabine treatment with pneumonitis diagnosed when the granulocyte count was normal; a course of chlorambucil and prednisone ensued but disease nevertheless progressed, leading to the patient’s death. There were no toxic deaths reported on the CVP arm.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In phase II studies, fludarabine has demonstrated activity in heterogenous populations of patients both relapsed from and refractory to alkylating agents. Overall response rates have been in the range of 40% to 50%, most of which are PRs of 10 to 12 months’ duration.^15-18 The purpose of this study was to determine whether patients with previously responsive disease would have superior response rates and response durations when treated with fludarabine in comparison with an alkylator-based regimen.

The study was closed before the original accrual target was met because widespread availability of the drug in the community together with the stringent entry criteria allowed us to only randomize 91 patients in the 3 years planned for enrollment. The statistical calculations were based on detecting a 20% difference in the pro-portion of patients remaining free of progression at the 18-month time point, which we believed would represent a clinically meaningful difference. Longer follow-up allowed a sufficient number of events to occur, despite the smaller patient cohorts, to make possible the detection of a larger than expected difference in this primary end point.

The CVP regimen chosen as the standard arm was arrived at by consensus among the investigators invited to participate in the study from across Canada and reflected the pattern of practice within this community. Although more dose-intensive alkylator-based regimens are described, none has reported superior results to any other in a randomized study. Given the rate of hematologic toxicity and febrile neutropenia seen in our standard CVP regimen, which was not statistically different from that seen with fludarabine, it is not likely that patients on this arm can be considered to have been undertreated.

The major finding of this study was superiority for the fludarabine arm in PFS and time to next treatment, in terms of both medians for each entire group and proportions of patients at discrete time points (12, 18, 24, 36, and 48 months), despite the similar response rates seen in both groups. This was of sufficient magnitude to be of statistical significance and, we believe, clinical relevance. This gain must be balanced against a modest, though not statistically significant, increase in grade 3 or 4 infectious complications and antibiotic use. The study committee also concluded that three deaths on the fludarabine arm were related to the toxicity of the agent, and this must be kept in mind when selecting treatment for a particular patient. There was no difference in overall survival between the two groups, in keeping with the difficulty of making such an impact on a chronic relapsing disease with a variety of available treatment options. Moreover, as treatment on progression was not mandated by the protocol, it would be expected that a significant proportion of patients crossed over to receive fludarabine after relapse from CVP and vice versa. Extrapolating from the only existing crossover data in a related lymphoproliferative disease, chronic lymphocytic leukemia, where previously untreated patients were randomized, 46% relapsing after response to chlorambucil responded to fludarabine, whereas only 7% relapsing from fludarabine responded to chlorambucil.¹⁴

It is important to place the results of this study into the context of other reports dealing with this patient population. No randomized studies have been reported in relapsed low-grade lymphoma in the recent past, and all treatment decisions have been based on phase II reports. This study does confirm that fludarabine is the most active agent for the treatment of this disease at relapse after initial alkylator- or anthracycline-based chemotherapy. Rituximab, a humanized murine monoclonal antibody directed at the CD20 epitope expressed in most B-cell lymphoproliferative disorders, is reported to have a response rate in the 40% to 50% range, with a median duration of 10 to 12 months in a number of phase II studies that included patients with both relapsed and refractory disease, some of whom had already received fludarabine.^26,27 A direct comparison of the two agents has not been performed.

Two reports of phase III results in previously untreated patients with advanced-stage low-grade lymphoma, in which fludarabine was one of the randomized arms, are relevant to our findings. The early results of a study of similar design conducted under the auspices of the European Organization for Research and Treatment of Cancer have been reported in abstract form.²⁸ Three hundred eighty-one patients were randomized, either at diagnosis or after a period of observation, to CVP or fludarabine. Response rate (69% v 53%; P = .001) favored fludarabine, whereas PFS at short follow-up was 400 days with fludarabine versus 300 days with CVP (medians not reached; P value not stated). These preliminary results are consistent with our own findings in a sensitive-relapse population further into the history of their disease. In contrast, a randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA) has compared fludarabine to cyclophosphamide, doxorubicin, teniposide, and prednisolone (CHVP) and interferon alfa-2b in previously untreated patients older than 59 years with follicular lymphoma and poor prognostic features. Patients on both arms received treatment for 18 months and CHVP-interferon was associated with a higher response rate (71% v 59%), longer time to progression (63% v 49% at 2 years), and longer overall survival (77% v 62% at 2 years) than fludarabine at a relatively short median follow-up of 29 months for the 131 patients randomized.²⁹ The many reasons for the wide variation in outcomes for clinical trials in low-grade NHL include the heterogeneity of patient populations, histologic subtypes, prognostic factors, eras of treatment and reporting, duration of follow-up, and disease biology.

The results of this randomized study indicate a role for fludarabine earlier in the course of relapsed advanced-stage low-grade lymphoma. In comparison with CVP, fludarabine treatment was associated with superior PFS and TFS, with maintenance of high QoL scores. Investigators continue to explore combining this agent with other active drugs, and to move novel treatment strategies up to the time of initial diagnosis in attempts to improve the response rate, duration, and, ultimately, the survival of patients.^30-33 Only randomized controlled trials in identifiable patient populations with well-defined disease entities will allow us to determine where best to use the many approaches available to us in treating these chronic relapsing malignancies.

APPENDIX Participating Investigators and Institutions
The following investigators and institutions participated in this study:R. Klasa, British Columbia Cancer Agency, Vancouver, British Columbia; R. Meyer, Hamilton Regional Cancer Centre, Hamilton, Ontario; C. Shustik, McGill Oncology Group, Montreal, Quebec; C. Sawka, Toronto Sunnybrook Regional Cancer Centre, Toronto, Ontario; A. Smith and M. Kovaks, London Regional Cancer Centre, London, Ontario; R. Guévin, Centre Hospitalier de l’Université de Montréal (St-Luc), Montreal, Quebec; M. Samosh, Hotel Dieu Hospital, St. Catharine’s, Ontario; M. Rubinger, Cancercare Manitoba, Winnipeg, Manitoba; A. Maksymiuk, Saskatoon Cancer Centre, Saskatoon, Saskatchewan; F. Couture, Hôtel-Dieu de Québec, Quebec City, Quebec; L. Fernandez, Victoria General Hospital, Halifax, Nova Scotia; J. Sturgeon, Princess Margaret Hospital, Toronto, Ontario; B. L’Espérance, Hôpital du Sacré-Coeur, Montréal, Quebec; A. Belch, Cross Cancer Institute, Edmonton, Alberta; L. Yelle, Centre Hospitalier de l’Université de Montreal (Notre-Dame), Montreal, Quebec; D. Vergidis, Thunder Bay Regional Cancer Clinic, Thunder Bay, Ontario; H. Rayner, British Columbia Cancer Agency, Victoria, British Columbia; K. Grewal, The General Hospital, St-John’s, Newfoundland; and D. Dryer, Queen Elizabeth Hospital, Charlottetown, Prince Edward Island.

	ACKNOWLEDGMENTS

 
Supported by Berlex Canada, Inc.

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Submitted November 15, 2001; accepted August 12, 2002.

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