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Journal of Clinical Oncology, Vol 18, Issue 5 (March), 2000: 987
© 2000 American Society for Clinical Oncology

Phase I Study of Fludarabine Plus Cyclophosphamide in Patients With Previously Untreated Low-Grade Lymphoma: Results and and Long-Term Follow-Up—A Report From the Eastern Cooperative Oncology Group

By Howard S. Hochster, Martin M. Oken, Jane N. Winter, Leo I. Gordon, Bruce G. Raphael, John M. Bennett, Peter A. Cassileth

From the New York University, New York, NY; Virginia Piper Cancer Institute, Minneapolis, MN; Northwestern University, Chicago, IL; University of Rochester Cancer Center, Rochester, NY; and University of Miami, Miami, FL.

Address reprint requests to Howard Hochster, MD, New York University School of Medicine, 160 East 32nd St, New York, NY 10016; email howard.hochster{at}med.nyu.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To determine the toxicity and recommended phase II doses of the combination of fludarabine plus cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma.

PATIENTS AND METHODS: Previously untreated patients with low-grade lymphoma were entered onto dosing cohorts of four patients each. The cyclophosphamide dose, given on day 1, was increased from 600 to 1,000 mg/m2. Fludarabine 20 mg/m2 was administered on days 1 through 5. The first eight patients were treated every 21 days; later patients were treated every 28 days. Prophylactic antibiotics were required.

RESULTS: Prolonged cytopenia and pulmonary toxicity each occurred in three of eight patients treated every 3 weeks. The 19 patients treated every 28 days, who were given granulocyte colony-stimulating factor as indicated, did not have undue nonhematologic toxicity. Dose-limiting toxicity was hematologic. At the recommended phase II/III dose (cyclophosphamide 1,000 mg/m2), grade 4 neutropenia was observed in 17% of all cycles and 31% of first cycles. Grade 3 or 4 thrombocytopenia was seen in only 1% of all cycles. The median number of cycles per patient was six (range, two to 11) for all patients enrolled. The response rate was 100% of 27 patients entered; 89% achieved a complete and 11% a partial response. Nineteen of 22 patients with bone marrow involvement had clearing of the marrow. Median duration of follow-up was more than 5 years; median overall and disease-free survival times have not been reached. Kaplan-Meier estimated 5-year overall survival and disease-free survival rates were 66% and 53%, respectively.

CONCLUSION: The recommended dosing for this combination in patients with previously untreated low-grade lymphoma is cyclophosphamide 1,000 mg/m2 day 1 and fludarabine 20 mg/m2 days 1 through 5. The regimen has a high level of activity, with prolonged complete remissions providing 5-year overall and disease-free survival rates as high as those reported for other therapeutic approaches in untreated patients.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE OPTIMAL THERAPEUTIC approach for patients with low-grade or indolent non-Hodgkin’s lymphoma remains controversial. These patients have high rates of response to treatment with conventional chemotherapeutic agents. Treatment with single agents such as cyclophosphamide or chlorambucil is associated with overall response rates of 80% to 90% and complete remission rates of 30% to 50%.1 Combination therapy with alkylating agents plus various agents including prednisone, vincristine, doxorubicin, bleomycin, procarbazine, and carmustine has thus far failed to show an advantage in time to progression or survival over single-agent therapy in prospectively randomized clinical trials.2-4 Eastern Cooperative Oncology Group (ECOG) study E2474 compared the combination of cyclophosphamide, vincristine, procarbazine, and prednisone; that of carmustine, cyclophosphamide, vincristine, prednisone; and cyclophosphamide-prednisone in a three-arm study and found similar response rates (60% for the combination regimens and 52% for cyclophosphamide-prednisone) and equivalent 2-year survival.2 Similarly, in a Cancer and Leukemia Group B (CALGB) study comparing cyclophosphamide and the combination of cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin, the complete response (CR) rate for either treatment was 66%.3 More recently, the addition of interferon alfa-2b to cyclophosphamide therapy did not improve outcome, compared with cyclophosphamide alone, in the intergroup CALGB-ECOG randomized study, which found an overall response rate of 85% to 88% (with no difference in treatment arms) and a CR rate of 42%.4 This was reflected in the 5-year freedom-from-progression rate of 32%.

It is well established that therapy may be delayed in indolent low-grade lymphoma until symptoms or organ compromise occurs, without jeopardizing survival.5 In 13 years of follow-up, the National Cancer Institute study comparing aggressive therapy involving the prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide (ProMACE)–cytarabine, bleomycin, vincristine, and methotrexate (CytaBOM) regimen with initial observation has shown no difference in survival.6 Nevertheless, most patients with this disease eventually become symptomatic and require chemotherapy to control disease manifestations. Many chemotherapy programs are active in reducing bulk disease, but no chemotherapy program has improved survival more than single-agent alkylator therapy in patients with low-grade lymphoma.7 Newer and more effective agents that may alter the natural history of indolent lymphomas are needed. One such agent is fludarabine.

Fludarabine phosphate (2-fluoro-ara-adenine-monophosphate, 9-ß-D-arabinofuranosyl-2-adenine monophosphate) is a deamination-resistant analog of vidarabine (ara-A). Fluorine substitution at the number 2 position of the purine moiety confers resistance to adenine deaminase, the enzyme responsible for inactivation of the parent compound. Fludarabine is prepared as the monophosphate of fluoro-ara-A for improved solubility in water. On administration of fludarabine, the phosphate is rapidly removed by serum phosphatases, and it is mainly found in the serum as 2-fluoro-ara-A, which has a distribution half-life of 0.6 hours and a terminal half-life of 9.2 hours.8 This nucleoside is taken up and rephosphorylated within the cell, eventually to the triphosphate. In several phase I studies of fludarabine, dose-dependent myelosuppression was the major limiting toxicity.8-14 The schedule of daily x 5 days was selected for phase II studies because of its lack of toxicity, especially the neurologic toxicity seen at higher doses.15

Fludarabine has significant activity in chronic lymphocytic leukemia and has become an important alternative for first-line therapy for this disease.16 In our previous ECOG study (E4484), fludarabine was highly active in heavily pretreated patients with non-Hodgkin’s lymphoma, particularly in those with low-grade lymphoma.17 Fifty-seven assessable patients were treated at a dosage of 18 mg/m2 intravenously (IV) daily x 5 days, which resulted in eight complete and eight partial remissions (overall response rate of 28%). The highest response rate by histologic subtype was seen in the follicular small cleaved-cell lymphoma group, with three CRs and five partial responses (PRs) among 11 patients treated (overall response rate of 72%). For all patients with low-grade histologies (22 patients), the overall response rate was 45%. This therapy was associated with tolerable grade 2 to 3 leukopenia, rare grade 3 to 4 thrombocytopenia, and an incidence of clinically significant nonhematologic toxicity of less than 10%.17

We therefore evaluated this promising drug in combination with a standard alkylating agent, cyclophosphamide, in a multi-institutional phase I trial, conducted under the auspices of ECOG.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility
The goal of this limited-institution, multicenter study (ECOG 1491) was to determine the toxicity and optimal dose combination of fludarabine with cyclophosphamide in chemotherapy-naive patients with low-grade lymphoma. Eligibility criteria included no previous treatment (except for administration of corticosteroids) along with a pathologic diagnosis of low-grade malignant non-Hodgkin’s lymphoma (small lymphocytic lymphoma, follicular small cleaved-cell lymphoma, or follicular mixed small- and large-cell lymphoma).

Patients were required to have Ann Arbor stage III or IV disease with at least one objective measurable disease parameter, including any adenopathy or mass that could be measured during a physical examination or that was >= 5 cm on a computed tomographic (CT) scan. In the event of splenomegaly or hepatomegaly, extension 5 cm below the costal margin was considered evidence of measurable disease. Biopsy proof of hepatic involvement was required if this was the sole area of measurable disease.

Each patient was required to have a WBC count >= 4,000/µL, granulocyte count (absolute neutrophil count) >= 2,500/µL, and platelet count >= 100,000/µL. In the event of biopsy-proven involvement of bone marrow, patients were allowed to be entered onto the study with WBC counts greater than 2,000/µL or platelet counts greater than 75,000/µL. Also required were an ECOG performance status of 0 to 1; blood urea nitrogen levels <= 25 mg/dL or serum creatinine levels <= 2.0 mg/dL; liver enzyme concentrations less than three times the upper limit of normal, unless due to documented liver involvement; and written informed consent. All patients underwent bilateral iliac crest bone marrow biopsies, although a unilateral biopsy was acceptable if results were positive. Patients who were pregnant or lactating, human immunodeficiency virus–positive, or younger than 15 years of age or who had significant neurologic disorders or CNS involvement were excluded.

Chemotherapy
Patients were treated with IV cyclophosphamide on day 1 and fludarabine given as a 30-minute IV infusion daily on days 1 through 5. Cycles were initially repeated every 21 days, but cycles were extended to 28 days after the first eight patients were enrolled. Fludarabine was supplied by the National Cancer Institute in 50-mg vials and was given as outlined in Table 1. The proper dose was drawn up after reconstitution with 2 mL of sterile water and was then dissolved in 100 mL of 5% dextrose for administration as a 30-minute infusion. Cyclophosphamide, available commercially, was administered in 500 mL of 5% dextrose. Dosing for each cohort in this phase I study is listed in Table 1. At least four patients were treated at each dose level. Each succeeding dose level was instituted if there was no evidence of dose-limiting toxicity (DLT) in the previous cohort. DLT was defined as grade 4 hematologic toxicity, grade 2 neurologic toxicity, or any other (grade 3) toxicity. In the event that fewer than two patients of the four entered onto the study at a given dose level had DLT, the next cohort was begun at the next dose level. If two patients had DLT, an additional two patients were entered at that dose level. If three or four patients on any dose level experienced DLT, the prior dose was considered the maximum-tolerated dose (MTD). Ten patients were then entered at the MTD level to further determine toxicity and estimate efficacy.


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  		Table 1. Study Design
 
Dose Modifications
No dose modifications were made as a result of hematologic toxicity, because hematologic toxicity was expected to be the DLT of the combination. Patients who were known to have bone marrow involvement were expected to have more severe hematologic toxicity in the initial cycles. Patients with granulocyte counts of less than 2,500/µL or platelet counts of less than 100,000/µL on day 1 of the next cycle had treatment delayed until recovery to these minimal levels. Patients who did not recover by week 6 (a 2-week delay) were required to undergo repeat bone marrow biopsy for documentation of pancytopenia or progression of bone marrow involvement. In the event of hemorrhagic cystitis, cyclophosphamide therapy was stopped until resolution and subsequent doses were 50% of the initial dose. Use of standard antiemetics was encouraged. Patients who had grade 4 nausea and vomiting were removed from the study. Patients who developed neutropenia-related fever were treated with co-trimoxazole one tablet orally bid for all subsequent cycles. After the first eight patients were entered, co-trimoxazole one tablet orally bid was required for all patients as prophylaxis for Pneumocystis carinii pneumonia (PCP) and acyclovir was required as herpes zoster prophylaxis. Patients with documented septicemia had a 25% dose reduction of both drugs in subsequent cycles.

Duration of Therapy
All patients were treated until maximum response and then for two more cycles. Patients achieving complete remission were treated with two additional cycles before therapy was ended. A maximum of eight cycles was given for any one patient. Patients whose disease progressed were taken off study.

Disease Evaluation
Each patient underwent a prestudy physical examination, tumor measurement, performance status evaluation, a complete blood count, chemistry analyses, liver function tests, bone marrow biopsy, chest x-ray, CT scans of the chest and abdomen, and, if the sole evidence of disease was in the liver, liver biopsy. Complete blood counts were repeated weekly, with physical examination, tumor measurements, and blood chemistry analyses performed during each cycle. Restaging was required every two cycles, including CT scans and chest x-ray, if the initial findings were positive. ECOG toxicity and response criteria were used.18 Follow-up visits occurred every 3 months until death.

Statistical Considerations
All cases underwent central pathology review to confirm diagnosis. This phase I study of a two-drug combination had the goal of accruing a maximum of 20 patients in the phase I dose-escalation portion of the study and an additional 10 patients at the MTD. The incidence of DLT as defined earlier was approximately 25% to 33% in prior ECOG studies of low-grade lymphoma (E4477, E6484, and E7486), which included both single-agent cyclophosphamide therapy and combination chemotherapy with cyclophosphamide, vincristine, prednisone, and doxorubicin.19 Lower incidence of toxicity was noted with single-agent fludarabine in E4484. Given these figures and the number of patients involved, it was estimated that there was a 41% chance of escalating above a dose level with an underlying 50% rate of DLT, and only a 10% chance of escalating above a dose level with an underlying DLT rate of 70%. Survival and time to progression were estimated using the Kaplan-Meier method20 and StatView statistical software (Statistical Consultants, Research Triangle Park, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Twenty-seven patients were entered onto the study between July 8, 1991, and September 30, 1993. Patient characteristics are listed in Table 2. The median age was 45 years (range, 27 to 77 years) and seven of 27 subjects were elderly (> 60 years). The median time from diagnosis to study entry was 1.5 months (range, 0.5 to 27 months). Twenty-two had stage IV disease (all with bone marrow involvement). None of the patients had increased lactate dehydrogenase levels, although 14 patients had the negative prognostic factor of bulk disease. Only one patient had extranodal involvement (other than marrow), with a retro-orbital mass.


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  		Table 2. Patient Characteristics
 
Protocol Therapy
Patients were treated according to the study design, outlined in Table 1. Five patients were entered at the first dose level (one patient was considered inassessable because he refused to continue therapy beyond two cycles). Three patients made up the second dose cohort. After independent review of the toxicity encountered, the cycle was lengthened to 28 days and prophylaxis for PCP and herpes zoster was added. Provision for use of granulocyte colony-stimulating factor (G-CSF) prophylactically in cycles following an episode of grade 4 neutropenia was also added. Three additional patients were then accrued at the second dose level without DLT, and after the initial four patients were enrolled at the third dose level, accrual was expanded at this level to gain additional experience with the combination.

Hematologic Toxicity
Of the first eight patients who were entered onto the study, three were removed because of complications of grade 4 neutropenia after one or two cycles. The incidence of grade 4 hematologic toxicity was 50% in these first two cohorts. At this point, the study was amended as described. Hematologic toxicity data are listed in Table 3. In total, 155 cycles were given, including 100 cycles at dose level 3, which we consider the recommended phase II dose. In all cycles, only one episode of grade 4 and one of grade 3 thrombocytopenia were observed. Grade 4 neutropenia was the major hematologic toxicity, with an incidence of 18% for all cycles and 28% for all first cycles (given without G-CSF). The incidence of grade 3 neutropenia was 26% for the first cycles and 25% for all cycles. Three patients (of the 19 entered after protocol amendment) received G-CSF. The median number of cycles given per patient was six (range, 2 to 11) for all 27 patients entered.


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  		Table 3. Hematologic Toxicity
 
Nonhematologic Toxicity
Major nonhematologic toxicity included pulmonary and infectious toxicity (Table 4). Three episodes of interstitial pneumonia occurred in the first eight patients and three in the19 patients entered after protocol amendment. The most severe episode occurred in a patient in the first group who presented with adult respiratory distress syndrome and required intubation. Bronchoscopic lung biopsy was negative for PCP or other pathogens and consistent with a drug reaction. Another four of the six patients with pulmonary toxicity presented with similar symptoms, including fever, cough, and shortness of breath. In three cases, results of gallium scans were positive in the lung. Only one of these four patients had documented PCP; the other three underwent nondiagnostic bronchoscopic lavage and biopsy. In the case of the two patients treated after protocol amendment, patient compliance with co-trimoxazole prophylaxis was questionable. The sixth patient had persistent interstitial infiltrates of unknown etiology in the left lower lobe from the time of initial diagnosis. This was considered to be grade 1 toxicity and was treated with corticosteroids. In summary, there were six cases of pulmonary toxicity, one of which was mild and of uncertain etiology and five of which were more serious. In four of these cases, one could not distinguish between interstitial pneumonia due to drug toxicity and PCP. One patient had documented PCP. All patients recovered from pulmonary toxicity.


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  		Table 4. Nonhematologic Toxicity
 
With regard to infectious toxicity, there were one case of grade 4 fungal sepsis during prolonged pancytopenia (associated with a vasculitic and pemphigoid skin reaction and grade 2 mucositis), one case of lobar pneumonia (grade 1), and one case of venous access port infection (grade 3). Herpes zoster radiculopathy occurred in three patients: during therapy in two patients and 3 months later in one patient. Two patients developed presumed herpes simplex. The overall incidence of grade 3 and 4 infection (including the case of documented PCP) was 11% (three of 27 patients).

Response
All 27 patients entered onto the study responded to cyclophosphamide and fludarabine therapy, including the six patients who went off study early because of toxicity (three because of prolonged cytopenia and three because of pulmonary toxicity). All of the patients who experienced toxicity that prohibited completion of protocol therapy (maximum response plus two cycles) were in the initial dosing cohorts (dose levels before protocol amendment). Most patients showed signs of response in clinically palpable nodes by the second course of therapy, and all showed at least a PR by the end of the second cycle, when restaging was required. In three patients, PR was the overall best response; two of these patients were among those who discontinued therapy prematurely because of toxicity. Complete remission occurred in 24 (89%) of 27 patients; in this group, 19 of 22 patients with bone marrow involvement had clearing of the marrow.

Long-Term Follow-Up
After a median follow-up of 61 months (range, 54 to 80+ months), 12 patients remained alive without evidence of disease, eight were alive but relapsed, and three died from lymphoma. Four additional patients died from other causes (two from hematologic or infectious toxicity, one from myocardial infarction that was not treatment related, and one from lung cancer 4 years after completion of treatment for lymphoma). Progression-free survival and overall survival are shown by Kaplan-Meier curves in Figs 1 and 2. The 5-year disease-free survival rate was 53%, with the median time to progression not yet reached. The 5-year overall survival rate was 66%, with the median survival time not yet reached. The 95% confidence interval on the plateau of these curves is approximately ±23% because of the small study sample. These results are similar to the upper range of outcomes previously reported for patients with low-grade lymphoma.21



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  		Fig 1. Kaplan-Meier progression-free survival curve. Solid line, cumulative survival; {diamondsuit}, event times; +, censor times.

 


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  		Fig 2. Kaplan-Meier overall survival curve. Solid line, cumulative survival; {diamondsuit}, event times; +, censor times.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Because of our favorable experience with fludarabine in patients with previously treated low-grade lymphoma, we conducted a phase I/II study of cyclophosphamide and fludarabine in patients who had not received prior chemotherapy. The study was designed to determine the MTD of these two drugs given on a 3-week schedule. We found that there was excessive toxicity (both prolonged cytopenia and pulmonary toxicity) when these drugs were administered on such a schedule. After review of the toxicity occurring in the initial eight patients enrolled at the first two dose levels, cycles were lengthened to 28 days. Prophylaxis for opportunistic infections with both oral co-trimoxazole and acyclovir was also added. Additional patients were accrued at the second and third dose levels to increase the detection of any cumulative toxicity of this regimen. Review of our experience with the 27 study patients led us to conclude that the third dose level (cyclophosphamide 1,000 mg/m2 day 1 and fludarabine 20 mg/m2 days 1 through 5 every 28 days) was the recommended dose for phase II and III studies. We came to this conclusion because (a) the incidence of toxicity that we observed was not clearly related to the dose of cyclophosphamide, (b) we had reached a standard dose of cyclophosphamide used in combination chemotherapy regimens, (c) we did not desire to escalate to a dose that necessitated treatment with growth factors, and (d) the comparative regimens in general use for treatment of low-grade lymphoma are relatively nontoxic.

Despite the fact that six patients could not complete therapy according to protocol, the response rate in this study was 100%, with an 89% CR rate. With median long-term follow-up of more than 5 years, median time to progression and overall survival have not yet been reached. It is difficult to compare the prognosis for the study patients with those in other trials reported in the literature. Half of our patients had bulky disease, and seven (26%) of 27 patients were older than 60 years. Patients were not formally required to meet specific criteria regarding progression, extent of disease, or symptoms to be eligible for treatment in this protocol, although the phase I nature of the study and the early toxicity encountered led investigators to enroll patients only when they believed that therapy was truly necessary. However, the WBC count (>= 4,000/µL) and absolute neutrophil count (>= 2,500/µL) required are somewhat higher than those required in other reported trials. Even given these favorable survival statistics, we recognize that the possibility of continued relapse with further follow-up exists and that these results may prove no better than those achieved with other approaches when larger samples and longer follow-up are involved.

Besides our previous study (E4484),17 described earlier in this article, additional studies of fludarabine have been conducted. The M.D. Anderson Cancer Center group studied the combination regimen of fludarabine, mitoxantrone, and dexamethasone in 51 previously treated patients with recurrent or relapsed indolent lymphoma.22 These investigators reported a CR rate of 47% and a PR rate of 47% in this patient population, with median progression-free survival durations of 21 months in the CR group and 9 months in the PR group. Toxicity in the form of opportunistic infections was similar to that in our study. In a recent Canadian randomized study of second-line therapy in 91 patients with low-grade lymphoma, response rates for single-agent fludarabine therapy and combination therapy with cyclophosphamide, vincristine, and prednisone were similar, although progression-free and treatment-free survival were both statistically improved by a factor of two with 2 years’ follow-up in the fludarabine treatment arm.23

Single-agent fludarabine as first-line treatment was the focus of a multicenter study by the French Groupe d’Etude des Lymphomes de l’Adulte.24 In this study, the overall response rate was 65% and the CR rate was 37% for the 49 assessable patients (of 54 enrolled). Median time to progression was 13.6 months, which may be compared with the median time of more than 60 months in our study. The Southwest Oncology Group recently reported on its experience with fludarabine and mitoxantrone (S95-01) as first-line therapy in 81 eligible patients with low-grade lymphoma.25 They reported a response rate of 91% and a CR rate of 43%. Two-year progression-free and overall survival rates were estimated to be 63% and 93%, respectively, with a median of 32 months of follow-up, which compares favorably with the findings reported here.

In the most recent intergroup low-grade lymphoma study, conducted by CALGB and ECOG, 581 subjects were randomly assigned to oral cyclophosphamide alone or oral cyclophosphamide with or without interferon alfa-2b in a 2 x 2 design.4 The response rate (rates did not differ across treatment arms) was 85% to 88% and the CR rate was 42%, but the 5-year failure-free survival rate was only 32%. The 5-year overall survival rate was 69%, similar to that in the current study, regardless of use of interferon alfa-2b.

Encouraged by the favorable long-term experience with the cyclophosphamide-fludarabine regimen and its high response rate, we have begun a phase III study comparing cyclophosphamide-fludarabine with a standard regimen of cyclophosphamide, vincristine, and prednisone (E1496). Responding patients will undergo a second randomization and be assigned to anti-CD20 antibody or observation. This trial will establish whether the cyclophosphamide-fludarabine regimen piloted here is better than conventional therapy and whether a biologic intervention after chemotherapeutic cytoreduction can improve long-term survival, a goal not clearly achieved in low-grade lymphoma to date.


   ACKNOWLEDGMENTS
 
Supported in part by Public Health Service grants no. CA16395, CA17145, CA11083, CA66636, and CA21115 from the National Cancer Institute, National Institutes of Health, Bethesda, MD.

The authors thank the ECOG Operations Office staff for their support and Sandra Horning, MD, for her insightful comments on the manuscript.


   NOTES
 
The contents of this article are solely the responsibility of the authors and do not necessarily reflect the official views of the National Cancer Institute.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. DeVita VT, Jaffe ES, Mauch P, et al: Lymphocytic lymphomas, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 3). Philadelphia, PA,Lippincott, 1989, pp 1741-1798

2. Ezdinli EZ, Anderson JR, Melvin F, et al: Moderate versus aggressive chemotherapy of nodular lymphocytic poorly differentiated lymphoma. J Clin Oncol 3:769-775, 1985[Abstract/Free Full Text]

3. Peterson BA, Frizzera JR, Anderson JR, et al: Response of low grade lymphoma to cyclophosphamide or cyclophosphamide, Adriamycin, vincristine, prednisone and bleomycin. Proc Am Soc Clin Oncol 4:211a, 1985 (abstr)

4. Peterson BA, Petroni GR, Oken MM, et al: Cyclophosphamide versus cyclophosphamide plus interferon alfa-2b in follicular low grade lymphomas: An intergroup phase III study (CALGB 8691 and ECOG 7486). Proc Am Soc Clin Oncol 16:14a, 1997 (abstr 48)

5. Horning SJ, Rosenberg SA: The natural history of initially untreated low-grade non-Hodgkin’s lymphoma. N Engl J Med 311:1471-1475, 1984[Abstract]

6. Longo DL: Updated results of the NCI randomized trial. Presented at the Workshop on ProMACE-CytaBOM, Modena, Italy, September 22, 1997

7. Horning SJ: Natural history of and therapy for the indolent non-Hodgkin’s lymphomas. Semin Oncol 20:75-88, 1993 (suppl 5)[Medline]

8. Hersh MR, Kuhn JG, Phillips JL, et al: Pharmacokinetic study of fludarabine phosphate (NSC 312887). Pharmacol 17:277-280, 1986

9. Hutton JJ, Von Hoff DD, Kuhn J, et al: Phase I clinical investigation of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate (NSC 312887), a new purine antimetabolite. Cancer Res 44:4183-4186, 1984[Abstract/Free Full Text]

10. Kavanagh JJ, Krakoff IH, Bodey GP: Phase I study of fludarabine (2-fluoro-ara-AMP). Clin Oncol 21:1009-1011, 1985

11. Casper ES, Mittelman A, Kelson D, et al: Phase I clinical trial of fludarabine phosphate (F-ara-AMP). Pharmacol 15:233-235, 1985

12. Warrell RP Jr, Berman E: Phase I and II study of fludarabine phosphate in leukemia: Therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol 4:74-79, 1986[Abstract]

13. Danhauser L, Plunkett W, Keating M, et al: 9-beta-D-Arabinofuranosyl-2-fluoroadenine 5'-monophosphate pharmacokinetics in plasma and tumor cells of patients with relapsed leukemia and lymphoma. Chemother Pharmacol 18:145-152, 1986

14. Leiby JM, Grever MR, Staubus AE, et al: Phase I clinical investigation of fludarabine phosphate by a loading-dose and continuous-infusion schedule. J Natl Cancer Inst 80:447-449, 1988[Abstract/Free Full Text]

15. Chun HG, Leyland-Jones BR, Caryk SM, et al: Central nervous system toxicity of fludarabine phosphate. Cancer Treat Rep 70:1225-1228, 1986[Medline]

16. Keating MJ, Kantarijian H, Talpaz M, et al: Fludarabine: A new agent with major activity against CLL. Blood 74:19-25, 1989[Abstract/Free Full Text]

17. Hochster H, Kim K, Green MD, et al: Activity of fludarabine in previously treated non-Hodgkin’s low grade lymphoma: Results of an Eastern Cooperative Oncology Group study. J Clin Oncol 10:28-32, 1992[Abstract]

18. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Oncol 5:649-655, 1982

19. Smalley R, Weller E, Hawkins MJ, et al: Alpha interferon in non-Hodgkin’s lymphoma: An update of the ECOG I-COPA trial (E6484). Blood 92:486a, 1998 (suppl 1, abstr 2004)

20. Kaplan FL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 52:457-481, 1958

21. Armitage JO, Lister AT: Non-Hodgkin’s lymphoma, ASCO Spring Educational Book, pp 338-341, 1998

22. McLaughlin P, Hagemeister FB, Romaguera JE, et al: Fludarabine, mitoxantrone, and dexamethasone: An effective new regimen for indolent lymphoma. J Clin Oncol 14:1262-1268, 1996[Abstract/Free Full Text]

23. Klasa R, Meyer R, Shustik C, et al: Fludarabine versus CVP in previously treated patients with progressive low grade non-Hodgkin’s lymphomas (lg-NHL). Proc Am Soc Clin Oncol 18:9a, 1999 (abstr 28)

24. Solal-Celigny P, Brice P, Brousse N, et al: Phase II trial of fludarabine monophosphate as first-line treatment in patients with advanced follicular lymphoma: A multicenter study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 14:514-519, 1996[Abstract/Free Full Text]

25. Velasquez W, Lew D, Miller T, et al: SWOG 95-01: A phase II trial of a combination of fludarabine and mitoxantrone (FN) in untreated advanced low grade lymphoma—An effective, well tolerated therapy. Proc Am Soc Clin Oncol 18:9a, 1999 (abstr 27)

Submitted July 12, 1999; accepted September 27, 1999.


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