the Hematology and Stem Cell Transplantation Division and Clinical Laboratory Division, National Cancer Center Hospital
    Research Center for Cancer Prevention and Screening, National Cancer Center
    Department of Radiology, St Lukes International Hospital
    Department of Pathology, Teikyo University Hospital
    Department of Biostatistics/Epidemiology and Preventive Health Sciences, School of Health Sciences and Nursing, University of Tokyo, Tokyo
    Departments of Hematology and Cell Therapy and Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya
    Department of Hematology and Oncology, Tokai University Hospital, Isehara
    Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai
    Division of Oncology/Hematology and Diagnostic Radiology Division, National Cancer Center Hospital East, Kashiwa
    Department of Hematology, Imamura Bun-in Hospital, Kagoshima
    Department of Hematology, Kyoto Prefectural University of Medicine, Kyoto
    Nihon Schering K.K., Osaka, Japan.

    ABSTRACT

    PURPOSE: Although intravenous (IV) fludarabine phosphate is effective against indolent B-cell non-Hodgkin's lymphoma (B-NHL), IV administration for 3 to 5 consecutive days is inconvenient in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine phosphate in patients with indolent B-NHL, we conducted a multicenter phase II study.

    PATIENTS AND METHODS: Patients with relapsed indolent B-NHL received fludarabine phosphate tablets orally once daily on days 1 through 5 every 28 days for three to six cycles. The efficacy was separately analyzed in a mantle-cell lymphoma (MCL) cohort and indolent B-NHL except for MCL (IL) cohort. The primary end point was the overall response rate (ORR).

    RESULTS: Fifty-two patients, including 46 in the IL cohort (41 with follicular lymphoma) and six in the MCL cohort, were registered, and all patients were eligible. Forty-one patients (79%) had received rituximab as prior therapy. In the IL cohort, the ORR and complete response rate were 65% (30 of 46 patients; 95% CI, 50% to 79%) and 30% (14 of 46 patients; 95% CI, 18% to 46%), respectively. One of six patients with MCL achieved a partial response. The median times to treatment failure for the 46 patients in the IL cohort and for the six patients in the MCL cohort were 8.6 and 6.1 months, respectively. Hematologic toxicities, including grade 4 neutropenia (37%), were the most frequent toxicities, and nonhematologic toxicities were mild.

    CONCLUSION: Oral fludarabine phosphate is highly effective in patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab and is more convenient than the IV formulation.

    INTRODUCTION

    The majority of patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL), mainly consisting of follicular lymphoma, are incurable by current treatments. Most patients initially respond to chemotherapy, but the clinical course follows a pattern of repeated relapse. The disease has a relatively long natural history, with a median survival time of 7 to 10 years.1 Thus, effective treatment that maintains a good quality of life is warranted.

    The use of alkylating agents as monotherapy or in combination has been one of the most frequently applied treatments for patients with indolent B-NHL. Cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy did not show therapeutic superiority to treatment without doxorubicin.2 Recent improvements have included rituximab, a chimeric anti-CD20 monoclonal antibody, which has activity as a single agent3,4 and in combination.5,6 Except for chlorambucil and oral cyclophosphamide, these treatments are administered by intravenous (IV) infusion, and frequent visits to the outpatient clinic are required. For this indolent disease, effective oral therapy is preferable.

    Fludarabine phosphate is a purine analog that has a high efficacy for B-cell chronic lymphocytic leukemia as an IV formulation.7 In addition, using the dose and schedule of 18 to 30 mg/m2/d daily for 5 days, every 3 to 5 weeks, IV fludarabine has shown overall response rates (ORRs) ranging from 27% to 65%, with response durations of 10 to 12 months, as a monotherapy for selected patients with relapsed indolent NHL8-11 and exhibited a better progression-free survival than cyclophosphamide, vincristine, and prednisone.12 The oral form of fludarabine phosphate has a bioavailability of 55%,13 and in a phase II study for B-cell chronic lymphocytic leukemia, using fludarabine 10-mg tablets at a dose of 40 mg/m2/d for 5 days, repeated every 4 weeks, the ORR (51%, 40 of 78 patients) was similar to the ORR of IV fludarabine.14 Therefore, it is expected that oral fludarabine is effective for indolent B-NHL.

    In Japan, a phase I study of oral fludarabine was conducted on 12 patients with relapsed indolent B-NHL.15 The mean bioavailability of 63% obtained in Japanese patients was similar to the 55% bioavailability obtained in whites.13 Objective responses were observed in eight of the 12 patients. Given the toxicity profiles, the recommended dose for the subsequent phase II study was set at 40 mg/m2/d daily for 5 days every 4 weeks.15 To further assess the efficacy and toxicity of oral fludarabine phosphate in patients with relapsed indolent B-NHL, we conducted a multicenter phase II study.

    PATIENTS AND METHODS

    Patient Selection

    Patients with relapsed or refractory, histologically confirmed, indolent B-NHL, including small lymphocytic lymphoma, lymphoplasmacytic lymphoma, follicular lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, nodal marginal zone B-cell lymphoma, and mantle cell lymphoma (MCL), according to the WHO classification16 were eligible. Additional eligibility criteria included measurable disease; adequate hematologic (absolute neutrophil count  1,500/μL and platelet count  75,000/μL), renal (serum creatinine < 1.5x the upper limit of normal [ULN]), and hepatic (AST and ALT < 2.5x ULN and total bilirubin < 1.5x ULN) function; an Eastern Cooperative Oncology Group performance status of 0 to 217; age between 20 and 74 years; and expected survival of 3 months or longer. Patients with infection or serious complications or CNS disease or who had received purine analogs, such as fludarabine, cladribine, and pentostatin, were excluded. Other exclusion criteria included positivity for hepatitis B virus surface antigen, hepatitis C virus, or HIV antibody; other active malignancy; interstitial lung disease; and a history of autoimmune hemolytic anemia. Patients had to have been more than 4 weeks from the last chemotherapy or more than 3 months from the last rituximab treatment. The study protocol was approved by the institutional review board of each participating institution before the patients were enrolled onto the study. Also, all participants gave their informed consent before they entered the study.

    Central Pathology Review

    Unstained microscopic slides of lymphoma tissues obtained on initial biopsy and/or relapse were collected and stained with hematoxylin and eosin. In addition, immunohistochemical analyses were conducted using monoclonal antibodies (mAbs) including an anti-CD20 mAb (L26; DAKO, Glostrup, Denmark),18 anti-CD3 mAb (PS1; Novocastra, Newcastle upon Tyne, United Kingdom), anti-CD5 mAb (4C7; Novocastra), anti-CD10 mAb (56C6; Novocastra), and anti-cyclin D1 polyclonal antibody (MBL Co Ltd, Nagoya, Japan). Preparations that were stained with hematoxylin and eosin and immunohistochemically treated were microscopically examined by three hematopathologists (Yo.M., S. Nak., and S.M.). The diagnosis by the central review committee was regarded as the final diagnosis in cases where there was a discrepancy between the diagnosis of an institution and the diagnosis of the committee.

    Protocol Treatment

    Patients were planned to receive fludarabine phosphate tablets orally once daily on days 1 through 5 every 28 days for three to six cycles. In the first cycle, fludarabine phosphate tablets were administered at 40 mg/m2/d. Thereafter, the dose was determined according to the assessment criteria for starting subsequent treatment cycles (starting criteria) as listed in Table 1. If a patient did not fulfill the criteria, the protocol treatment was delayed by 1-week increments until recovery. If the treatment was delayed for more than 7 days, the dose was reduced to 30 mg/m2/d for all subsequent cycles. If postponement lasted longer than 14 days, the protocol treatment was interrupted. Prophylactic use of sulfamethoxazole/trimethoprim and acyclovir was allowed but not mandatory, and granulocyte colony-stimulating factor was used if necessary.

    Patient Monitoring and Follow-Up

    Patients were admitted during the first cycle, but from the second cycle, they could be treated as outpatients. The following evaluations were performed during the pretreatment screening period: vital signs, ECG, laboratory studies, bone marrow aspiration, and computed tomography (CT) imaging. During treatment, the patients were observed by physical examination, CBC counts, and serum chemistry every week. CT scan and bone marrow aspiration were performed 4 weeks after the start of the first, third, and sixth courses. The patients were observed until 12 weeks after completion of the protocol treatment or until the assessment of progressive disease (PD).

    Data Analysis

    Responses were assessed according to the International Workshop Criteria for NHL19 as follows. Complete response (CR) required the complete disappearance of all lesions and radiologic or biologic abnormalities and the absence of new lesions. CR unconfirmed (CRu) described patients who met the criteria of CR but who had an indeterminate bone marrow assessment or a more than 75% decrease from baseline in the sum of the products of the greatest perpendicular diameters (SPD) of all the measurable lesions but with a residual mass. Partial response (PR) was defined as a more than 50% decrease from baseline in the SPD of all the measured lesions, no increase in size of any other lesions, and no new lesions. Stable disease was defined as neither a 50% decrease nor a 50% increase in the SPD of the measured lesions, and PD was defined as the appearance of any new lesion or a more than 50% increase in the SPD from nadir. Confirmation of response by repeat measurement 28 or more days later was not required. In addition to the efficacy evaluation at each participating institute, an independent, third-party panel of three radiologists (T.T., S. Naw., and M.M.) carried out a central evaluation using the collected CT films. The primary efficacy variable was best ORR (the relative frequency of responders showing CR, CRu, or PR) in the indolent B-NHL except for MCL (IL) and MCL cohorts. Secondary efficacy parameters included the CR rate and time to treatment failure (TTF), which was defined as the time period from the date of enrollment to the date of the assessment of PD, the date of death as a result of any cause, or the date necessitating other antilymphoma treatment, whichever occurred earlier.

    Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 2.0. Follicular Lymphoma International Prognostic Index (FLIPI) scores were calculated by summing the number of risk factors (age > 60 years, Ann Arbor stage III or IV, hemoglobin < 12 g/dL, elevated lactate dehydrogenase, and > four nodal areas).20 The following three risk groups were defined: low (none or 1 risk factor), intermediate (two risk factors), and poor risk (three to five risk factors).

    Statistical Methods

    The efficacy was separately analyzed in the IL and MCL cohorts. Only the assessment of central evaluation was relevant for efficacy evaluations. For the IL cohort, the study was designed assuming the threshold ORR of 25% to reliably detect an expected ORR of 45%. With the level of significance at 5% (one tailed), the required sample size to attain a statistical power of 80% was 36 patients. Assuming that up to 20% of the enrolled patients might be judged unassessable, the sample size was set at 45 patients. For the MCL cohort, the threshold ORR was set at 15%. It was designed to detect an expected ORR of 40%, with the level of significance at 5% (one tailed), and the required sample size to attain a statistical power of 70% was 14 patients. Therefore, considering a 20% possible exclusion rate, the sample size for the MCL cohort was initially set at 18 patients. However, because of slow accrual, we decided to prematurely close the recruitment for the MCL cohort.

    RESULTS

    Patient Characteristics

    Between February 2003 and October 2003, 52 patients with relapsed or refractory indolent B-NHL were enrolled from 16 institutes. Forty-seven patients were enrolled onto the IL cohort, and five were enrolled onto the MCL cohort. In the central pathology review, one patient enrolled onto the IL cohort was found to have MCL. Therefore, the final number of patients belonging to each category was 46 in the IL cohort and six in the MCL cohort, as shown in Table 2. The central pathology review revealed that the IL cohort consisted mostly of follicular lymphoma patients (89%). The low number of MCL patients was primarily a result of the small population of MCL patients in Japan.21 The majority of patients, 67% and 83% in the IL and MCL cohorts, respectively, had advanced-stage disease on entering the study. According to the International Prognostic Index,22 44 patients (85%) belonged to the low- or low-intermediate–risk group. When we applied the FLIPI20 to the IL cohort, 25 patients (54%) were low risk, 13 patients (28%) were intermediate risk, and six patients (13%) were poor risk. All 52 patients had received chemotherapy except for one patient in the IL cohort who had received rituximab alone.

    Protocol Treatment

    In total, 243 cycles of the protocol treatment were delivered to the 52 patients, for a median of six cycles per patient (range, one to six cycles) and a mean of 4.7 cycles. The protocol treatment was discontinued in 10 patients before they completed the third cycle. The reasons for discontinuation were as follows: four patients developed PD, two developed adverse events (one patient had herpes zoster and one had interstitial lung disease), two withdrew their consent, and two did not meet the starting criteria. After the third cycle, 13 patients did not complete the planned six cycles of treatment. The reasons were as follows: four patients developed PD (one with herpes zoster), four had CRu judged as not requiring further therapy by the investigators, and seven did not meet the starting criteria (two with PD). Overall, 29 patients (56%) completed six cycles of the protocol treatment, whereas 11 patients (21%) were taken off study because of either adverse events or because they did not meet the starting criteria. According to the starting criteria, 12 patients (11 in the IL cohort and one in the MCL cohort) received reduced doses of 30 mg/m2/d in subsequent treatment cycles. The reasons were as follows: seven patients had low neutrophil counts, one had a low platelet count, one had elevated bilirubin, and three had infections. Of these 12 patients, three eventually discontinued the treatment; two patients were in CRu and one patient discontinued treatment because of not meeting the starting criteria.

    Efficacy

    Table 3 lists the clinical responses to oral fludarabine. In the IL cohort, the ORR and CR rates were 65% (30 of 46 patients; 95% CI, 50% to 79%) and 30% (14 of 46 patients; 95% CI, 18% to 46%), respectively; and 23 (62%) of the 37 patients who had received prior rituximab responded to oral fludarabine. The MCL cohort consisted of six patients, of whom one achieved PR. The ORRs and CR rates correlated well with the risk groups according to the FLIPI. The median TTF for the 46 patients in the IL cohort was 8.6 months (95% CI, 6.6 to 12.0 months), and the median TTF for the 30 responders in the IL cohort was 12.0 months (95% CI, 8.6 months to not defined; Fig 1). The median TTF for the six patients in the MCL cohort was 6.1 months (95% CI, 4.6 to 8.7 months).

    Adverse Events

    Hematologic toxicities and nonhematologic adverse events are listed in Tables 4 and 5, respectively. Hematologic toxicity was the most frequently encountered toxicity. Grade 4 hematologic toxicities included neutropenia in 19 patients (37%). No patients developed grade 4 thrombocytopenia. Granulocyte colony-stimulating factor was used in 40 (16%) of 243 cycles. Grade 3 infections occurred in 10 patients (19%) with 11 episodes, but neutropenic fever requiring admission occurred in only one patient. Two patients (4%) developed herpes zoster. They were not taking prophylactic acyclovir. One patient was found to have laryngeal cancer 1 month after completion of the sixth cycle of the protocol treatment and was treated with radiation.

    Nausea/vomiting and diarrhea occurred in 50% and 37% of patients, respectively, but these toxicities were mostly of grade 1 or 2. All patients recovered with or without supportive treatment, and no patient required withdrawal from the study as a result of these toxicities. One patient developed grade 2 interstitial pneumonitis during the second cycle of treatment and recovered by treatment with high-dose glucocorticoid. The investigator assessed the relationship of this event as being possibly related to oral fludarabine.

    Of 49 patients who received two or more cycles of the protocol treatment, 43 could receive the second and later cycles as outpatients. Two patients had prolonged initial hospitalization, one because of the occurrence of interstitial pneumonitis and the other as a precaution against infection. Four patients required admission as a result of adverse events (one patient each with pyelonephritis, bronchitis, pneumonia, and febrile neutropenia); all of the patients recovered.

    After the follow-up period, two patients developed serious adverse events that were considered to be related to oral fludarabine. One patient developed grade 3 thrombocytopenia 1 year after completion of the sixth cycle of fludarabine treatment, when the platelet count decreased to 16 x 103/μL. Bone marrow examination revealed no dysplasia with a normal karyotype. The thrombocytopenia was improving but not recovered. One patient developed myelodysplastic syndrome (MDS) 7 months after receiving the fifth cycle of oral fludarabine. He showed PD to the fludarabine treatment and received rituximab and cyclophosphamide, vincristine, and prednisone thereafter. He developed anemia, and bone marrow examination revealed MDS with chromosome abnormalities. He received transfusions, but his MDS evolved into overt leukemia 6 months after diagnosis, and he died. The patient had been treated for follicular lymphoma for 20 years with multiple chemotherapy regimens including alkylating agents and radiation.

    Two other deaths occurred after completing the study; one patient died as a result of PD, and the other patient died from a Staphylococcal infection after receiving subsequent chemotherapy. Both deaths were considered to be unrelated to oral fludarabine treatment.

    DISCUSSION

    This is the first study to document that oral fludarabine has an excellent efficacy profile against relapsed indolent B-NHL. For patients with indolent B-NHL except for MCL, the ORR was 65%, which is at least equivalent to the results for IV fludarabine monotherapy.8-12,23 Also, the median TTF of 8.6 months was at least comparable to the TTF of 4.6 months for a similar population.24 In a study using IV fludarabine in patients with relapsed indolent B-NHL, Klasa et al12 reported an ORR of 64% and a progression-free survival time of 11 months, which is similar to this study. It was difficult to recruit MCL patients in this study, and the results for this population are not conclusive. Because the IV formulation is effective against MCL,23,25-27 we assume that the oral formulation is also effective.

    Hematologic toxicities were frequently encountered, but neutropenic fever requiring hospital admission occurred in only one patient, and no patients required a platelet transfusion. Presumably because of the oral formulation, relatively high incidences of GI toxicities were encountered, but most were mild and easily managed. In total, nonhematologic toxicities were mild.

    According to the guideline for conducting clinical trials on anticancer agents in Japan, all 52 patients received the first cycle during admission. For 43 (88%) of the 49 patients who received two or more cycles, the second or later cycles were administered on an outpatient basis. The low admission requirement indicates that oral fludarabine is suitable for outpatients.

    Two cases of malignancy occurred after completion of the fludarabine treatment. One patient who developed laryngeal cancer had complained of a sore throat, and we considered it to have no relationship with fludarabine. The patient who developed MDS after fludarabine treatment had a long disease course with multiple chemotherapies and radiotherapy, which may have contributed to the development of secondary MDS. In a review by Cheson et al,28 patients with chronic lymphocytic leukemia or hairy cell leukemia who are treated with purine analogs have a higher incidence of secondary malignancy than expected according to the Surveillance, Epidemiology, and End Results 5-year age- and sex-specific incidence rates for the accumulated person-years at risk. However, these values are consistent with the increase that is already associated with these diseases. Although these two cases of malignancy are not considered to be related to the fludarabine treatment, patients who have a long course of disease or history of multiple chemotherapies need to be closely monitored for the development of second malignancy.

    The high efficacy and low toxicity profiles of oral fludarabine for patients with relapsed indolent B-NHL in the present study and the reported favorable results of several phase II studies on combination chemotherapy containing IV fludarabine23,29,30 suggest that oral fludarabine might be a promising agent in combination with other antilymphoma agents including rituximab. In addition to the definitive role as a useful palliative monotherapy for patients with relapsed indolent B-NHL, oral fludarabine is expected to show efficacy in combination therapy for relapsed and untreated patients, warranting further investigations.

    In conclusion, oral fludarabine phosphate is highly effective for patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab and is more convenient than the IV formulation. Further investigations including combination with other antilymphoma agents are warranted.

    Appendix

    The participating institutions and principal investigators of the Fludarabine Study Group included the following: Sapporo Hokuyu Hospital (M. Kasai, Y. Kiyama), Tohoku University Hospital (K. Ishizawa, J. Kameoka, H. Harigae), National Cancer Center Hospital East (H. Minami, K. Itoh, M. Nakata), National Cancer Center Hospital (K. Tobinai, Y. Kobayashi, T. Watanabe), Keio University (S. Okamoto), Tokai University School of Medicine (T. Hotta, study chair; Y. Ogawa), Hamamatsu University School of Medicine (K. Ohnishi, K. Shigeno), Aichi Cancer Center Hospital (Y. Morishima, M. Ogura, Y. Kagami), Kyoto Prefectural University of Medicine (M. Taniwaki, K. Nomura, Y. Matsumoto), Matsushita Memorial Hospital, Osaka (N. Uoshima), Hyogo Medical Center for Adults (T. Murayama), Okayama University School of Medicine (K. Shinagawa), Kyushu University School of Medicine (K. Nagafuji), Hara Sanshin Hospital (T. Kamimura), Nagasaki University School of Medicine (K. Tsukasaki), and Imamura Bun-in Hospital (A. Utsunomiya, Y. Takemoto).

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Kensei Tobinai, Michinori Ogura, Hironobu Minami, Yasuo Ohashi, Masaki Hayashi, Taku Seriu, Tomomitsu Hotta

    Financial support: Masaki Hayashi, Taku Seriu

    Administrative support: Tomomitsu Hotta

    Provision of study materials or patients: Kensei Tobinai, Takashi Watanabe, Michinori Ogura, Yasuo Morishima, Yoshiaki Ogawa, Ken-ichi Ishizawa, Hironobu Minami, Atae Utsunomiya, Masafumi Taniwaki, Yoshihiro Matsuno, Shigeo Nakamura, Tomomitsu Hotta

    Collection and assembly of data: Kensei Tobinai, Takashi Watanabe, Michinori Ogura, Yasuo Morishima, Yoshiaki Ogawa, Ken-ichi Ishizawa, Hironobu Minami, Atae Utsunomiya, Masafumi Taniwaki, Yoshihiro Matsuno, Masaki Hayashi, Taku Seriu, Tomomitsu Hotta

    Data analysis and interpretation: Kensei Tobinai, Michinori Ogura, Takashi Terauchi, Shigeru Nawano, Masaki Matsusako, Yoshihiro Matsuno, Shigeo Nakamura, Shigeo Mori, Yasuo Ohashi, Masaki Hayashi, Taku Seriu, Tomomitsu Hotta

    Manuscript writing: Kensei Tobinai, Masaki Hayashi

    Final approval of manuscript: Kensei Tobinai, Takashi Watanabe, Michinori Ogura, Yasuo Morishima, Yoshiaki Ogawa, Ken-ichi Ishizawa, Hironobu Minami, Atae Utsunomiya, Masafumi Taniwaki, Takashi Terauchi, Shigeru Nawano, Masaki Matsusako, Yoshihiro Matsuno, Shigeo Nakamura, Shigeo Mori, Yasuo Ohashi, Masaki Hayashi, Taku Seriu, Tomomitsu Hotta

    Acknowledgment

    We thank the investigators (physicians and staff) at the participating institutions; K. Esaki, MD (Fujita Health University), K. Toyama, MD (Tokyo Medical College), and N. Horikoshi, MD (Cancer Institute Hospital) as members of the Independent Monitoring Committee; and Nihon Schering K.K. for their help.

    NOTES

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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