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© 2000 American Society for Clinical Oncology Randomized Trial of Fludarabine Versus Fludarabine and Idarubicin as Frontline Treatment in Patients With Indolent or Mantle-Cell LymphomaFrom the Institute of Hematology and Medical Oncology and University of Bologna, Bologna; Division of Hematology, Pesaro Hospital, Pesaro; Division of Hematology, University of Napoli, Napoli; Division of Hematology, Dolo Hospital, Dolo; Division of Hematology, Ravenna Hospital, Ravenna; Division of Hematology, Cesena Hospital, Cesena; Division of Hematology, Taranto Hospital, Taranto; Division of Hematology, La Cattolica University of Roma, Roma; Division of Internal Medicine, University of Bari, Bari; Division of Oncology, Forli Hospital, Forli; Division of Hematology, Latina Hospital, Latina; Division of Hematology, Potenza Hospital, Potenza; and Division of Hematology, University of Genova, Genova, Italy. Address reprint requests to Pier Luigi Zinzani, MD, Istituto di Ematologia e Oncologia Medica, Policlinico S. Orsola, Via Massarenti 9, 40138 Bologna, Italy; email plzinzo{at}med.unibo.it
PURPOSE: A first comparative trial of fludarabine (FLU) alone versus FLU plus idarubicin (FLU-ID) for indolent or mantle-cell lymphomas. PATIENTS AND METHODS: From September 1995 to July 1998, 199 patients aged 25 to 65 years (median, 54 years) with newly diagnosed stages II to IV indolent or mantle-cell lymphomas (standard risk according to the International Prognostic Index) were enrolled onto a multicenter, 1:1 randomized study. Of the 199 patients who were able to be assessed, 101 were assigned to the FLU group (six monthly cycles of FLU 25 mg/m2/d on days 1 through 5) and 98 to the FLU-ID group (six monthly cycles of FLU 25 mg/m2/d on days 1 through 3 and idarubicin 12 mg/m2 on day 1). RESULTS: In the FLU group, complete response (CR) and partial response rates were 47% and 37%, respectively, whereas in the FLU-ID group, they were 39% and 42%, respectively. In-depth analysis of the CR rate with respect to histologic type showed that FLU seemed to be superior to FLU-ID in treating follicular lymphomas (60% v 40%, respectively), whereas FLU-ID seemed to be more effective than FLU in treating nonfollicular lymphomas (small lymphocytic, 43% v 29%, respectively; immunocytoma, 38% v 23%, respectively; P = not significant), excluding the mantle-cell subset (in which there was no difference between the two groups). No striking differences were observed between the two protocols in terms of overall response or toxicity, which was generally mild. However, with a median follow-up of 19 months, only 29 patients (62%) who received FLU alone have maintained their initial CR, compared with 32 (84%) of those who received FLU-ID therapy (P = .021). CONCLUSION: Although the FLU-ID regimen may not significantly improve the induction of CR in most indolent-lymphoma patients, our preliminary data do suggest that, with respect to FLU alone, it may be capable of conferring a longer-lasting CR and that it might be superior in terms of CR rate in small lymphocytic and immunocytoma subtypes.
FROM A THERAPEUTIC point of view, indolent and mantle-cell lymphomas are particularly controversial diseases,1-3 with treatment options ranging from monochemotherapeutic palliative treatments4 to frontline high-dose therapy followed by autologous hematopoietic rescue.5-7 Along with deeper insights into the pathogenesis of both indolent and mantle-cell lymphomas and the development of corresponding therapies, new cytostatic agents are much needed to overcome the limitations of current treatment options. The purine analogs, fludarabine (FLU) in particular, represent a novel group of antimetabolite compounds that are highly active in the treatment of lymphoid malignancies. They certainly broaden the therapeutic armory and may provide the basis for more effective and potentially curative lymphoma treatment. Objective overall rates ranging from 30% to 70% and complete response (CR) rates ranging from 10% to 38% have been reported in noncomparative studies that evaluate FLU monotherapy.8-14 In general, previously treated patients showed lower response rates when compared with untreated ones and when analyzed separately. In more recent studies, experimental evidence that FLU is a potent inhibitor of repair of DNA damage has encouraged the combination of this purine analog with other agents such as mitoxantrone and idarubicin. As a result, higher overall response rates (70% to 90%) and, especially, higher CR rates (25% to 45%) have been observed.15-19 Moreover, phases I/II and phase II trials using FLU in combination with cyclophosphamide in patients with previously untreated indolent lymphoma resulted in overall response rates of near 90% to 95%.20,21 We evaluated the efficacy and the toxicity of FLU versus FLU and idarubicin (FLU-ID) as first-line treatment in indolent- or mantle-cell lymphoma patients in a multicenter, randomized, comparative trial.
Patients Between September 1995 and July 1998, 208 previously untreated patients with indolent or mantle-cell lymphomas were enrolled from several Italian cooperative institutions and randomly (1:1) assigned to receive either FLU or FLU-ID. Eligibility criteria included the following: age between 18 and 65 years; a confirmed, centralized, histologic diagnosis according to the Revised European-American Lymphoma classification22 of B-cell indolent lymphoma (including follicular lymphoma, immunocytoma, and small lymphocytic lymphoma) or mantle-cell lymphoma; stages II to IV disease according to the Ann Arbor staging system23; fewer than three prognostic factors (low, low-intermediate, and high-intermediate subsets) according to the International Prognostic Index (IPI)24; an Eastern Cooperative Oncology Group (ECOG)25 performance status of 0, 1, or 2; HIV negativity when tested at diagnosis; and normal renal, pulmonary, and hepatic functions. Approval was obtained from the institutional review board. Informed consent was obtained from all patients before the start of therapy in accordance with the Declaration of Helsinki. Staging and subsequent restaging evaluations included bone marrow biopsy (including immunohistochemical analysis), immunophenotypic profile of the peripheral blood, and hematologic and chemical survey, in addition to chest radiograms, abdominal ultrasonography, and computed tomography of the chest and abdomen in all patients. Of the 208 patients enrolled, 199 fulfilled the criteria for entry (101 in the FLU and 98 in the FLU-ID groups) (Table 1). The nine patients who were excluded were so because of incorrect diagnosis (three patients), loss to follow-up (three patients), and protocol violations (three patients). The two groups were comparable in terms of histologic subtype, stage, extranodal site involvement symptoms, performance status, bulky disease status, age, sex distribution, lactate dehydrogenase levels, and IPI stratification.
Treatment Schedule The monotherapy group was treated with FLU 25 mg/m2/d (by IV infusion over a 30-minute period) for 5 consecutive days; the FLU-ID regimen consisted of FLU 25 mg/m2/d on days 1 through 3 and idarubicin 12 mg/m2 on day 1 only. Both regimens were repeated every 28 days, as was dictated by peripheral-blood counts and clinical circumstances, for a total of six cycles. In particular, a course of chemotherapy was postponed for a given patient for 1 week if his or her WBC count was less than 3,000 cells/mm3 and/or platelets were fewer than 80,000 platelets/mm3. No dose reduction was allowed throughout the study. No patient was allowed to receive more than six cycles of chemotherapy, whereas patients with disease progression during treatment received fewer than six cycles. According to our standard procedures for previously untreated patients, neither granulocyte and granulocyte-macrophage colony-stimulating factor nor Pneumocystis carinii prophylaxis was given.
Patient Evaluation and Response Criteria
Statistical Analysis
The significance of the differences between the curves was estimated by the log-rank test.29 The
Response and Survival The clinical results are summarized in Table 2. The overall response rates (CR + PR) were 84% (85 of 101 patients; 95% CI, 0.770 to 0.913) in the FLU group and 81% (79 of 98 patients; 95% CI, 0.728 to 0.884) in the FLU-ID group (P = not significant [NS]). The CR and PR rates, as defined above, were 47% (47 of 101 patients; 95% CI, 0.368 to 0.563) and 37% (38 of 101 patients; 95% CI, 0.282 to 0.471), respectively, for the FLU group and 39% (38 of 98 patients; 95% CI, 0.291 to 0.484) and 42% (41 of 98 patients; 95% CI, 0.321 to 0.526), respectively, for the FLU-ID group (P = NS in both cases).
Regarding the histologic subtypes, CR rates for the FLU group were 60% (36 of 60 patients; 95% CI, 0.476 to 0.724) among those with follicular lymphomas, 29% (five of 17; 95% CI, 0.133 to 0.531) among those with small lymphocytic lymphomas, 23% (three of 13; 95% CI, 0.082 to 0.503) among those with immunocytomas, and 27% (three of 11; 95% CI, 0.097 to 0.576) among those with mantle-cell lymphomas. In the FLU-ID group, the CR rates were 40% (17 of 43 patients; 95% CI, 0.249 to 0.541) among those with follicular lymphomas, 43% (nine of 21; 95% CI, 0.245 to 0.635) among those with small lymphocytic lymphomas, 38% (six of 16; 95% CI, 0.185 to 0.614) among those with immunocytoma lymphomas, and 33% (six of 18; 95% CI, 0.163 to 0.563) among those with mantle-cell lymphomas. As for the PR distribution, PR rates for the FLU group were 27% (16 of 60 patients; 95% CI, 0.155 to 0.379) among those with follicular lymphomas, 59% (10 of 17; 95% CI, 0.360 to 0.784) among those with small lymphocytic lymphomas, 54% (seven of 13; 95% CI, 0.291 to 0.768) among those with immunocytomas, and 45% (five of 11; 95% CI, 0.213 to 0.720) among those with mantle-cell lymphomas. In the FLU-ID group, the PR rates were 44% (19 of 43 patients; 95% CI, 0.293 to 0.590) among those with follicular lymphomas, 43% (nine of 21; 95% CI, 0.245 to 0.635) among those with small lymphocytic lymphomas, 50% (eight of 16; 95% CI, 0.280 to 0.720) among those with immunocytoma lymphomas, and 28% (five of 18; 95% CI, 0.125 to 0.509) among those with mantle-cell lymphomas. At the time of analysis, the median follow-up time was 19 months (range, 6 to 38 months) from the end of treatment. Among the 47 patients who achieved CR with FLU treatment, 18 (38%) relapsed (median time, 9 months; range, 2 to 25 months). Of these, 13 had follicular lymphomas, two had small lymphocytic lymphomas, two had immunocytomas, and one had a mantle-cell lymphoma (Table 3). Of the 38 patients who attained CRs with the FLU-ID regimen, only six (16%) relapsed: one had the follicular subtype, two had small lymphocytic lymphomas, two had immunocytomas, and one had a mantle-cell lymphoma (Table 3). Of these six patients, two relapsed after 7 months, two after 11 months, and two after 13 months. The major advantage of FLU-ID treatment over single-agent FLU treatment seemed to be a reduced relapse rate (16% v 38%, respectively; 95% CI, 0.044 to 0.406; P = .021).
The global OS rate at 42 months of follow-up was 72% (median follow-up, 25 months; range, 6 to 45 months). The OS rate was 72.6% for the FLU group and 72.2% for the FLU-ID group (Fig 1). The global RFS rate at 36 months of follow-up was 67%: 48% for the FLU group versus 88% for the FLU-ID group (median follow-up, 19 months; range, 6 to 38 months; P = .009) (Fig 2). At 36 months of follow-up, the PFS rate was 90.5% for the FLU-ID group and 56% for the FLU group (P = .012) (Fig 3). Among all the different histologic subtypes, only in follicular lymphoma of the FLU-ID group was there a statistically significant advantage in terms of both RFS (P = .05) (Fig 4) and PFS (P = .006) (Fig 5). The lack of significant findings for other histologic subtypes could be a result of the small number of patients in those subtypes.
Toxicity No differences were observed between the two therapeutic groups. No fatalities resulting from drug-toxic effects occurred. Hematologic side effects were present in 53 (8.7%) of 606 courses of FLU treatment and in 45 (7.7%) of 588 courses of the FLU-ID regimen, whereas toxicity  grade 3 according to the ECOG scale was observed in 23 (3.8%) of 606 FLU courses and in 22 (3.7%) of 588 FLU-ID courses. However, both granulocytopenia and thrombocytopenia were usually of short duration, and only 20 (1.7%) of 1194 courses were temporarily postponed for 1 week; no transfusions were ever required. No dose reduction was applied, and no trend toward cumulative myelosuppression was recorded. Five patients (three from the FLU group and two from the FLU-ID group) had infectious episodes, including one case of pneumonia, two of bronchitis, and two febrile episodes of clinically suspected infectious origin in the context of neutropenia. Nonhematologic toxicities were rare and generally mild, occurring in 20 (3.3%) of 606 courses in the FLU group and in 20 (3.4%) of 588 courses in the FLU-ID group. Nausea was the major nonhematologic side effect, comprising 29 cases of the 40 total, and was equally distributed between the two groups of the study, whereas no vomiting was reported. Five patients experienced peripheral neuropathy, which disappeared within 5 weeks with related treatment. Transient grade 2 hepatic toxicity, in terms of AST and ALT abnormal values, was observed in six patients (two from the FLU group and four from the FLU-ID group). There were no instances of renal or cardiac toxicity. None of the patients presented alopecia or autoimmune hemolytic anemia. Only one case of dermatomal herpes zoster was observed, which occurred 4 months after the end of the FLU treatment.
Recent developments have led to a number of new treatment options that might be useful in treating both indolent and mantle-cell lymphomas. Among those currently under investigation, purine analog-based combination regimens have had promising results. Whereas 2-chlorodeoxyadenosine and pentostatin have both found roles in the treatment of hairy cell leukemia, FLU has emerged as the purine analog most widely used in the treatment of indolent lymphoma. FLU has been shown to be active both as first-line therapy and as salvage treatment for patients who are either refractory to or who have relapsed after alkylating-based therapy. Phase II trials that use single-agent FLU in treating previously untreated patients have reported overall response rates of 60% to 70% with CR rates of 38%.10,12,31 Response rates generally have been higher in patients with lymphomas with follicular histology than in those with immunocytomas or in mantle-cell lymphomas.32-34 In patients with relapsed or refractory indolent lymphoma, overall response rates of 30% to 50% and CR rates of 10% to 15% have been reported.8-13 Phase II14-21 and phase III35,36 trials that use FLU in combination regimens (with mitoxantrone, idarubicin, or cyclophosphamide) have generally shown higher response rates compared with those that use single-agent FLU. Both of the phase III trials35,36 compared FLU in combination regimens with conventional chemotherapy. The present study represents the first comparative trial of FLU alone versus a regimen containing FLU (FLU-ID) in untreated indolent or mantle-cell lymphomas. Our results indicate that although FLU-ID does not seem to significantly improve response, it is capable of increasing RFS rate, a finding that is difficult to explain. One way to investigate this finding would be to evaluate molecular response (bcl-2) and the subsequent interpretation of the CR quality after the first-line treatment.37 However, the real significance of molecular remissions, particularly with respect to follicular lymphoma, is still far from being completely defined. Although this was not one of the aims of the current study, it is part of the rationale of a new ongoing study, a randomized trial comparing a cyclophosphamide, doxorubicin, vincristine, and prednisone regimen with a FLU-containing regimen, with clinical and molecular responses as end points. Concerning the follicular subset, which was the only one with a significant number of patients enrolled, in terms of CR rate our data confirm the real efficacy of FLU alone: the surprisingly high percentage of CRs that we observed (60% v 37% reported by Solal-Celigny et al12 ) was probably a result of the exclusion of IPI high-risk patients from our trial. On the contrary, in the other histologic subtypes, the CR rate was superior but not statistically significant in the FLU-ID group. This observation somewhat confirms the important role of additional drugs in the FLU regimen in the treatment of patients with nonfollicular indolent lymphomas.
In terms of side effects, we observed no substantial differences between the two groups. In particular, aside from hematologic toxicity (ECOG scale grade In conclusion, these data suggest two main considerations: (1) in patients with follicular lymphomas, although FLU-ID initially leads to an inferior CR rate, it eventually confers a higher quality of response, as is shown in the superior RFS rate; (2) in patients with the other histologic subtypes, FLU-ID seems to produce either better (in the cases of small lymphocytic and immunocytomas, although P = NS) or equivalent (in the case of mantle-cell) CR rates with respect to FLU.
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Zinzani PL, Magagnoli M, Gherlinzoni F, et al: To what extent can indolent lymphoma be considered? Results of a long term follow-up study from a single center. Haematologica 83:502-507, 1998 6. Dana BW, Dahlberg S, Nathwani BN, et al: Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol 11:644-651, 1993[Abstract]
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Freedman AS, Gribben JG, Neuberg D, et al: High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission. Blood 88:2780-2786, 1996 8. Redman JR, Cabanillas F, Velasquez WS, et al: Phase II trial of fludarabine phosphate in lymphoma: An effective new agent in low-grade lymphoma. J Clin Oncol 109:790-794, 1992 9. Hochster HS, 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]
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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 13. Pigaditou A, Rohatiner AZ, Whelan JS, et al: Fludarabine in low-grade lymphoma. Semin Oncol 20:24-27, 1993 (suppl 7)[Medline] 14. Whelan JS, Davis CL, Rule S, et al: Fludarabine phosphate for the treatment of low-grade lymphoid malignancy. Br J Cancer 64:120-123, 1991[Medline] 15. McLaughlin P, Hagemeister FB, Swan F, et al: Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma. J Clin Oncol 12:575-579, 1994[Abstract] 16. Zinzani PL, Bendandi M, Tura S: FMP regimen (fludarabine, mitoxantrone, prednisone) as therapy in recurrent low-grade non-Hodgkin’s lymphoma. Eur J Haematol 55:262-266, 1995[Medline]
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used according to the Mantel and Haenszel method.
