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Journal of Clinical Oncology, Vol 23, No 4 (February 1), 2005: pp. 694-704 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.172 Rituximab in Combination With Fludarabine Chemotherapy in Low-Grade or Follicular LymphomaFrom the Roswell Park Cancer Institute, Buffalo, NY; Berlex Laboratories, Richmond; Genentech Inc, San Francisco; and IDEC Pharmaceuticals, San Diego, CA Address reprint requests to Myron S. Czuczman, MD, Divisions of Hematologic Oncology and Bone Marrow Transplantation, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263; e-mail: myron.czuczman{at}roswellpark.org
PURPOSE: To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naïve or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. PATIENTS AND METHODS: This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. RESULTS: An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naïve and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. CONCLUSION: Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.
Non-Hodgkin's lymphomas (NHLs) are a diverse group of lymphoid malignancies with differing patterns of behavior and responses to treatment.1 The vast majority of low-grade or follicular B-cell lymphomas initially respond to alkylating agent–based combination chemotherapy,2 and although complete responses are more frequent with purine analogs such as fludarabine, overall survival is not enhanced.3 Novel combinations are therefore under investigation for these patients. One such promising combination is fludarabine plus cyclophosphamide (F+C), which shows synergistic activity in vitro.4 A significant number of chronic lymphocytic leukemia (CLL) and indolent B-cell NHL patients treated with F+C experience significant hematologic toxicity5 and even increased mortality when high doses of cyclophosphamide are used.6 Combination fludarabine, mitoxantrone, and dexamethasone (FND) has been evaluated in previously treated7,8 and untreated9 patients with indolent B-cell lymphoma. The phase II study of FND7 in recurrent or refractory indolent lymphoma demonstrated an overall response rate of 94% (47% rate of complete response [CR]), median overall survival of 34 months, and median failure-free survival (FFS) of 14 months. In the upfront setting, FND had an overall response rate of 97% (79% rate of CR), with an 84% 5-year survival rate and 41% 5-year FFS rate. Of note, 20% of upfront FND patients did not complete all of the assigned FND courses. Despite its excellent antitumor activity, the FND regimen has been associated with significant myelosuppression and an increased risk of infections, in particular opportunistic infections (eg, Pneumocystis carinii pneumonia [PCP]). Rituximab is a chimeric anti-CD20 monoclonal antibody with significant single-agent antitumor activity against B-cell lymphoma and CLL.10-14 Rituximab's biologic activity is associated with antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity, and direct apoptosis. Byrd et al15 have previously shown that caspase-3 and caspase-9 are activated in CLL cells after rituximab infusion and that this is associated with induction of apoptosis via the mitochondrial pathway. Fludarabine16 and other chemotherapeutic agents used in the therapy of CLL and NHL also activate similar apoptotic pathways, providing a rationale for combining fludarabine and rituximab. In contrast to fludarabine plus chemotherapy combinations, a combination of fludarabine and rituximab (F+R) should have a reduced toxicity profile, because these agents have no significant overlapping toxicities. Fludarabine toxicity is mainly hematologic,17 resulting in cytopenias and an increased risk of infection, whereas rituximab shows predominantly infusion-related toxicities.18 Indeed, F+R demonstrates synergistic antitumor activity in vitro,19,20 and seems to act by non–cross-resistant mechanisms. Fludarabine inhibits RNA and DNA synthesis and DNA repair.3 Rituximab can deplete target B cells via activation of the host immune system and apoptotic signaling pathways.21 In addition, rituximab has been shown in vitro to sensitize drug-resistant lymphoma cell lines to cytotoxic chemotherapy.22 An early clinical trial using rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) seemed to add significant antitumor activity to CHOP alone and set a precedence for further rituximab plus chemotherapy studies. Historically, treatment of indolent lymphoma patients with CHOP alone yields overall response rates of approximately 65%.23,24 Results from the first phase II multi-institutional CHOP plus rituximab clinical trial demonstrated a 100% overall response rate with durable remissions.25-27 On the basis of single-agent activity, documented synergy, and fludarabine's better nonhematologic toxicity profile compared with CHOP, a phase II clinical trial of F+R was undertaken. The primary aims of this open-label, single-arm, single-center phase II pilot study were to evaluate the safety and efficacy of rituximab in combination with fludarabine in treatment-naïve or patients who had experienced relapse with low-grade and/or follicular NHL. Secondary aims included evaluation of changes in peripheral-blood lymphocyte subsets (especially natural killer [NK] cells) and the ability to convert and maintain bcl-2 negativity (by qualitative polymerase chain reaction [PCR]) post-therapy.
Patients Between May 1998 and November 2000, 40 adult patients with histologically documented CD20-positive low-grade or follicular lymphoma (International Working Group subtypes A through D) with bidimensionally measurable disease were enrolled onto this study. Patients were to have an expected survival of 6 months or more, Karnofsky performance status greater than 60%, be treatment-naïve or have received  four prior standard chemotherapies, have recovered from any significant toxicity associated with prior therapy, and have adequate hematologic, renal, and hepatic function. The following exclusion criteria were applied: HIV positivity, serious nonmalignant disease, CNS lymphoma, chemotherapy within 4 weeks of the first scheduled study treatment, or prior therapy with fludarabine, purine antimetabolites, or anti-CD20 immunotherapy. Other exclusion criteria included the presence of another primary malignancy (other than squamous or basal cell carcinoma of the skin or in situ carcinoma of the cervix) for which the patient had not been disease-free for at least 5 years and major surgery within 4 weeks. Pregnant and lactating women and patients of childbearing potential, unless using accepted birth control measures, were not eligible for enrollment. Institutional review board approval was given for this study, and all patients gave their written, informed consent to participate.
Study Design
In the event of significant treatment-associated nonhematologic toxicity (ie, National Cancer Institute Common Toxicity Criteria grade  2), treatment was delayed for 1-week increments up to a total of 3 weeks until the toxicity improved to grade 1. If postponement lasted longer than 3 weeks, treatment was discontinued. With respect to hematologic parameters, significant unexpected toxicities were seen in the initial 10 patients, leading to the following changes to the study design. First, in the event of grade 3 hematologic toxicity (unsupported with growth factors) that persists 2 consecutive weeks, the dose of fludarabine was to be reduced by 40% (25 mg/m2/d on days 1 through 3) for all subsequent cycles. Patients without hematologic recovery after a 3-week interruption/delay were to be discontinued. Second, prophylactic trimethoprim/sulfamethoxazole was discontinued because it was believed to have been contributing to therapy-associated cytopenias and, because concurrent corticosteroids were not used in the F+R regimen, the risk for PCP was considered low. Third, granulocyte colony-stimulating factor (G-CSF) support was to be limited during active therapy. Permitted treatment support included transfusion of blood and blood products, antibiotics, antiemetics, and colony-stimulating factors (G-CSF and/or granulocyte macrophage colony-stimulating factor). No concurrent antineoplastic therapy (including radiation therapy) or treatment with corticosteroids (other than transient topical application) was permitted.
Patient Monitoring
Follow-Up
Response Criteria and Data Analysis The primary measure of efficacy for this study was CR rate at 30 weeks (1 month after completion of study therapy). Secondary efficacy parameters included PR rate at 30 weeks, time to progression (TTP), duration of response, survival, depletion of CD20+ cells from peripheral blood, and molecular clearing of bcl-2 (14;18 chromosomal translocation)–positive cells from blood and/or marrow aspirate samples.
Statistical Methods In addition, evaluation of changes in peripheral-blood lymphocyte subsets (in particular, B cells, T cells, NK cells, and activated NK cells [ie, NK cells with CD122 coexpression]) in peripheral blood after F+R treatment were performed. All statistical calculations for this analysis were performed using procedures from SAS/STAT software (The SAS System 8.1; SAS Institute, Cary, NC). The distributions of percentage changes in cell counts were analyzed using both the sign test and the Wilcoxon signed ranks test. Both the Kolmogorov-Smirnov test and the Cramer-von Mises tests were used to test the maximum likelihood fit of the lognormal distribution to the observed distribution of pretreatment. Box plots of the observed distributions of cell counts stratified by time were prepared using a logarithmic scale on the vertical axis. Normal values for B cells, NK cells, and activated NK cells were determined from a population of 20 healthy individuals and represented by three numbers: the lower 10th percentile, the median, and the upper 90th percentile.
Demographics
Patient baseline clinical characteristics are listed in Table 1. All patients had advanced stage (III, IV) disease, and the majority were previously untreated (68%). The majority of patients (65%) were IWFB. The median patient age was 53 years (range, 40 to 77 years). The most frequent extranodal site of disease was bone marrow (65%). Half the patients had IPI scores of 0 or 1, and the others had IPI scores of
Clinical Outcome Table 2 shows the clinical outcome for the two patient subgroups. A major difference between these two patient groups was that 70% in subgroup 1 received a growth factor, whereas only 24% of those in subgroup 2 received them. In total, there were 40 patients enrolled onto the study, and among them, the overall response rate (CR and PR) was equal to 90% (95% CI, 76% to 97%). Two patients in the entire sample had progressive disease secondary to transformed lymphoma before completion of therapy. Overall, 34 of 40 patients completed all planned therapy. Six patients were taken off therapy for the following reasons: three patients for prolonged cytopenia (two patients from subgroup 1 and one patient from subgroup 2), two patients for large-cell transformation, and one patient for pulmonary hypersensitivity. For the whole group, the median duration of response, TTP, and overall survival have not been reached after a median follow-up time of 44 months (range, 15 to 66 months). At last follow-up, 22 (61%) of 36 patients had ongoing responses. There were 34 patients (85%) known to be alive at last contact, and six patients (15%) who had died. All deaths were due to NHL, including the two patients with transformed NHL noted above. Figures 2 and 3 show the progression-free survival and overall survival curves for the patients in this study sample.
The probability of overall survival in an ITT basic for all 40 patients at 50 months was equal to 0.80 (not shown). The overall survival rate among the subset of patients who completed all therapy (n = 34) was slightly higher, being equal to 0.83. There were no statistically significant differences in survival times between the newly diagnosed patients and the patients who experienced relapse. The median survival time was not achieved in either group. There were also no significant differences in clinical response between the previously treated versus previously untreated patients or follicular versus nonfollicular patients. Among the newly diagnosed patients, 22 (81%) of 27 patients achieved a CR, and in the previously treated patients, 10 (77%) of 13 patients achieved a CR. Two (7%) of 27 of the newly diagnosed patients had a PR, compared with two (15%) of 13 patients in the previously treated group. Three patients (11%) in the newly diagnosed group and one patient (8%) in the relapsed group demonstrated progressive disease during therapy.
The relationships of histology, IPI score, disease type, sex, and age (> 60 years v
Toxicity Most patients had either no or only grade 1 or 2 anemia or thrombocytopenia (Table 2). However, there were eight patients (80%) in subgroup 1 with grade 3/4 neutropenia, and 21 patients (72%) in subgroup 2 with grade 3 or 4 neutropenia. Overall, grade 3 or 4 neutropenia was transient and reversible in subgroup 2 patients. Whereas 70% of patients in subgroup 1 required G-CSF support, only 24% of the patients in subgroup 2 received G-CSF support. In fact, two of the total seven patients in subgroup 2 who received transient G-CSF did so only after completion of all scheduled study drugs. In subgroup 2 patients, transient therapy delay was required in nine patients: starting with the third cycle of therapy in four patients, the fourth cycle in two patients, the fifth cycle in one patient, and the sixth cycle in two patients. Excluding the single patient removed from study at midtherapy secondary to prolonged cytopenia in subgroup 2, three patients required a 40% fludarabine dose reduction: one patient starting at cycle 4 and two patients with cycle 6 only. Additional data, not documented in Table 2, included infectious complications and/or hospitalizations, which were limited to the following: staphylococcal or culture-negative Mediport infections (n = 3), neutropenic fever requiring hospitalization (n = 4), primary or secondary herpes simplex/zoster skin infections (n = 6), and recurrent urinary tract infection (n = 1). There were no differences in infectious complications noted between patients in subgroup 1 versus subgroup 2. Overall, infectious complications (especially no occurrence of PCP or other serious opportunistic infection) seen in the ITT group seemed to be similar to that expected in a similar population treated with fludarabine alone. However, acyclovir prophylaxis was subsequently prescribed to all treated patients for 6 to 12 months after completion of therapy because of the relatively high incidence of herpes infections (six of 40 patients; 15%) believed to be secondary to T-cell depletion from fludarabine. No patient receiving acyclovir prophylaxis developed herpes infection. Typical first-dose rituximab infusional toxicities were seen in our study population, as has been previously described in other trials.11-14 Fludarabine was well tolerated, and no acute infusion reactions were seen. Intermittent grade 1 to 2 fludarabine-associated nausea/vomiting and liver function test abnormalities were seen in one patient, which resolved after completion of therapy. One case of interstitial pneumonitis believed to be secondary to fludarabine was seen in a single patient in subgroup 1 that necessitated taking them off of study after fludarabine cycle 5. This patient's symptoms resolved quickly with initiation of corticosteroids. Quantitative serum immunoglobulins (IgG, IgA, and IgM) were obtained pretherapy and monitored during and after treatment completion. In the 34 patients who completed all therapy, 79% (27 of 34 patients) demonstrated stable (n = 24) to improved (n = 3) quantitative immunoglobulin levels.
Factors Associated With Grade 3 or 4 Neutropenia
Molecular bcl-2 Monitoring by PCR There were 16 patients who were positive for bcl-2 by PCR in peripheral blood ± bone marrow aspirate before therapy. Among these, 87% (13 of 15 patients) converted to bcl-2–negative after treatment in peripheral blood. Among the 16 patients who were bcl-2–positive pretreatment in bone marrow aspiration samples, 88% (14 of 16 patients) became negative for bcl-2 after therapy. In those patients converting to negative, repeat bcl-2 studies were performed on a yearly basis. Serial bcl-2 assays have remained negative for up to 4 years in patients to date.
Flow Cytometric Monitoring of Lymphocyte Subsets
Although a variety of treatment approaches are currently available for the initial treatment of indolent B-cell lymphoma, no optimal therapy has yet been identified. A recent randomized phase III study compared the safety and efficacy of fludarabine versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade lymphoma after previous response to alkylator-based therapy.30 Patients in the fludarabine arm had improved progression-free survival and treatment-free survival and better social function scores compared with patients treated on the cyclophosphamide, vincristine, and prednisone arm. In particular, an overall response rate of 64% (9% rate of CR), a median progression-free survival time of 11 months, and a treatment-free survival time of 15 months were demonstrated in patients treated with fludarabine. In a previously published phase II trial of fludarabine as first-line treatment of advanced follicular lymphoma,31 54 patients received a median of seven cycles of fludarabine (with 41% receiving nine cycles) and achieved a 65% overall response rate (37% rate of CR) and an overall median relapse-free survival duration of 15.6 months in responders. The first rituximab combination immunochemotherapy trial demonstrated that rituximab can be safely given with standard CHOP chemotherapy,25 with a resultant 100% overall response rate (57% rate of CR), in 38 assessable patients with a durable remission duration and the ability to molecularly clear blood and/or marrow of bcl-2–positive cells by PCR testing. The initial rationale behind our decision to evaluate fludarabine and rituximab was the hope that this combination might achieve similar efficacy as R-CHOP, but with less toxicity. Furthermore, because of the significant number of older patients with comorbid medical problems, a less aggressive, non–anthracycline-containing combination immunochemotherapy such as F+R could prove to be a valuable addition to current therapeutic options. In addition, basic research has demonstrated that fludarabine and rituximab have synergistic antitumor activity.19,20 Although late onset of response has been a feature of some studies using rituximab monotherapy,32 F+R induced a relatively rapid rate of response. In the 34 patients who completed therapy, 82% (28 of 34 patients) demonstrated maximal or near maximal nodal responses by midtherapy. Although B-cell and T-cell subsets were overall depleted by this regimen, NK cells (including activated NK cells) were relatively preserved. The first report of the potential sparing effect of infusional fludarabine on human T-10 positive (ie, probably NK) cells determined by flow cytometric evaluation of peripheral-blood mononuclear cells postchemotherapy was conducted by Boldt et al in 1984.33 Other researchers not only have corroborated this finding of a relative sparing of NK cells, but have also found that fludarabine may actually stimulate NK-cell lytic activity.34-36 This relative sparing, and possible activation, of NK cells by fludarabine may significantly contribute to the excellent antitumor activity demonstrated here by the F+R combination. NK cells likely play an important role as a major effector cell used in the destruction of rituximab-bound tumor cells via ADCC.37 Theoretically, it is possible that the addition of other agents to F+R (eg, drugs that deplete NK cells, corticosteroids, and so on) that may decrease ADCC and complement-mediated cytotoxicity activity may have a potentially negative impact on overall antitumor activity. The relative sparing of NK cells, along with the preservation of mean quantitative immunoglobulin levels in the majority of our patients, may explain the low incidence of infectious complications seen in our study. However, acyclovir prophylaxis is recommended in patients receiving F+R combination therapy because of the relatively high incidence of herpes infections seen.
Discontinuations resulting from cytopenia or infectious complications were rare in this study, and dose reductions of fludarabine occurred typically late in the course of therapy. Furthermore, transient therapy delays were necessary in less than one third of the patients in subgroup 2. Review of several previously published reports of fludarabine monotherapy38-42 in patients with either previously treated or untreated CLL and/or indolent B-cell lymphoma documented that myelosuppression is the major adverse effect associated with this drug, dermatomal herpes/zoster infection is not uncommon, and that nonhematologic toxicities are typically mild. In an article by Keating et al,38 post-therapy CD4 and CD8 lymphocyte counts are substantially decreased and seem to slowly increase, but do not reach median pretreatment values at more than 24 months. Results from our F+R trial are consistent with these previously published observations. Two phase II trials of combination F+R in CLL have recently been published.43,44 In the German trial,43 31 patients (11 previously untreated) received four cycles of fludarabine and four infusions of rituximab. An overall response rate of 87% (33% rate of CR; 55% rate of PR) and a median duration of response of 75 weeks were reported. The other trial was a randomized phase II Cancer and Leukemia Group B study (CALGB 9712)44 of fludarabine with concurrent versus sequential rituximab in previously untreated B-CLL patients. Concurrent rituximab and fludarabine (six cycles) resulted in an overall response rate of 90% (47% rate of CR; 43% rate of PR). This overall and CR rate was lower in the sequential arm (overall response rate = 77%; CR = 28%). At a median follow-up time of 23 months, median response duration and survival had not been reached for either arm. Comparing both arms, the concurrent arm experienced an increased incidence of grade 3 or 4 neutropenia of uncertain etiology. Notably, this finding was not accompanied by any increased risk of infections in the concurrent arm. Factors that could potentially be associated with an increased risk of developing grade 3 or 4 neutropenia were evaluated in our F+R study population. Of interest, the presence of marrow involvement (and potential resultant decrease in marrow reserve) was not found to be associated with grade 3 or 4 neutropenia. However, patients with IPI
Statistical analysis of clinical characteristics versus TTP were evaluated in our F+R patients. Older patients (ie, older than 60 years; n = 12 of 40 patients) demonstrated more than 2.5 times the risk of experiencing relapse earlier than younger patients (ie, In conclusion, we have demonstrated that concurrent F+R immunochemotherapy resulted in excellent antitumor activity and is well tolerated in previously treated and untreated patients with indolent B-cell lymphoma (overall response rate = 90% in ITT group; 80% rate of CR, 10% rate of PR; 88% bcl-2 conversion rate by PCR), with median TTP not reached at 44+ months. Molecular remissions up to 4 years have been demonstrated to date. This is encouraging because other work has indicated that patients who achieve molecular remission during the first year of treatment have a significantly longer FFS at 4 years compared with those who do not (76% v 38%; P < .001).45 Although the majority of patients experienced transient, reversible grade 3 or 4 neutropenia, this was not associated with a higher-than-expected infection risk. The low infection rate in our study population is likely multifactorial: minimal to no mucosal membrane breakdown associated with F+R, preservation of serum immunoglobulin levels in approximately 80% of patients; and relative sparing and possible activation of NK cells related to fludarabine therapy. Secondary to the documented hematologic toxicity and the finding that more than 80% of patients had experienced maximal or near maximal nodal response by midtherapy using the current F+R schedule, a trial of reduced fludarabine (eg, possibly day 1 rituximab plus days 3 through 5 of fludarabine every 28 days for six to eight cycles) is warranted and should potentially maintain excellent activity with less hematologic toxicity. Our data support use of an F+R arm in future phase III studies comparing rituximab chemotherapy regimens to each other in an attempt to define an optimal therapy for patients with indolent B-cell lymphoma.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: M.K. Rock, Berlex Labs; M. Benyunes, Genentech. Consultant/Advisory Role: M.S. Czuczman, Biogen IDEC; A. Grillo-Lopez, Biogen IDEC, Genentech, Roche. Stock ownership: Z.P. Bernstein, Biogen IDEC; M. Skipper, Biogen IDEC; M. Benyunes, Genentech; A. Grillo-Lopez, Genentech. Honoraria: A. Koryzna, Biogen IDEC; M. Skipper, Biogen IDEC; A. Chanan-Khan, Biogen IDEC, Genentech; A. Grillo-Lopez, Biogen IDEC, Genentech, Roche; S.H. Bernstein, Biogen IDEC, Genentech. Research funding: M.S. Czuczman, Biogen IDEC; S.H. Bernstein, Biogen IDEC. Expert testimony: A. Grillo-Lopez, Biogen IDEC. Other remuneration: A. Grillo-Lopez, Biogen IDEC.
Supported by Genentech Inc, IDEC Pharmaceuticals, and Berlex Laboratories. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
