Abbreviated Chemotherapy With Fludarabine Followed by Tositumomab and Iodine I 131 Tositumomab for Untreated Follicular Lymphoma
http://www.100md.com
▲還散笫雖悝◎
the Center for Lymphoma and Myeloma, Division of Hematology and Medical Oncology, Division of Nuclear Medicine, and Department of Pathology, Weill Medical College of Cornell University and New York Presbyterian Hospital, New York, NY
Corixa Corporation, Seattle, WA
ABSTRACT
PURPOSE: To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma.
PATIENTS AND METHODS: Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab.
RESULTS: After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT.
CONCLUSION: Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.
INTRODUCTION
Despite the availability of numerous treatment options for indolent non-Hodgkin's lymphoma (NHL), median survival, which continues to be in the range of 8 to 10 years, has not clearly improved over the last four decades.1 Although standard chemotherapy, immunotherapy such as rituximab, and radiotherapy typically yield high initial response rates, virtually all patients with indolent lymphoma ultimately relapse.1每3 The disease often transforms to a higher grade and more aggressive histology,4每11 and response rates and durations of response typically diminish with each treatment.3,9 Therefore, a primary goal in the development of new therapies for NHL is to identify individual agents or combination regimens that will not only improve the response rate but also the duration of response and, potentially, survival.
Tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corporation, Seattle, WA and GlaxoSmithKline, Philadelphia, PA) is a promising new radioimmunotherapeutic agent that has demonstrated efficacy in patients with previously untreated or relapsed/refractory low-grade NHL.12每15 This treatment regimen is composed of an unlabeled anti-CD20 monoclonal antibody (tositumomab) and a radiolabeled monoclonal antibody (iodine I 131 tositumomab). An advantage of radioimmunotherapy (RIT) over unlabeled antibody therapy for NHL is that the direct cytotoxic effects of the antibody are potentiated by the radionuclide.16 Therefore, complete response (CR) rates are higher and durations of response are generally longer than those achieved with unlabeled antibody treatments such as rituximab.17 Reported overall response rates to iodine I 131 tositumomab have ranged from 57% to 95%, and CR rates have ranged from 20% to 75%, depending on the patient's prior treatment history.13每15 In a study of 76 previously untreated patients with follicular grade 1 or grade 2 NHL, Kaminski et al15 reported that iodine I 131 tositumomab yielded a 95% overall response rate (75% CR), with an estimated 5-year progression-free survival (PFS) rate of 59%, and 40 (77%) of 57 patients who achieved a CR remained in CR from 4.3 to 7.7 years after treatment. However, in contrast to the current study, patients with more than 25% bone marrow involvement at study entry were excluded from the trial (and generally in studies using RIT). In addition, the use of iodine I 131 tositumomab as a single agent in patients who had not received prior chemotherapy (and who were, therefore, relatively immunocompetent) led to an increase in human antimurine antibody (HAMA) response to 63% versus the approximate 10% rate observed in previously treated NHL.
Although the high response rates achieved with iodine I 131 tositumomab alone are encouraging, combination regimens of chemotherapy followed by RIT offer some potential benefits. Debulking before RIT potentially reduces overall tumor burden and decreases bone marrow involvement, potentially improving treatment efficacy, while also allowing RIT in patients who would otherwise be ineligible to receive RIT because of extensive marrow disease. The debulking step should also decrease marrow involvement, potentially decreasing marrow involvement每associated hematologic toxicity. In addition, pre-RIT therapy should lower the post-RIT therapy HAMA rate through chemotherapy-related immunosuppression. The Southwest Oncology Group (SWOG) recently reported a phase II trial consisting of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by iodine I 131 tositumomab in patients with previously untreated, advanced-stage indolent follicular lymphoma.18 The overall response rate to the entire treatment regimen in 90 eligible patients was 90%. The CR rate increased from 39% after CHOP to 66% for the complete regimen. A recent abstract preliminarily reported on 30 patients treated with cyclophosphamide, vincristine, and prednisone followed by iodine I 131 tositumomab.19 An overall response rate of 100% and a CR rate of 80% were reported; and with a median follow-up of 2.3 years, 77% of patients remained in response. However, full courses of CHOP and cyclophosphamide, vincristine, and prednisone may include substantial acute toxicity, including neuropathy and alopecia. Additionally, some older patients are not candidates for CHOP because of cardiomyopathy or other comorbidities. We sought to develop an abbreviated (three cycles) chemotherapy regimen with a favorable toxicity profile to be used in sequential combination with RIT. Abbreviated chemotherapy should result in small-volume disease that, theoretically, should be particularly susceptible to radiation cross-fire effects.20,21
Fludarabine was an attractive candidate chemotherapeutic agent for the development of abbreviated chemotherapy before RIT. Single-agent fludarabine, a purine analog, typically achieves response rates of 29% to 75% in indolent lymphoma, and higher responses have been achieved when fludarabine was used in combination with mitoxantrone with or without dexamethasone (71% to 90%)22每27 or as part of stem-cell transplantation.28 Fludarabine synergizes in vitro with anti-CD20 antibodies, including iodine I 131 tositumomab, in follicular lymphoma.29,30 We postulated that fludarabine-induced immunosuppression could reduce the formation of HAMA in patients treated with murine monoclonal antibodies. Finally, with the exception of myelosuppression, fludarabine and iodine I 131 tositumomab have few overlapping toxicities.
The objectives of the present study were to establish the safety and efficacy of a sequential regimen consisting of three cycles of fludarabine (25 mg/m2 for 5 days every 5 weeks) followed 6 to 8 weeks later by iodine I 131 tositumomab in patients with previously untreated follicular NHL. We also tested the hypothesis that abbreviated chemotherapy could successfully debulk patients with bulky disease and/or extensive bone marrow involvement.
PATIENTS AND METHODS
Eligibility
Patients 18 years of age with previously untreated, stage III or IV histologically confirmed small lymphocytic, follicular grade 1, 2, or 3, and monocytoid B-cell NHL were eligible for enrollment. All patients had CD20+ lymphoma. Subjects were required to have adequate performance status (Karnofsky performance status 60%), adequate hepatic and renal function, an absolute neutrophil count of more than 1,500 cells/米L, and a platelet count of more than 100,000/米L. Patients with CNS involvement, HIV infection, serum HAMA positivity at baseline, other malignancies diagnosed within 5 years, and prior therapy for NHL including chemotherapy, radiotherapy, or immunotherapy were excluded. The Institutional Review Board of Weill Medical College of Cornell University and New York Presbyterian Hospital approved the study, and all patients provided written informed consent. All eligible patients evaluated at the institution were offered the opportunity to participate in the study.
Study Design and Treatment Plan
The study was an open-label, prospective, phase II evaluation of the safety and efficacy of sequential therapy. Patients first received an abbreviated course of three cycles of fludarabine (25 mg/m2 for 5 days every 5 weeks). Given the myelosuppressive effects of fludarabine (as well as those of RIT), we empirically opted for a conservative 5-week (rather than 4-week) fludarabine treatment interval. Six to 8 weeks after completion of fludarabine, the iodine I 131 tositumomab was initiated. Patients underwent dosimetry studies to determine the appropriate patient-specific activity of iodine I 131 tositumomab required to deliver a fixed dose of 75 cGy, as previously described.13,31 The dose was attenuated to 65 cGy for patients with platelet counts between 100,000 and 150,000/米L. The maximum-tolerated dose has not been established for patients with more than 25% of the intertrabecular space involved by lymphoma.32 One patient, who still had bone marrow involvement of more than 25% of the intertrabecular space after fludarabine, received a protocol-specified, attenuated therapeutic dose of 45 cGy. Iodine supplementation was provided in the form of saturated solution of potassium iodide or Lugol's solution.
Study Analysis and Data Handling
Patients who completed fludarabine and the postfludarabine response evaluation before receiving iodine I 131 tositumomab were assessable for efficacy. All patients were assessable for safety; however, safety data are presented for those patients who received the entire regimen of both fludarabine and iodine I 131 tositumomab. Tumor response was assessed 5 weeks after the third fludarabine cycle and 12 weeks and 24 weeks after completion of iodine I 131 tositumomab by physical examination; computed tomography scans of the chest, abdomen, and pelvis; and bone marrow biopsies if the bone marrow was positive for lymphoma at baseline. Additional tumor response assessments were performed every 6 months thereafter. Standard criteria in use at the time of study design were prospectively used to assess antitumor response and other disease outcomes. CR was defined as the complete disappearance of all detectable disease, including bone marrow involvement (unchanging residual radiographic abnormalities 2 cm in diameter and thought to represent scar tissue could be present). A partial response (PR) was defined as more than 50% reduction in the sum of the products of the largest perpendicular diameters of all measurable lesions and no new lesions. Progressive disease was defined as the appearance of new lesions or a more than 25% increase in the sum of the products of the longest perpendicular diameters of all measurable lesions. Responses not meeting these criteria were categorized as stable disease. Duration of response was defined as the time from the first documented response to the first documentation of disease progression. PFS was defined as the time from the start of treatment (ie, first fludarabine cycle) until the first documentation of progression or death. 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 [LDH], and > four nodal areas).33 For FLIPI analyses, two patients with missing baseline LDH values were classified as having nonelevated LDH based on other available LDH values. Patients with none or one, two, or more than two risk factors were classified as having low, intermediate, or high risk, respectively.
The level of significance for all comparative analyses was set at 0.05, with exact CIs calculated from binomial distributions. Analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC). Duration of response, PFS, and survival data were analyzed using the censored data techniques of Kaplan-Meier. Differences in CR rates across patient subgroups were tested for statistical significance using the 2 statistic (Yates-corrected for two groups), and differences in PFS were tested using the log-rank test. The following factors were examined: sex, age ( 60 v > 60 years), Ann Arbor stage (II or III v IV), time from diagnosis ( 1 v > 1 year), bulky disease (< 5 v 5 cm), histology (follicular grade 1 v grade 2), baseline LDH (low or normal v elevated), baseline hemoglobin (< 12 v 12 g/dL), baseline marrow Bcl-2 translocation, extranodal disease sites (zero or one v two sites), number of nodal sites ( four v > four sites), bone marrow involvement (absent v present), and FLIPI (low or intermediate risk v high risk). Multivariate analyses of PFS were performed using the Cox proportional hazards model.34
The safety and tolerability of the combination were evaluated by changes in hematologic parameters and other clinical laboratory values, by physical examination, and by the frequency and severity of adverse events (AEs). Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 1. In this version, grade 3 thrombocytopenia was defined as a platelet count of less than 50,000/米L, and grade 4 thrombocytopenia was defined as a platelet count of less than 10,000/米L. CBC and platelet counts were obtained weekly as needed and could be discontinued when postnadir grade 1 toxicity was reported on two separate measurements. Serum chemistries were performed at 2, 12, and 25 weeks and then every 6 months after tositumomab and iodine I 131 tositumomab therapy. Thyroid-stimulating hormone (TSH) was measured every 6 months.
HAMA
Serum was tested for HAMA at baseline before fludarabine and at 12 and 24 weeks after the therapeutic dose of iodine I 131 tositumomab. An enzyme-linked immunosorbent assay (ImmuSTRIP ELISA for HAMA; Immunomedics, Morris Plains, NJ) was used to detect serum HAMA according to the manufacturer's instructions.
RESULTS
Patient Characteristics and Disposition
Thirty-eight therapy-na?ve patients were enrolled onto the trial between August 1998 and June 1999. Three patients were removed from the study during the fludarabine phase of treatment. One patient was withdrawn after review of additional pathology material that demonstrated evidence of coexisting Hodgkin's disease in addition to follicular lymphoma. One patient was withdrawn with comorbid illness (cardiac disease unrelated to protocol therapy, but precluding it), and one patient was withdrawn because of prolonged thrombocytopenia after fludarabine, resulting in a failure to meet eligibility criteria for iodine I 131 tositumomab. The first two patients had no response assessments (PFS of 0.7+ and 2.1+ months, respectively), whereas the third patient had one response assessment (PR to fludarabine and PFS of 4.8+ months). Patient demographics and baseline disease characteristics for the 35 patients receiving iodine I 131 tositumomab are listed in Table 1. The median time from NHL diagnosis to initiation of fludarabine was 3 months (range, 1 to 64 months). Approximately half of patients had follicular grade 1 NHL, and the remaining half of the patients had follicular grade 2 NHL. Most patients (74%) had bone marrow involvement, including six patients (17%) with 25% bone marrow involvement before fludarabine. The median baseline greatest tumor diameter was 5.2 cm; 60% of the patients had tumors 5 cm in diameter, and four patients (11%) had tumors 10 cm in diameter. The median FLIPI was 2, and 43% of patients had a high-risk FLIPI score.
Antitumor Response
Thirty-five patients completed both fludarabine and iodine I 131 tositumomab and were assessable for response. After three cycles of fludarabine, the overall response rate was 89% (31 of 35 patients). Three patients (9%) attained a CR, 28 attained a PR, and four patients (11%) demonstrated stable disease. Of the 21 patients with bulky disease ( 5 cm) at enrollment, 12 (75%) had the maximum tumor diameter decrease to less than 5 cm after fludarabine.
The response rate of the 35 patients to the complete regimen was 100%, and 30 patients (86%) achieved a CR as best response (Table 2). After a median follow-up of 58 months, the median duration of response was not reached (range, 3 to 64+ months; Fig 1). Similarly, the median PFS was not reached, but it will be at least 49 months. The estimated 5-year PFS rate is 56% (Fig 2).
In univariate analyses, no factors were significant predictors of CR. In univariate analyses, elevated LDH (P = .002) and high-risk FLIPI score (P = .001) were significant predictors of PFS, whereas baseline hemoglobin was near significant (P = .054). In multivariate analyses, only a high-risk FLIPI score (relative risk = 5.9; 95% CI, 1.8 to 18.7) was a significant predictor of PFS. The 5-year PFS rate for the 20 patients with low- or intermediate-risk FLIPI scores was 79% compared with 27% for the 15 patients with high-risk FLIPI scores (Fig 3). The 5-year PFS rate for the 21 patients without elevated LDH was 75% compared with 25% for the 12 patients with elevated LDH.
Three patients (9%) died. Two patients died because of disease progression (one patient died at 16 months and one died at 26 months after the start of fludarabine therapy). One patient died in remission from trauma unrelated to disease or study drug.
Bone marrow involvement with lymphoma decreased over time and after the completion of each phase of treatment. Before fludarabine treatment, 26 (74%) of 35 patients had bone marrow involvement. After fludarabine treatment, only seven (39%) of 18 assessed patients had bone marrow involvement. After completion of the fludarabine regimen, five of the six patients with 25% bone marrow involvement at baseline had a reduction to less than 25% bone marrow involvement and then received the full iodine I 131 tositumomab dose of 65 or 75 cGy. The remaining patient received a radiation dose of 45 cGy. After the completion of iodine I 131 tositumomab, bone marrow involvement was eliminated in all patients except two (6%) of the 32 assessed patients at the month 6 evaluation. Both of these patients had progressive disease at the month 6 evaluation. Of the 14 patients who have developed progressive disease at any time on study, four of the progressive disease determinations were based on the recurrence of bone marrow involvement without associated measurable disease.
Finally, Bcl-2 positivity was monitored by polymerase chain reaction (PCR) analysis. Overall 13 patients (39%) tested positive for Bcl-2 gene rearrangements at the baseline bone marrow assessment, and 20 patients (61%) tested negative. PFS was similar for patients based on their baseline Bcl-2 status, with 5-year PFS rates of 54% and 65% for patients with Bcl-2 positivity and negativity, respectively. Of the 13 patients in this study who tested positive by PCR for Bcl-2 gene translocation, 10 (77%) were PCR negative at month 12. This group had a 5-year PFS rate of 70%, which was significantly greater than the PFS rate of the three patients who were not PCR negative at month 12.
Safety and Tolerability
The combined therapy was well tolerated. Three patients had dose reductions of fludarabine (two patients for leukopenia and one after weight loss), and six patients received a delayed dose of fludarabine (four patients for neutropenia, one for febrile neutropenia, and one as a result of inclement weather). One (3%) of 35 dosimetric and one (3%) of 35 therapeutic iodine I 131 tositumomab administrations had infusion rate adjustments for decreased blood pressure.
A total of 483 AEs were reported after fludarabine or tositumomab and iodine I 131 tositumomab. The most common nonhematologic AEs (Table 3) were asthenia (60%), nausea (49%), and fever (46%). One patient had a grade 1 flu-like symptom complex occurring 4 days after tositumomab and iodine I 131 tositumomab. Only four patients experienced a grade 3 or 4 nonhematologic AEs within 3 months of the last treatment administration. Two patients each experienced one grade 3 or 4 AE (nausea and fever) after fludarabine, and two patients each experienced one grade 3 or 4 AE (nausea and headache) after iodine I 131 tositumomab. Three patients experienced a serious AE. All three serious AEs were febrile neutropenia (one event after fludarabine and two after iodine I 131 tositumomab). All three serious AEs resolved after administration of granulocyte colony-stimulating factor.
The most common toxicities were hematologic (Table 4). Hematologic toxicities, nadirs, and durations are listed in Table 4. Neutropenia was the most common toxicity, with 29% of patients experiencing grade 3 or 4 neutropenia after fludarabine and 74% of patients experiencing grade 3 or 4 neutropenia after iodine I 131 tositumomab. Overall, 18 patients (51%) developed an absolute neutrophil count of less than 500 cells/米L (six patients after fludarabine and 16 patients after iodine I 131 tositumomab), and one patient (3%) developed a platelet count less of than 10,000 cells/米L after iodine I 131 tositumomab. At the discretion of the treating physician, seven patients received growth factors after fludarabine, and 11 patients received hematologic supportive care after iodine I 131 tositumomab, with seven patients receiving blood products and nine patients receiving growth factors. Overall, 15 patients (43%) received hematologic supportive care at any time, including seven patients (20%) who received blood products, two patients (6%) who received a platelet transfusion, and 10 patients who received growth factors. All patients had hematologic recovery to at least grade 2.
Eleven (31%) of 35 patients experienced at least one infectious episode after fludarabine. These episodes included one case of pneumonia and one case of herpes zoster. The majority of episodes were respiratory or sinus infections or coughs. Nine (26%) of 35 patients experienced at least one infection after iodine I 131 tositumomab, including one patient with herpes zoster. The remaining patients had cough and/or fever, respiratory infection, or bronchitis. With the exception of the three patients with neutropenic fever described previously, none of the patients were hospitalized for infection. Eleven patients had "B" symptoms present at baseline, all of which resolved after therapy.
Two patients had baseline low titer HAMA (79 and 133 ng/mL) before receiving fludarabine and were HAMA negative on subsequent evaluations at 12 and 24 weeks after iodine I 131 tositumomab. Neither of the two patients required an infusion adjustment, but one of the two patients experienced a grade 1 infusion-related AE during the therapeutic administration. Of the remaining 33 patients, two patients (6%) developed HAMA 184 and 195 days after the initiation of iodine I 131 tositumomab. Both patients had a CR to therapy and later progressed at 39 and 41 months after iodine I 131 tositumomab.
One patient was hypothyroid before study entry. Of the remaining 34 patients, four patients (12%) developed elevated TSH levels. Three of the four patients initiated thyroid supplementation. One other patient initiated thyroid supplementation without a documented elevated TSH.
In long-term follow-up, one patient developed myelodysplasia 58 months after initiation of fludarabine and 51 months after disease progression. The patient had received three treatments with rituximab after progression. With the exception of a squamous cell carcinoma of the neck, no other malignancies have been reported.
DISCUSSION
High response rates to standard and investigational therapies for follicular NHL have not clearly translated into significant improvements in survival to date.1 Although most patients respond to initial treatments, response rates typically diminish with each subsequent therapy.3,9 Therefore, multimodality therapies combining chemotherapy with immunotherapy and RIT regimens are under investigation for the potential to improve PFS and overall survival. We report the first trial of a novel strategy of abbreviated chemotherapy followed by RIT. With this approach, iodine I 131 tositumomab effectively converted minimal responses and PRs after abbreviated chemotherapy into PRs and CRs after RIT. The 100% response rate, 86% CR rate, and response duration achieved with this regimen are encouraging and compare favorably with other chemoimmunotherapy35每37 or RIT regimens studied in similar patient populations.15,18,19
In evaluating these findings, it is important to consider that any single-institution, phase II study of initial therapy for indolent lymphoma is potentially subject to patient selection biases. Our subjects were slightly younger than the average age reported for follicular NHL. Within the limits of a small study, however, the distribution of FLIPI scores at study entry (with 43% of patients at high risk) suggests that our population was roughly representative of patients generally diagnosed with this disease. Although none of the five FLIPI risk factors were individual significant predictors of PFS, the PFS time was significantly longer in patients with a low- or intermediate-risk FLIPI score. In this group of 20 patients, three patients progressed, one patient died from trauma unrelated to NHL disease, and 16 patients continue in ongoing CR. In the group of 15 patients with high-risk FLIPI scores, 11 patients had progressive NHL, and four patients continue in CR. Further assessment of the FLIPI with regard to prognosis after initial therapy is warranted in larger numbers of uniformly treated patients, particularly aiming for a risk-adapted treatment selection strategy. One might speculate that follicular NHL patients with high-risk FLIPI scores (and a high LDH) may harbor an occult large-cell transformation and that this group might particularly benefit from an anthracycline-containing regimen (perhaps with RIT, as in the SWOG study).
Chromosomal translocation of the t(14;18) region of the Bcl-2 proto-oncogene occurs in approximately 50% of NHL patients.38 Previous studies have revealed that patients with the t(14;18) Bcl-2 translocation detectable by PCR after bone marrow transplantation are at an increased risk for relapse.39 Therefore, Bcl-2 is a useful molecular marker to monitor the effective elimination of residual disease. Of the 13 patients in this study who tested positive by PCR for Bcl-2 gene translocation, 10 patients (77%) who had a month-12 molecular response also had a 5-year PFS rate of 70%. The molecular response rate achieved in this study is similar to that achieved by Czuczman et al37 in patients receiving rituximab in combination with a standard regimen of CHOP. Because the immunotherapeutic effect of tositumomab is potentiated by a radionuclide in the tositumomab and iodine I 131 tositumomab treatment regimen, the potential for a durable CR may potentially be higher with tositumomab and iodine I 131 tositumomab therapy than for rituximab when combined with chemotherapy. This issue is the subject of a randomized trial of concurrent CHOP plus rituximab versus CHOP followed by iodine I 131 tositumomab that is underway by the SWOG and Cancer and Leukemia Group B.
In the study reported here, we chose an alternative strategy of an abbreviated course (three cycles) of fludarabine as the chemotherapy component of a sequential regimen for several reasons. Fludarabine has long been recognized as a well-tolerated chemotherapy agent (without significant cardiac or neurologic toxicity and no alopecia) that has been applied extensively as treatment for a variety of hematologic malignancies. Fludarabine has also been combined with rituximab as treatment for indolent NHL, with high response rates and multiyear remissions observed.40 For our study, the initial treatment step of three cycles of fludarabine provided substantial tumor reduction in the form of PRs in most patients, as well as bone marrow cytoreduction to a level ( 25% involvement) allowing RIT. This sequential chemotherapy plus RIT approach (both in this study and in the CHOP plus tositumomab and iodine I 131 tositumomab regimen) has manageable hematologic toxicity, although it seems more myelosuppressive than RIT alone in the upfront setting. Additionally, because fludarabine is immunosuppressive, in addition to reducing lymphoma bone marrow involvement, we hypothesized that it could decrease HAMA production during the tositumomab and iodine I 131 tositumomab therapy phase of treatment. Indeed, the HAMA rate of 6% in the present study is comparable to the 10% rate41 normally seen with patients who have previously received chemotherapy and is remarkably less than the 63% HAMA rate observed in a study of iodine I 131 tositumomab in previously untreated patients.15 It is noteworthy that our report is the first demonstration that a specific chemotherapeutic agent can suppress HAMA formation. Additionally, this regimen was not associated with the HAMA-related flu-like symptom complex that was frequently observed in patients receiving iodine I 131 tositumomab as sole initial therapy. Finally, preclinical studies also demonstrate potential advantages of the use of fludarabine in combination with iodine I 131 tositumomab. Fludarabine plus rituximab yielded cytotoxic activity in six B-cell chronic lymphocytic leukemia cell lines that were resistant to either agent alone.29 Johnson and Press30 demonstrated synergy in that the combination of fludarabine and iodine I 131 tositumomab produced cytotoxicity 3.5- to 5.2-fold over the level expected if the effects of chemotherapy and iodine I 131 tositumomab treatment were added. Results with fludarabine in these preclinical studies were superior to those with alkylating agents, supporting the potential benefit of the use of a purine analog.
The present study is not the first to examine standard-dose chemotherapy in conjunction with RIT in patients with previously untreated follicular lymphoma. The phase II trial of SWOG evaluated six cycles of CHOP chemotherapy followed by iodine I 131 tositumomab in patients with previously untreated, advanced-stage, low-grade follicular lymphoma.18 That study did not examine the ability of CHOP to specifically reduce bone marrow involvement and/or reduce bulky disease before iodine I 131 tositumomab, and it also did not assess efficacy in specific FLIPI subgroups. Theoretically, the reduction of macroscopic disease could improve the likelihood of elimination of residual disease by both the unlabeled monoclonal antibody and the radiolabeled antibody. It is also possible that partial debulking (to a PR rather than a CR) before RIT could be optimal, in that less bulky masses may be more responsive to RIT, but cytoreduction to microscopic disease only may preclude the full effects of radiation cross fire in a tumor lesion that seems to enhance radiation dose and may optimize response.20,21 However, longer follow-up and comparative studies are necessary to determine whether the high CR rate and progression-free interval observed here are superior to other regimens and whether overall survival may be impacted. The relatively brief duration of this therapy, favorable toxicity profile (particularly from the patient's perspective), and promising efficacy in this study suggest that this approach offers advantages that warrant further evaluation.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported by K23 award No. RR16814 from the National Institutes of Health, and grants from the Cornell Center for Aging Research and Clinical Care, the Lymphoma Research Foundation, the Dorothy Rodbell Cohen Foundation, and the Brian Rooney Fund of the Lymphoma Foundation, as well as research grants from Corixa Corporation.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Link B, Kaminski M, Coleman M, et al: Phase II study of CVP followed by tositumomab and iodine I 131 tositumomab (Bexxar therapeutic regimen) in patients with untreated follicular non-Hodgkin's lymphoma. J Clin Oncol 22:560a, 2004 (abstr 6520, suppl)
Humm J: Dosimetric aspects of radiolabeled antibodies for tumor therapy. J Nucl Med 27:1490每1497, 1986
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Zinzani P, Lauria F, Rondelli D, et al: Fludarabine: An active agent in the treatment of previously-treated and untreated low-grade non-Hodgkin's lymphoma. Ann Oncol 4:575每578, 1993
Tondini C, Balzarotti M, Rampinelli I, et al: Fludarabine and cladribine in relapsed/refractory low-grade non-Hodgkin's lymphoma: A phase II randomized study. Ann Oncol 11:231每233, 2000
McLaughlin P, Hagemeister F, Swan FJ, et al: Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma. J Clin Oncol 12:575每579, 1994
Seymour J, Grigg A, Szer J, et al: Fludarabine and mitoxantrone: Effective and well-tolerated salvage therapy in relapsed indolent lymphoproliferative disorders. Ann Oncol 12:1455每1460, 2001
Khouri I, Saliba R, Giralt S, et al: Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 98:3595每3599, 2001
DiGaetano N, Xiao Y, Erba E, et al: Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone. Br J Haematol 114:800每809, 2001
Johnson T, Press O: Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal antibodies and chemotherapy for treatment of B-cell lymphomas. Int J Cancer 85:104每112, 2000
Wahl RL, Kroll S, Zasadny KR: Patient-specific whole-body dosimetry: Principles and a simplified method for clinical implementation. J Nucl Med 39:14S每20S, 1998 (suppl 8)
Mones J, Coleman M, Kostakoglu L, et al: A dose-escalation study of tositumomab and iodine I 131 tositumomab (Bexxar) in patients with previously treated non-Hodgkin's lymphoma with > 25% bone marrow involvement. J Clin Oncol 22:574a, 2004 (abstr 6575, suppl)
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Corixa Corporation, Seattle, WA
ABSTRACT
PURPOSE: To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma.
PATIENTS AND METHODS: Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab.
RESULTS: After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT.
CONCLUSION: Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.
INTRODUCTION
Despite the availability of numerous treatment options for indolent non-Hodgkin's lymphoma (NHL), median survival, which continues to be in the range of 8 to 10 years, has not clearly improved over the last four decades.1 Although standard chemotherapy, immunotherapy such as rituximab, and radiotherapy typically yield high initial response rates, virtually all patients with indolent lymphoma ultimately relapse.1每3 The disease often transforms to a higher grade and more aggressive histology,4每11 and response rates and durations of response typically diminish with each treatment.3,9 Therefore, a primary goal in the development of new therapies for NHL is to identify individual agents or combination regimens that will not only improve the response rate but also the duration of response and, potentially, survival.
Tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corporation, Seattle, WA and GlaxoSmithKline, Philadelphia, PA) is a promising new radioimmunotherapeutic agent that has demonstrated efficacy in patients with previously untreated or relapsed/refractory low-grade NHL.12每15 This treatment regimen is composed of an unlabeled anti-CD20 monoclonal antibody (tositumomab) and a radiolabeled monoclonal antibody (iodine I 131 tositumomab). An advantage of radioimmunotherapy (RIT) over unlabeled antibody therapy for NHL is that the direct cytotoxic effects of the antibody are potentiated by the radionuclide.16 Therefore, complete response (CR) rates are higher and durations of response are generally longer than those achieved with unlabeled antibody treatments such as rituximab.17 Reported overall response rates to iodine I 131 tositumomab have ranged from 57% to 95%, and CR rates have ranged from 20% to 75%, depending on the patient's prior treatment history.13每15 In a study of 76 previously untreated patients with follicular grade 1 or grade 2 NHL, Kaminski et al15 reported that iodine I 131 tositumomab yielded a 95% overall response rate (75% CR), with an estimated 5-year progression-free survival (PFS) rate of 59%, and 40 (77%) of 57 patients who achieved a CR remained in CR from 4.3 to 7.7 years after treatment. However, in contrast to the current study, patients with more than 25% bone marrow involvement at study entry were excluded from the trial (and generally in studies using RIT). In addition, the use of iodine I 131 tositumomab as a single agent in patients who had not received prior chemotherapy (and who were, therefore, relatively immunocompetent) led to an increase in human antimurine antibody (HAMA) response to 63% versus the approximate 10% rate observed in previously treated NHL.
Although the high response rates achieved with iodine I 131 tositumomab alone are encouraging, combination regimens of chemotherapy followed by RIT offer some potential benefits. Debulking before RIT potentially reduces overall tumor burden and decreases bone marrow involvement, potentially improving treatment efficacy, while also allowing RIT in patients who would otherwise be ineligible to receive RIT because of extensive marrow disease. The debulking step should also decrease marrow involvement, potentially decreasing marrow involvement每associated hematologic toxicity. In addition, pre-RIT therapy should lower the post-RIT therapy HAMA rate through chemotherapy-related immunosuppression. The Southwest Oncology Group (SWOG) recently reported a phase II trial consisting of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by iodine I 131 tositumomab in patients with previously untreated, advanced-stage indolent follicular lymphoma.18 The overall response rate to the entire treatment regimen in 90 eligible patients was 90%. The CR rate increased from 39% after CHOP to 66% for the complete regimen. A recent abstract preliminarily reported on 30 patients treated with cyclophosphamide, vincristine, and prednisone followed by iodine I 131 tositumomab.19 An overall response rate of 100% and a CR rate of 80% were reported; and with a median follow-up of 2.3 years, 77% of patients remained in response. However, full courses of CHOP and cyclophosphamide, vincristine, and prednisone may include substantial acute toxicity, including neuropathy and alopecia. Additionally, some older patients are not candidates for CHOP because of cardiomyopathy or other comorbidities. We sought to develop an abbreviated (three cycles) chemotherapy regimen with a favorable toxicity profile to be used in sequential combination with RIT. Abbreviated chemotherapy should result in small-volume disease that, theoretically, should be particularly susceptible to radiation cross-fire effects.20,21
Fludarabine was an attractive candidate chemotherapeutic agent for the development of abbreviated chemotherapy before RIT. Single-agent fludarabine, a purine analog, typically achieves response rates of 29% to 75% in indolent lymphoma, and higher responses have been achieved when fludarabine was used in combination with mitoxantrone with or without dexamethasone (71% to 90%)22每27 or as part of stem-cell transplantation.28 Fludarabine synergizes in vitro with anti-CD20 antibodies, including iodine I 131 tositumomab, in follicular lymphoma.29,30 We postulated that fludarabine-induced immunosuppression could reduce the formation of HAMA in patients treated with murine monoclonal antibodies. Finally, with the exception of myelosuppression, fludarabine and iodine I 131 tositumomab have few overlapping toxicities.
The objectives of the present study were to establish the safety and efficacy of a sequential regimen consisting of three cycles of fludarabine (25 mg/m2 for 5 days every 5 weeks) followed 6 to 8 weeks later by iodine I 131 tositumomab in patients with previously untreated follicular NHL. We also tested the hypothesis that abbreviated chemotherapy could successfully debulk patients with bulky disease and/or extensive bone marrow involvement.
PATIENTS AND METHODS
Eligibility
Patients 18 years of age with previously untreated, stage III or IV histologically confirmed small lymphocytic, follicular grade 1, 2, or 3, and monocytoid B-cell NHL were eligible for enrollment. All patients had CD20+ lymphoma. Subjects were required to have adequate performance status (Karnofsky performance status 60%), adequate hepatic and renal function, an absolute neutrophil count of more than 1,500 cells/米L, and a platelet count of more than 100,000/米L. Patients with CNS involvement, HIV infection, serum HAMA positivity at baseline, other malignancies diagnosed within 5 years, and prior therapy for NHL including chemotherapy, radiotherapy, or immunotherapy were excluded. The Institutional Review Board of Weill Medical College of Cornell University and New York Presbyterian Hospital approved the study, and all patients provided written informed consent. All eligible patients evaluated at the institution were offered the opportunity to participate in the study.
Study Design and Treatment Plan
The study was an open-label, prospective, phase II evaluation of the safety and efficacy of sequential therapy. Patients first received an abbreviated course of three cycles of fludarabine (25 mg/m2 for 5 days every 5 weeks). Given the myelosuppressive effects of fludarabine (as well as those of RIT), we empirically opted for a conservative 5-week (rather than 4-week) fludarabine treatment interval. Six to 8 weeks after completion of fludarabine, the iodine I 131 tositumomab was initiated. Patients underwent dosimetry studies to determine the appropriate patient-specific activity of iodine I 131 tositumomab required to deliver a fixed dose of 75 cGy, as previously described.13,31 The dose was attenuated to 65 cGy for patients with platelet counts between 100,000 and 150,000/米L. The maximum-tolerated dose has not been established for patients with more than 25% of the intertrabecular space involved by lymphoma.32 One patient, who still had bone marrow involvement of more than 25% of the intertrabecular space after fludarabine, received a protocol-specified, attenuated therapeutic dose of 45 cGy. Iodine supplementation was provided in the form of saturated solution of potassium iodide or Lugol's solution.
Study Analysis and Data Handling
Patients who completed fludarabine and the postfludarabine response evaluation before receiving iodine I 131 tositumomab were assessable for efficacy. All patients were assessable for safety; however, safety data are presented for those patients who received the entire regimen of both fludarabine and iodine I 131 tositumomab. Tumor response was assessed 5 weeks after the third fludarabine cycle and 12 weeks and 24 weeks after completion of iodine I 131 tositumomab by physical examination; computed tomography scans of the chest, abdomen, and pelvis; and bone marrow biopsies if the bone marrow was positive for lymphoma at baseline. Additional tumor response assessments were performed every 6 months thereafter. Standard criteria in use at the time of study design were prospectively used to assess antitumor response and other disease outcomes. CR was defined as the complete disappearance of all detectable disease, including bone marrow involvement (unchanging residual radiographic abnormalities 2 cm in diameter and thought to represent scar tissue could be present). A partial response (PR) was defined as more than 50% reduction in the sum of the products of the largest perpendicular diameters of all measurable lesions and no new lesions. Progressive disease was defined as the appearance of new lesions or a more than 25% increase in the sum of the products of the longest perpendicular diameters of all measurable lesions. Responses not meeting these criteria were categorized as stable disease. Duration of response was defined as the time from the first documented response to the first documentation of disease progression. PFS was defined as the time from the start of treatment (ie, first fludarabine cycle) until the first documentation of progression or death. 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 [LDH], and > four nodal areas).33 For FLIPI analyses, two patients with missing baseline LDH values were classified as having nonelevated LDH based on other available LDH values. Patients with none or one, two, or more than two risk factors were classified as having low, intermediate, or high risk, respectively.
The level of significance for all comparative analyses was set at 0.05, with exact CIs calculated from binomial distributions. Analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC). Duration of response, PFS, and survival data were analyzed using the censored data techniques of Kaplan-Meier. Differences in CR rates across patient subgroups were tested for statistical significance using the 2 statistic (Yates-corrected for two groups), and differences in PFS were tested using the log-rank test. The following factors were examined: sex, age ( 60 v > 60 years), Ann Arbor stage (II or III v IV), time from diagnosis ( 1 v > 1 year), bulky disease (< 5 v 5 cm), histology (follicular grade 1 v grade 2), baseline LDH (low or normal v elevated), baseline hemoglobin (< 12 v 12 g/dL), baseline marrow Bcl-2 translocation, extranodal disease sites (zero or one v two sites), number of nodal sites ( four v > four sites), bone marrow involvement (absent v present), and FLIPI (low or intermediate risk v high risk). Multivariate analyses of PFS were performed using the Cox proportional hazards model.34
The safety and tolerability of the combination were evaluated by changes in hematologic parameters and other clinical laboratory values, by physical examination, and by the frequency and severity of adverse events (AEs). Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria version 1. In this version, grade 3 thrombocytopenia was defined as a platelet count of less than 50,000/米L, and grade 4 thrombocytopenia was defined as a platelet count of less than 10,000/米L. CBC and platelet counts were obtained weekly as needed and could be discontinued when postnadir grade 1 toxicity was reported on two separate measurements. Serum chemistries were performed at 2, 12, and 25 weeks and then every 6 months after tositumomab and iodine I 131 tositumomab therapy. Thyroid-stimulating hormone (TSH) was measured every 6 months.
HAMA
Serum was tested for HAMA at baseline before fludarabine and at 12 and 24 weeks after the therapeutic dose of iodine I 131 tositumomab. An enzyme-linked immunosorbent assay (ImmuSTRIP ELISA for HAMA; Immunomedics, Morris Plains, NJ) was used to detect serum HAMA according to the manufacturer's instructions.
RESULTS
Patient Characteristics and Disposition
Thirty-eight therapy-na?ve patients were enrolled onto the trial between August 1998 and June 1999. Three patients were removed from the study during the fludarabine phase of treatment. One patient was withdrawn after review of additional pathology material that demonstrated evidence of coexisting Hodgkin's disease in addition to follicular lymphoma. One patient was withdrawn with comorbid illness (cardiac disease unrelated to protocol therapy, but precluding it), and one patient was withdrawn because of prolonged thrombocytopenia after fludarabine, resulting in a failure to meet eligibility criteria for iodine I 131 tositumomab. The first two patients had no response assessments (PFS of 0.7+ and 2.1+ months, respectively), whereas the third patient had one response assessment (PR to fludarabine and PFS of 4.8+ months). Patient demographics and baseline disease characteristics for the 35 patients receiving iodine I 131 tositumomab are listed in Table 1. The median time from NHL diagnosis to initiation of fludarabine was 3 months (range, 1 to 64 months). Approximately half of patients had follicular grade 1 NHL, and the remaining half of the patients had follicular grade 2 NHL. Most patients (74%) had bone marrow involvement, including six patients (17%) with 25% bone marrow involvement before fludarabine. The median baseline greatest tumor diameter was 5.2 cm; 60% of the patients had tumors 5 cm in diameter, and four patients (11%) had tumors 10 cm in diameter. The median FLIPI was 2, and 43% of patients had a high-risk FLIPI score.
Antitumor Response
Thirty-five patients completed both fludarabine and iodine I 131 tositumomab and were assessable for response. After three cycles of fludarabine, the overall response rate was 89% (31 of 35 patients). Three patients (9%) attained a CR, 28 attained a PR, and four patients (11%) demonstrated stable disease. Of the 21 patients with bulky disease ( 5 cm) at enrollment, 12 (75%) had the maximum tumor diameter decrease to less than 5 cm after fludarabine.
The response rate of the 35 patients to the complete regimen was 100%, and 30 patients (86%) achieved a CR as best response (Table 2). After a median follow-up of 58 months, the median duration of response was not reached (range, 3 to 64+ months; Fig 1). Similarly, the median PFS was not reached, but it will be at least 49 months. The estimated 5-year PFS rate is 56% (Fig 2).
In univariate analyses, no factors were significant predictors of CR. In univariate analyses, elevated LDH (P = .002) and high-risk FLIPI score (P = .001) were significant predictors of PFS, whereas baseline hemoglobin was near significant (P = .054). In multivariate analyses, only a high-risk FLIPI score (relative risk = 5.9; 95% CI, 1.8 to 18.7) was a significant predictor of PFS. The 5-year PFS rate for the 20 patients with low- or intermediate-risk FLIPI scores was 79% compared with 27% for the 15 patients with high-risk FLIPI scores (Fig 3). The 5-year PFS rate for the 21 patients without elevated LDH was 75% compared with 25% for the 12 patients with elevated LDH.
Three patients (9%) died. Two patients died because of disease progression (one patient died at 16 months and one died at 26 months after the start of fludarabine therapy). One patient died in remission from trauma unrelated to disease or study drug.
Bone marrow involvement with lymphoma decreased over time and after the completion of each phase of treatment. Before fludarabine treatment, 26 (74%) of 35 patients had bone marrow involvement. After fludarabine treatment, only seven (39%) of 18 assessed patients had bone marrow involvement. After completion of the fludarabine regimen, five of the six patients with 25% bone marrow involvement at baseline had a reduction to less than 25% bone marrow involvement and then received the full iodine I 131 tositumomab dose of 65 or 75 cGy. The remaining patient received a radiation dose of 45 cGy. After the completion of iodine I 131 tositumomab, bone marrow involvement was eliminated in all patients except two (6%) of the 32 assessed patients at the month 6 evaluation. Both of these patients had progressive disease at the month 6 evaluation. Of the 14 patients who have developed progressive disease at any time on study, four of the progressive disease determinations were based on the recurrence of bone marrow involvement without associated measurable disease.
Finally, Bcl-2 positivity was monitored by polymerase chain reaction (PCR) analysis. Overall 13 patients (39%) tested positive for Bcl-2 gene rearrangements at the baseline bone marrow assessment, and 20 patients (61%) tested negative. PFS was similar for patients based on their baseline Bcl-2 status, with 5-year PFS rates of 54% and 65% for patients with Bcl-2 positivity and negativity, respectively. Of the 13 patients in this study who tested positive by PCR for Bcl-2 gene translocation, 10 (77%) were PCR negative at month 12. This group had a 5-year PFS rate of 70%, which was significantly greater than the PFS rate of the three patients who were not PCR negative at month 12.
Safety and Tolerability
The combined therapy was well tolerated. Three patients had dose reductions of fludarabine (two patients for leukopenia and one after weight loss), and six patients received a delayed dose of fludarabine (four patients for neutropenia, one for febrile neutropenia, and one as a result of inclement weather). One (3%) of 35 dosimetric and one (3%) of 35 therapeutic iodine I 131 tositumomab administrations had infusion rate adjustments for decreased blood pressure.
A total of 483 AEs were reported after fludarabine or tositumomab and iodine I 131 tositumomab. The most common nonhematologic AEs (Table 3) were asthenia (60%), nausea (49%), and fever (46%). One patient had a grade 1 flu-like symptom complex occurring 4 days after tositumomab and iodine I 131 tositumomab. Only four patients experienced a grade 3 or 4 nonhematologic AEs within 3 months of the last treatment administration. Two patients each experienced one grade 3 or 4 AE (nausea and fever) after fludarabine, and two patients each experienced one grade 3 or 4 AE (nausea and headache) after iodine I 131 tositumomab. Three patients experienced a serious AE. All three serious AEs were febrile neutropenia (one event after fludarabine and two after iodine I 131 tositumomab). All three serious AEs resolved after administration of granulocyte colony-stimulating factor.
The most common toxicities were hematologic (Table 4). Hematologic toxicities, nadirs, and durations are listed in Table 4. Neutropenia was the most common toxicity, with 29% of patients experiencing grade 3 or 4 neutropenia after fludarabine and 74% of patients experiencing grade 3 or 4 neutropenia after iodine I 131 tositumomab. Overall, 18 patients (51%) developed an absolute neutrophil count of less than 500 cells/米L (six patients after fludarabine and 16 patients after iodine I 131 tositumomab), and one patient (3%) developed a platelet count less of than 10,000 cells/米L after iodine I 131 tositumomab. At the discretion of the treating physician, seven patients received growth factors after fludarabine, and 11 patients received hematologic supportive care after iodine I 131 tositumomab, with seven patients receiving blood products and nine patients receiving growth factors. Overall, 15 patients (43%) received hematologic supportive care at any time, including seven patients (20%) who received blood products, two patients (6%) who received a platelet transfusion, and 10 patients who received growth factors. All patients had hematologic recovery to at least grade 2.
Eleven (31%) of 35 patients experienced at least one infectious episode after fludarabine. These episodes included one case of pneumonia and one case of herpes zoster. The majority of episodes were respiratory or sinus infections or coughs. Nine (26%) of 35 patients experienced at least one infection after iodine I 131 tositumomab, including one patient with herpes zoster. The remaining patients had cough and/or fever, respiratory infection, or bronchitis. With the exception of the three patients with neutropenic fever described previously, none of the patients were hospitalized for infection. Eleven patients had "B" symptoms present at baseline, all of which resolved after therapy.
Two patients had baseline low titer HAMA (79 and 133 ng/mL) before receiving fludarabine and were HAMA negative on subsequent evaluations at 12 and 24 weeks after iodine I 131 tositumomab. Neither of the two patients required an infusion adjustment, but one of the two patients experienced a grade 1 infusion-related AE during the therapeutic administration. Of the remaining 33 patients, two patients (6%) developed HAMA 184 and 195 days after the initiation of iodine I 131 tositumomab. Both patients had a CR to therapy and later progressed at 39 and 41 months after iodine I 131 tositumomab.
One patient was hypothyroid before study entry. Of the remaining 34 patients, four patients (12%) developed elevated TSH levels. Three of the four patients initiated thyroid supplementation. One other patient initiated thyroid supplementation without a documented elevated TSH.
In long-term follow-up, one patient developed myelodysplasia 58 months after initiation of fludarabine and 51 months after disease progression. The patient had received three treatments with rituximab after progression. With the exception of a squamous cell carcinoma of the neck, no other malignancies have been reported.
DISCUSSION
High response rates to standard and investigational therapies for follicular NHL have not clearly translated into significant improvements in survival to date.1 Although most patients respond to initial treatments, response rates typically diminish with each subsequent therapy.3,9 Therefore, multimodality therapies combining chemotherapy with immunotherapy and RIT regimens are under investigation for the potential to improve PFS and overall survival. We report the first trial of a novel strategy of abbreviated chemotherapy followed by RIT. With this approach, iodine I 131 tositumomab effectively converted minimal responses and PRs after abbreviated chemotherapy into PRs and CRs after RIT. The 100% response rate, 86% CR rate, and response duration achieved with this regimen are encouraging and compare favorably with other chemoimmunotherapy35每37 or RIT regimens studied in similar patient populations.15,18,19
In evaluating these findings, it is important to consider that any single-institution, phase II study of initial therapy for indolent lymphoma is potentially subject to patient selection biases. Our subjects were slightly younger than the average age reported for follicular NHL. Within the limits of a small study, however, the distribution of FLIPI scores at study entry (with 43% of patients at high risk) suggests that our population was roughly representative of patients generally diagnosed with this disease. Although none of the five FLIPI risk factors were individual significant predictors of PFS, the PFS time was significantly longer in patients with a low- or intermediate-risk FLIPI score. In this group of 20 patients, three patients progressed, one patient died from trauma unrelated to NHL disease, and 16 patients continue in ongoing CR. In the group of 15 patients with high-risk FLIPI scores, 11 patients had progressive NHL, and four patients continue in CR. Further assessment of the FLIPI with regard to prognosis after initial therapy is warranted in larger numbers of uniformly treated patients, particularly aiming for a risk-adapted treatment selection strategy. One might speculate that follicular NHL patients with high-risk FLIPI scores (and a high LDH) may harbor an occult large-cell transformation and that this group might particularly benefit from an anthracycline-containing regimen (perhaps with RIT, as in the SWOG study).
Chromosomal translocation of the t(14;18) region of the Bcl-2 proto-oncogene occurs in approximately 50% of NHL patients.38 Previous studies have revealed that patients with the t(14;18) Bcl-2 translocation detectable by PCR after bone marrow transplantation are at an increased risk for relapse.39 Therefore, Bcl-2 is a useful molecular marker to monitor the effective elimination of residual disease. Of the 13 patients in this study who tested positive by PCR for Bcl-2 gene translocation, 10 patients (77%) who had a month-12 molecular response also had a 5-year PFS rate of 70%. The molecular response rate achieved in this study is similar to that achieved by Czuczman et al37 in patients receiving rituximab in combination with a standard regimen of CHOP. Because the immunotherapeutic effect of tositumomab is potentiated by a radionuclide in the tositumomab and iodine I 131 tositumomab treatment regimen, the potential for a durable CR may potentially be higher with tositumomab and iodine I 131 tositumomab therapy than for rituximab when combined with chemotherapy. This issue is the subject of a randomized trial of concurrent CHOP plus rituximab versus CHOP followed by iodine I 131 tositumomab that is underway by the SWOG and Cancer and Leukemia Group B.
In the study reported here, we chose an alternative strategy of an abbreviated course (three cycles) of fludarabine as the chemotherapy component of a sequential regimen for several reasons. Fludarabine has long been recognized as a well-tolerated chemotherapy agent (without significant cardiac or neurologic toxicity and no alopecia) that has been applied extensively as treatment for a variety of hematologic malignancies. Fludarabine has also been combined with rituximab as treatment for indolent NHL, with high response rates and multiyear remissions observed.40 For our study, the initial treatment step of three cycles of fludarabine provided substantial tumor reduction in the form of PRs in most patients, as well as bone marrow cytoreduction to a level ( 25% involvement) allowing RIT. This sequential chemotherapy plus RIT approach (both in this study and in the CHOP plus tositumomab and iodine I 131 tositumomab regimen) has manageable hematologic toxicity, although it seems more myelosuppressive than RIT alone in the upfront setting. Additionally, because fludarabine is immunosuppressive, in addition to reducing lymphoma bone marrow involvement, we hypothesized that it could decrease HAMA production during the tositumomab and iodine I 131 tositumomab therapy phase of treatment. Indeed, the HAMA rate of 6% in the present study is comparable to the 10% rate41 normally seen with patients who have previously received chemotherapy and is remarkably less than the 63% HAMA rate observed in a study of iodine I 131 tositumomab in previously untreated patients.15 It is noteworthy that our report is the first demonstration that a specific chemotherapeutic agent can suppress HAMA formation. Additionally, this regimen was not associated with the HAMA-related flu-like symptom complex that was frequently observed in patients receiving iodine I 131 tositumomab as sole initial therapy. Finally, preclinical studies also demonstrate potential advantages of the use of fludarabine in combination with iodine I 131 tositumomab. Fludarabine plus rituximab yielded cytotoxic activity in six B-cell chronic lymphocytic leukemia cell lines that were resistant to either agent alone.29 Johnson and Press30 demonstrated synergy in that the combination of fludarabine and iodine I 131 tositumomab produced cytotoxicity 3.5- to 5.2-fold over the level expected if the effects of chemotherapy and iodine I 131 tositumomab treatment were added. Results with fludarabine in these preclinical studies were superior to those with alkylating agents, supporting the potential benefit of the use of a purine analog.
The present study is not the first to examine standard-dose chemotherapy in conjunction with RIT in patients with previously untreated follicular lymphoma. The phase II trial of SWOG evaluated six cycles of CHOP chemotherapy followed by iodine I 131 tositumomab in patients with previously untreated, advanced-stage, low-grade follicular lymphoma.18 That study did not examine the ability of CHOP to specifically reduce bone marrow involvement and/or reduce bulky disease before iodine I 131 tositumomab, and it also did not assess efficacy in specific FLIPI subgroups. Theoretically, the reduction of macroscopic disease could improve the likelihood of elimination of residual disease by both the unlabeled monoclonal antibody and the radiolabeled antibody. It is also possible that partial debulking (to a PR rather than a CR) before RIT could be optimal, in that less bulky masses may be more responsive to RIT, but cytoreduction to microscopic disease only may preclude the full effects of radiation cross fire in a tumor lesion that seems to enhance radiation dose and may optimize response.20,21 However, longer follow-up and comparative studies are necessary to determine whether the high CR rate and progression-free interval observed here are superior to other regimens and whether overall survival may be impacted. The relatively brief duration of this therapy, favorable toxicity profile (particularly from the patient's perspective), and promising efficacy in this study suggest that this approach offers advantages that warrant further evaluation.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors have completed the disclosure declaration, 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
NOTES
Supported by K23 award No. RR16814 from the National Institutes of Health, and grants from the Cornell Center for Aging Research and Clinical Care, the Lymphoma Research Foundation, the Dorothy Rodbell Cohen Foundation, and the Brian Rooney Fund of the Lymphoma Foundation, as well as research grants from Corixa Corporation.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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