Originally published as JCO Early Release 10.1200/JCO.2004.04.020 on October 13 2004
Journal of Clinical Oncology, Vol 22, No 23 (December 1), 2004: pp. 4711-4716
© 2004 American Society of Clinical Oncology.
Prolonged Clinical and Molecular Remission in Patients With Low-Grade or Follicular Non-Hodgkin's Lymphoma Treated With Rituximab Plus CHOP Chemotherapy: 9-Year Follow-Up
Myron S. Czuczman,
Robin Weaver,
Baha Alkuzweny,
Judy Berlfein,
Antonio J. Grillo-López
From the Roswell Park Cancer Institute, Buffalo, NY; Biogen Idec, Cambridge, MA; and Neoplastic and Autoimmune Diseases Research Institute, Rancho Santa Fe, CA
Address reprint requests to Antonio J. Grillo-López, MD, Neoplastic and Autoimmune Diseases Research Institute, PO Box 3797, Rancho Santa Fe, CA 92067; e-mail: agrillo1{at}aol.com
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ABSTRACT
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PURPOSE: Long-term follow-up with updated time to disease progression (TTP) and duration of response (DR) data are presented from a multicenter, phase II trial of rituximab/cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) combination therapy in 40 patients with CD20+, B-cell, non-Hodgkin's lymphoma (NHL). Revised response rates based on International Workshop Response Criteria are also provided.
PATIENTS AND METHODS: Enrollment began in April 1994 and consisted of patients with histologically confirmed, low-grade, B-cell lymphoma who had received no prior chemotherapy or who had no more than four prior standard therapies. Patients received six cycles of CHOP and six infusions of rituximab.
RESULTS: Eight (21%) of the 38 treated patients were classified as International Working Formulation (IWF) A, 16 (42%) were IWF B, 13 (34%) were IWF C, and one (3%) was IWF D. Nine (24%) of 38 patients had received prior chemotherapy. Nine (24%) of 38 were considered poor risk according to the Follicular Lymphoma International Prognostic Index. Overall response rate was 100%; 87% of patients achieved a complete response or unconfirmed complete response. The median TTP and DR were 82.3 months and 83.5 months, respectively. Seven of eight patients who were bcl-2 positive at baseline converted to negative, and three of the seven patients have sustained the molecular remission.
CONCLUSION: Although a cure has not been found yet for follicular NHL, the R-CHOP combination provides a lengthy response duration in patients with relapsed or newly diagnosed indolent NHL.
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INTRODUCTION
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In the 1980s and 1990s, the gold standard for treatment of aggressive lymphoma was cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). CHOP was considered curative in this population in approximately 50% of patients.1,2 On the basis of the hypothesis that the cure rate could be increased by combining CHOP with the monoclonal antibody, rituximab (Rituxan; Biogen Idec, Cambridge, MA; and Genentech, San Francisco, CA), the first study of this combination therapy was initiated in 1994. Because CHOP alone is curative in a subset of patients with aggressive lymphoma, the decision was made to test the novel combination therapy in patients with indolent disease, as no cure exists for this population. Thus the first trial evaluated safety and efficacy of combination therapy in low-grade and follicular non-Hodgkin's lymphoma (NHL).3
After encouraging preliminary results of this study were published,4 three subsequent trials evaluating the rituximab/CHOP (R-CHOP) combination in patients with aggressive NHL were performed. The first was a phase II trial in patients with intermediate-grade disease.5 The overall response rate (ORR) in 33 front-line patients with advanced, aggressive B-cell NHL was 94% (31 of 33 patients), with a complete response (CR) in 20 patients and partial response (PR) in 11 patients. This was followed by a large, randomized trial in 399 previously untreated, older patients with diffuse large B-cell lymphoma by the Groupe d'Etude des Lymphomes de l'Adulte.6 Patients received either R-CHOP or CHOP alone. Combination treatment produced significantly better results compared with CHOP alone as follows: better CR rate (76% v 63%, P = .005), improved event-free survival (P < .001), and prolonged overall survival (P = .007). In the initial study in low-grade patients and in the first two trials in aggressive patients, no significant additional toxicities occurred beyond those observed with CHOP alone.
The third trial conducted in the aggressive population was a phase III randomized study using a different rituximab schedule from the Groupe d'Etude des Lymphomes de l'Adulte study. Patients were assigned to R-CHOP or CHOP alone. Those achieving a CR or PR were then randomly assigned to maintenance with rituximab or observation. Although the results from this study are still preliminary, patients derived benefit from the addition of rituximab to their therapy.7
This article presents updated time to progression (TTP) and duration of response (DR) data based on a 9-year follow-up of the original phase II trial of R-CHOP in low-grade and follicular NHL. In addition, response rates have been updated based on the International Workshop Response Criteria (IWRC) developed for NHL.4 The original publication presented response rates based on criteria outlined in the study protocol,8 as the IWRC had not been established yet.
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PATIENTS AND METHODS
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A complete description of the design of this phase II, open-label, single-arm, multicenter study has been reported previously.4 Enrollment for the trial began in April 1994, and the last patient was treated in March 1996. Patients with histologically confirmed, low-grade or follicular, B-cell lymphoma who had received no prior chemotherapy or who had no more than four prior standard therapies were eligible for enrollment. All patients were required to have acceptable hematologic status (hemoglobin  8 gm/dL, absolute neutrophil count 1,500/µL, and platelets 100,000/µL). Patients received six cycles of CHOP and six infusions of rituximab. Two infusions of rituximab were administered before the first cycle, single infusions before the third and fifth cycle, and two infusions after the sixth cycle. The study was approved by the institutional review board at each study site, and written informed consent was obtained from all patients. The primary efficacy end point of this study was ORR, PR rate, and CR rate; secondary efficacy end points were TTP for responders and DR. TTP was defined as the interval from the date of first dose to the date of progressive disease or date of last contact. DR was defined as the interval from the date of the first observation of objective response to the date of progressive disease or date of last contact. Response categories based on the IWRC have been described previously.8 Restaging evaluation to determine response was performed no later than 2 months after treatment was completed.
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RESULTS
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Forty patients were enrolled onto this phase II study, and two of the 40 patients were never treated. Thirty-eight patients completed all treatments; 35 patients completed at least one cycle of treatment. Median age was 49 years, with nine patients (24%) older than 60 years of age. According to the International Working Formulation (IWF) classification, eight (21%) of the 38 treated patients had IWF A disease, 16 (42%) had IWF B, 13 (34%) had IWF C, and one (3%) had IWF D. Nine (24%) of 38 patients had received prior chemotherapy. Nine (24%) of 38 were considered poor risk according to the Follicular Lymphoma International Prognostic Index (FLIPI), and 10 (27%) of 38 patients were in the intermediate/high or high International Prognostic Index risk group. Nearly two thirds (64%) of the patients had Ann Arbor stage IV disease at diagnosis, and 26% had stage III disease. Five (13%) patients had five nodal sites, and 26 patients (68%) had extranodal disease. This included 18 patients with bone marrow involvement, eight patients with splenomegaly, and seven patients with either pleural effusion, orbital mass, gastric wall, or mediastinal involvement. Eleven patients (29%) had high lactate dehydrogenase levels, and six patients (16%) entered the study with hemoglobin values  12 g/dL (Table 1).
ORR evaluated by the IWRC was 100%, with 87% (33 of 38 patients) CR/unconfirmed complete response (CRu) and 13% (five of 38 patients) PR (Table 2). ORR as reported previously, using the protocol-defined response criteria, was 100%, with a 58% CR rate (22 of 38 patients). Median TTP in all patients is 82.3 months (range, 4.5+ to 105.6+ months); median DR is 83.5 months (range, 3.1+ to 105.1+ months). As shown in Figure 1, TTP for CR/CRu patients was significantly longer than TTP for PR patients (P = .0001). The 16 (42%) of 38 patients in continuous long-term remission (77.3+ to 105.6+ months) all achieved a CR. Three of these 16 patients had received prior treatment. Figure 2 presents a Kaplan-Meier graph of TTP in previously treated versus previously untreated patients.
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Fig 1. Kaplan-Meier analysis of time to progression by response (N = 38). C, censored; Cr, complete response; Cru, unconfirmed complete response.
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Fig 2. Kaplan-Meier analysis of time to progression: previously untreated (n = 29) versus previously treated (n = 9). C, censored.
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Five (63%) of eight patients with IWF A histology and 28 (93%) of 30 patients with IWF B, C, or D histology achieved a CR/CRu. The median TTP for the IWF A patients (75.6 months) was not significantly different from the TTP in IWF B, C, or D patients (84.9+ months).
As shown in Table 1, more than half the patients were in the intermediate or poor risk group for FLIPI. Median TTP was longest for the good-risk group and decreased with increasing number of risk factors (Table 3).
Eight patients were bcl-2 positive (t[14;18] chromosome translocation) at baseline, as tested by sensitive polymerase chain reaction assay. All of these eight patients achieved a CR. One patient remained bcl-2 positive and experienced disease progression at 76 months; the remaining seven patients converted to bcl-2–negative after treatment. Three of these seven patients remain negative and are in ongoing remission at 85, 98, and 99 months. The other four patients converted to negative and then reverted to positive. Two of these patients are in ongoing remission at 100 and 101 months; two patients experienced disease progression at 31 and 85 months.
The safety of rituximab in combination with CHOP chemotherapy has been previously described.4 In general, the most frequent and severe adverse events were related to CHOP and included hematologic effects, nausea, vomiting, and alopecia. The most frequent rituximab events occurred during the infusion. These included grade 1 and 2 chills, fever, pruritis, and headache. No quantifiable immune response to the rituximab antibody was detected.
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DISCUSSION
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In this phase II trial, 38 patients were treated with R-CHOP combination therapy. All patients achieved a response, with an 87% CR/CRu rate. Sixteen patients are still in remission 6 to 9 years after treatment; three of these 16 patients had received prior treatment. In this article, response rate was reanalyzed using the IWRC. These criteria prove to be predictive of response duration. All 16 ongoing responders achieved a CR, whereas the five patients with PRs experienced relapse within 2.5 years. In addition, molecular remissions were noted in seven of eight patients tested for bcl-2 translocation and have been sustained for several years in three of the seven patients.
This was the first trial to evaluate rituximab in combination with CHOP. Therefore, it was essential to closely monitor adverse events occurring with the two therapies and determine whether additive toxicities occurred. To limit the possibility of additive toxicities, rituximab and the CHOP regimen were administered on different days. Several studies have since demonstrated the safety of the CHOP/rituximab combination. Therefore, to improve convenience for the patient, currently treatments are administered together. However, the optimal schedule for administering rituximab and chemotherapy concurrently has not yet been determined.
The value of the addition of rituximab to standard combination therapy in both aggressive and indolent B-cell lymphoma patients with a range of good and poor prognostic factors has now been demonstrated in several clinical trials.4-6,9,10 Specifically, in our study, many patients had adverse prognostic factors as determined by the FLIPI.11 Twenty-four percent of patients were in the poor category with three or more FLIPI risk factors, and 32% were in the intermediate category with two risk factors. These included age greater than 60 years in 24% of patients, more than five nodal sites in 13% of patients, increased serum lactate dehydrogenase level in 29% of patients, hemoglobin 12 g/dL in 16% of patients, and Ann Arbor stage III/IV in 89% of patients. Despite these poor prognostic factors, response rates and response duration were extremely favorable.
Significant advances have been made in the treatment of indolent B-cell lymphoma since this study was initiated; however, the disease still remains incurable. Several trials evaluating rituximab in combination with various chemotherapeutic agents and with other new therapeutic agents have produced promising results.9,12,13
Cytokine upregulation of effector cells by interferon alfa-2a,14 interleukin-2, or granulocyte colony-stimulating factor15,16 potentially improve rituximab-associated antibody-dependent cellular cytotoxicity without significantly increasing treatment-associated toxicity. Overall response rates in the range of 50% or greater and TTP exceeding the 13 months seen in the initial pivotal trial17 of rituximab alone have been demonstrated in trials evaluating combination rituximab-cytokine therapy.3,15,18
Non–anti-CD20 monoclonal antibodies evaluated in B-cell lymphoma include epratuzumab (anti-CD22), apolizumab (anti-HLA-DRß), alemtuzumab (anti-CD52), and galiximab (anti-CD80). Early clinical studies demonstrated safe toxicity profiles but limited antitumor activity.18-20 However, use in combination with rituximab may augment antitumor activity.21
Two US Food and Drug Administration–approved anti-CD20 radioimmunoconjugates are currently in use for the treatment of relapsed indolent B-cell lymphoma: yttrium-90 ibritumomab tiuxetan (Zevalin; Biogen Inc, Cambridge, MA) and 131Iodine-tositumomab (Bexxar; Corixa, Seattle, WA). Long-term follow-up of indolent lymphoma patients treated with either of these radioimmunoconjugates demonstrated high ORR (ie, range of 65% to 73%, with CRs demonstrated in 35% to 51% of patients) and median response durations in the range of 12.6 to 19.3 months.22-25 Long-term remissions of 5+ years have been demonstrated in a minority of patients.
Although more new options have become available for patients with indolent disease over the last several years, this study, with the longest observation time, has still produced the best response rate and response duration in low-grade or follicular NHL. A decade has passed since the study's inception, and 42% of patients are still in remission; median TTP is nearly 7 years. These long-term remissions are occurring in previously untreated patients, as well as in those who have had prior treatment. Although a cure has not been found yet for follicular lymphoma, the R-CHOP combination provides the possibility of prolonged response duration in patients with B-cell lymphoma.
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Authors' Disclosures of Potential Conflicts of Interest
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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: Robin Weaver, Biogen Idec; Baha Alkuzweny, Biogen Idec. Consultant/Advisory Role: Myron S. Czuczman, Biogen Idec; Judy Berlfein, Biogen Idec; Antonio J. Grillo-López, Genentech, Idec, Roche. Stock Ownership: Baha Alkuzweny, Biogen Idec; Judy Berlfein, Biogen Idec; Antonio J. Grillo-López, Genentech. Honoraria: Antonio J. Grillo-López, Genentech, Idec, Roche. Research Funding: Myron S. Czuczman, Biogen Idec. Expert Testimony: Antonio J. Grillo-López, Idec.
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NOTES
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Supported by clinical grants from Biogen Idec (formerly known as IDEC Pharmaceuticals Corporation), Cambridge, MA.
Presented in part at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Submitted April 5, 2004;
accepted September 2, 2004.
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O. W. Press and R. I. Fisher
In Reply
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G. A. Salles
Clinical Features, Prognosis and Treatment of Follicular Lymphoma
Hematology,
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S. S. Neelapu and L. W. Kwak
Vaccine Therapy for B-Cell Lymphomas: Next-Generation Strategies
Hematology,
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243 - 249.
[Abstract]
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D. L. Longo
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J Natl Cancer Inst,
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O. W. Press, J. M. Unger, R. M. Braziel, D. G. Maloney, T. P. Miller, M. LeBlanc, and R. I. Fisher
Phase II Trial of CHOP Chemotherapy Followed by Tositumomab/Iodine I-131 Tositumomab for Previously Untreated Follicular Non-Hodgkin's Lymphoma: Five-Year Follow-Up of Southwest Oncology Group Protocol S9911
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D. Decaudin, P. de Cremoux, A. Vincent-Salomon, R. Dendale, and L. L.-L. Rouic
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Blood,
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[Abstract]
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Y. S. Jhanwar and D. J. Straus
The Role of PET in Lymphoma
J. Nucl. Med.,
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K. Tobinai, T. Watanabe, M. Ogura, Y. Morishima, Y. Ogawa, K.-i. Ishizawa, H. Minami, A. Utsunomiya, M. Taniwaki, T. Terauchi, et al.
Phase II Study of Oral Fludarabine Phosphate in Relapsed Indolent B-Cell Non-Hodgkin's Lymphoma
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M. S. Czuczman
Controversies in Follicular Lymphoma: "Who, What, When, Where, and Why?" (Not Necessarily in That Order!)
Hematology,
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[Abstract]
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W. H. Wilson
R-CHOP strikes again with survival benefit in follicular lymphoma
Blood,
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R. I. Fisher, M. LeBlanc, O. W. Press, D. G. Maloney, J. M. Unger, and T. P. Miller
New Treatment Options Have Changed the Survival of Patients With Follicular Lymphoma
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B. Coiffier
State-of-the-Art Therapeutics: Diffuse Large B-Cell Lymphoma
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[Abstract]
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W. Hiddemann, C. Buske, M. Dreyling, O. Weigert, G. Lenz, R. Forstpointner, C. Nickenig, and M. Unterhalt
Treatment Strategies in Follicular Lymphomas: Current Status and Future Perspectives
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[Abstract]
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J. P. Leonard, M. Coleman, J. Ketas, M. Ashe, J. M. Fiore, R. R. Furman, R. Niesvizky, T. Shore, A. Chadburn, H. Horne, et al.
Combination Antibody Therapy With Epratuzumab and Rituximab in Relapsed or Refractory Non-Hodgkin's Lymphoma
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TOP
ABSTRACT
INTRODUCTION
