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Originally published as JCO Early Release 10.1200/JCO.2005.12.052 on January 18 2005 © 2005 American Society of Clinical Oncology. Rituximab Therapy for Patients With Newly Diagnosed, Advanced-Stage, Follicular Grade I Non-Hodgkin's Lymphoma: A Phase II Trial in the North Central Cancer Treatment GroupFrom the Department of Internal Medicine, Division of Hematology, and the Division of Hematopathology, Mayo Clinic, Rochester, MN; OHACI, Peoria, IL; Medical Oncology/Hematology, Guthrie Clinic, Milan, PA; Medical Oncology, Allan Blair Cancer Center, Regina, Saskatchewan, Canada; Oncologic Consultants PA, Minneapolis, MN; Hematology/Oncology, Mayo Clinic, Scottsdale, AZ; Medical Oncology and Medical Association, Iowa Oncology Research Association CCOP, Des Moines, IA Address reprint requests to Thomas E. Witzig, MD, Mayo Clinic 200 First St SW, Rochester, MN 55905; e-mail: witzig{at}mayo.edu
PURPOSE: Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC). PATIENTS AND METHODS: Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m2 intravenous weekly x 4 doses and were then followed for response and progression; no maintenance therapy was provided. RESULTS: Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months. CONCLUSION: Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.
Follicular non-Hodgkin's lymphoma (NHL) is frequently diagnosed in patients who are asymptomatic. Staging procedures often document advanced (stage III or IV) disease despite the lack of symptoms. Follicular lymphomas are very sensitive to initial chemotherapy and radiation therapy; however, these treatments have not been demonstrated to reliably cure the patient. Radiation therapy is useful for the occasional patient with stage I follicular lymphoma and those with bulky advanced-stage disease with organ compromise, but radiotherapy is not typically incorporated in the management of asymptomatic patients with advanced-stage disease. The traditional treatment options for this group of patients have been careful observation or chemotherapy. The discovery of active agents for relapsed disease can often impact the treatment of patients with previously untreated disease. Rituximab, a human chimeric unlabeled antibody to the CD20 antigen, has been in clinical use since it was approved in 1998. Initial studies included only patients with relapsed NHL and demonstrated a consistent overall response rate (ORR) across multiple studies of approximately 50%, with a time to progression (TTP) of approximately 1 year.1-7 Rituximab is typically administered weekly x 4 at a dose of 375 mg/m2. Other than infusion-related toxicities, it is generally well tolerated. Rituximab therapy can be repeated without cumulative toxicity8-10 and does not interfere with stem-cell collection.11-13 The primary issues are cost, and that rituximab, like chemotherapy, does not cure patients with advanced follicular NHL. Because of these characteristics, rituximab is a potentially excellent treatment choice for the patient who does not choose observation when diagnosed with asymptomatic, advanced-stage, follicular NHL. Rituximab offers the possibility of a remission, a delay in chemotherapy, and preservation of quality of life. The goals of this study were to define the ORR as well as the TTP after treatment with rituximab in previously untreated patients with a uniform histologic diagnosis—follicular grade 1 NHL. In addition, the time to subsequent treatment (TTSC) was evaluated as another measure of benefit. This parameter is especially relevant to follicular NHL because although the patient may experience progression as documented by sensitive computed tomography scans, observation may still be possible if they remain asymptomatic and without organ compromise. Since the efficacy of rituximab in the untreated patient population was unknown when this study was initiated, only patients eligible for observation were included so that if rituximab was ineffective, long-term patient outcome would not have been compromised. In addition, this patient population was most likely to benefit from single-agent immunotherapy.
This study was conducted in the North Central Cancer Treatment Group (NCCTG). Patients were eligible if they had follicular grade 1 low-grade B-cell NHL. The tumor cells were required to express CD20 by flow cytometry, frozen section, or paraffin-embedded immunostains. CD20 staining and pathology grading was confirmed by central NCCTG pathology review. Eligible patients were stage IIIA or IVA, previously untreated, with measurable disease, 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients were considered to have bulky disease if they had a tumor mass that was  5 cm in a single diameter. Furthermore, patients should have been candidates for observation had they not participated on this trial. Patients were ineligible for this trial if they had 5,000 circulating tumor cells, CNS lymphoma, HIV infection, active malignancies other than NHL, and/or the presence of comorbid conditions that would make it likely that the patient would not live for 1 year. Patients received rituximab in 375 mg/m2 weekly x 4 doses using standard infusion guidelines. Patients were pretreated with acetaminophen 650 mg by mouth, and diphenhydramine 50 mg by mouth or intravenously; prophylactic corticosteroids were not administered. There was no maintenance therapy provided in this study. Patients were restaged 1 month after treatment and were then followed up every 3 months for the first year and every 6 months during years 2 to 5. Pretreatment staging consisted of physical examination; CBC; blood chemistry assessment including lactate dehydrogenase (LDH); computed tomography scans of the chest, abdomen, and pelvis; and a bone marrow aspiration and biopsy (bilateral). If the bone marrow was initially positive for lymphomatous involvement, a repeat study was required to document a complete remission (CR). Categories of response were as defined by the International Workshop to standardize response criteria for NHL.14 Polymerase chain reaction to detect the presence of bcl-2 gene rearrangements was not performed in this study. Protocols were approved at the institutional review board of each of the participating NCCTG treatment sites and all patients provided signed informed consent before treatment. The primary end point of the study was the ORR CR or partial remission [PR]) to rituximab. The study design required a minimum of 21 and a maximum of 32 patients to provide 90% power to detect an effective treatment given that the true confirmed response rate was at least 75% v 50% or less (assuming a 5% type I error rate). An interim analysis was conducted on the first 21 patients entered onto the study. The decision criteria were such that we would consider this treatment promising if 21 or more confirmed responses were observed in the first 32 patients. Assuming that the number of confirmed responses was binomially distributed, CIs for the true confirmed response rate were constructed according to the method of Duffy and Santner.15 Secondary end points included toxicity, time to progression, and time to subsequent chemotherapy. Toxicity was determined using National Cancer Institute Common Toxicity Criteria version 2.0. TTP was defined as the time from registration to the date of progression. Patients who died without disease progression were censored at the date of their last evaluation. TTSC was defined as the time from end of active treatment to the date the patient started subsequent chemotherapy. The distributions of TTP and TTSC were estimated using the Kaplan-Meier method.16 A cumulative incidence approach was not used to evaluate TTSC given that the competing risk (death) only occurred in patients who had already gone on to subsequent treatment. Due to the small number of deaths and the resulting high degree of censoring, overall survival was not evaluated in these analyses.
Patient Characteristics Thirty-seven patients were enrolled onto this study between July 1999 and May 2001. One patient was determined ineligible after central pathology review, which revealed that the patient's histology was follicular grade 2. The median age was 59 years (range, 29 to 83 years), and 28% of patients (10 of 36) were older than 65 years. Characteristics of the patients in this study are summarized in Table 1.
Clinical Outcomes The ORR was 72% (26 of 36 patients; 95% CI, 57% to 84%). Of these, 36% (13 of 36 patients) had a CR, and 36% (13 of 36 patients) had a PR (Table 2) . Of the 26 patients who responded, 18 (69%) achieved their response by the first restaging at 1 month postrituximab; six patients (23%), by 3 months; and two patients (8%), at 6 months or later. Ten patients (28%) were stable on therapy, and no patient progressed on therapy. Of the 22 patients (61%) with initial bone marrow involvement, 13 had a repeat bone marrow after rituximab, and the marrow was negative for lymphoma in all 13 cases. Patients with marrow negative for lymphoma at diagnosis were not reassessed as part of the restaging following treatment.
The median follow-up on living patients as of October 2003 was 2.6 years (range, 1.6 to 4). Fourteen patients (39%) remain on observation in an unmaintained remission. Two patients received additional treatment despite lack of disease progression. The remaining 20 patients have disease progression (56%). Of these 20 patients, 15 have received subsequent chemotherapy and five patients remain asymptomatic and untreated. Overall, five patients have died—two without disease progression and three with disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached; Fig 1). To date, 18 patients have gone on to receive subsequent chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached; Fig 2).
Although trial eligibility specified that patients were not to have "B" symptoms, nor were they to be considered as requiring chemotherapy, six patients were enrolled with an elevated LDH. Despite the relatively small sample size, significant differences were observed in ORR between those with elevated versus normal pretreatment LDH (33% v 80%, respectively; P = .02). In addition, there were significant differences in TTP between patients with elevated versus normal pretreatment LDH (median, 0.5 v 2.6 years, respectively; P = .005; Fig 3). Notable differences were also observed between these elevated versus normal groups in terms of TTSC (median, 1.1 v 2.6 years, respectively; Fig 4).
Toxicity In general, rituximab was a well-tolerated treatment. Overall, 35 patients were assessable for toxicity. Severe adverse events (grade 3 or 4) were observed in five patients (14%). Grade 3 adverse events included neutropenia (one patient), leukopenia (one patient), rash (one patient), hemorrhage (one patient), infection without neutropenia (one patient), and colitis (one patient). Two grade 4 events observed were urticaria and rash. Of the severe adverse events reported, only the grade 3 neutropenia and the grade 4 events were believed by the treating physician to be at least possibly attributable to the rituximab treatment. These severe toxicities were seen in only two patients. In addition, 25 patients reported a maximum grade 1 or 2 toxicity, with the most common being fatigue (10 patients).
The optimal treatment of the newly diagnosed, advanced-stage but asymptomatic patient with follicular grade 1 NHL remains undefined. Despite treatment advances, patients with advanced-stage disease are considered treatable but rarely curable. For some patients, especially the older adult with significant comorbidities, asymptomatic follicular NHL is not life threatening and often becomes another chronic disease for the patient and physician to manage. Although chemotherapy and radiotherapy are effective and can usually be administered with minimal morbidity and rare mortality in these patients, they are associated with side effects. Thus, if the patient is truly asymptomatic, then treatment will not make them feel better than they felt at baseline. The only exception to this principle is that in some patients, the anxiety and emotional distress created by the knowledge of advanced-stage cancer that is being left untreated provides the rationale to offer therapy. Traditional treatment options for this group of patients include close observation or combination chemotherapy. The issues with chemotherapy include the risk of infection due to cytopenias, fatigue due to anemia and chemotherapy, long-term risk of myelodysplasia and acute nonlymphocytic leukemia from alkylating agents,17-19 and risk of stem-cell damage from alkylating agents and purine nucleoside analogs.20 It should be noted that there is a significant minority (15% to 20%) of patients who, when treated with chemotherapy, have prolonged disease-free survival and cure.21-23 The advantages of observation are the avoidance of the risks of chemotherapy and the chance that when treatment is needed, the patient can receive more effective treatments not previously available during initial diagnosis. The introduction of immunotherapy with rituximab in the late 1990s has introduced a new possible treatment option for patients in this situation. The advantages of rituximab are that it is not chemotherapy and is not associated with the typical chemotherapy side effects. In addition, the treatment is completed in 1 month and does not seem to conflict with any future treatment modalities. Multiple studies have documented the ORR to rituximab in the relapsed low grade NHL patient population at approximately 50% with an approximate 1-year TTP.1-7 This study addressed the role of rituximab monotherapy for patients with previously untreated, advanced-stage, asymptomatic follicular grade 1 patients. The results demonstrated that indeed the ORR was high at 72% with a 36% CR. This is substantially higher than the 50% and 7% responses for ORR and CR, respectively, in the relapsed patient population.1-7 The median TTP is also longer at 2.2 years compared with the approximate 1 year found in relapsed patients, and the median TTSC has not yet been reached. It is apparent from this study that a substantial group of patients in this situation have a long TTP/TTSC, whereas others rapidly progress and require additional treatment (Figs 1 and 2). The identification of those who may experience prolonged benefit from rituximab is problematic. In this study, the six patients with high LDH performed worse on several clinical outcomes. Thus, in future studies, we would not recommend that patients with a high serum LDH be considered for observation or immunotherapy alone. This study compares favorably with the results of the two other studies that have treated this group of patients with rituximab. Colombat et al24 reported 50 patients with the same rituximab schedule used in this study and found a very similar ORR of 73%, with a 27% CR/CR unconfirmed. No maintenance therapy was provided. Hainsworth et al25,26 used the same dose and schedule of rituximab as induction therapy and reported an ORR of 47%. However, the Hainsworth et al study differed substantially from ours and the study by Colombat et al24 in that patients could have either follicular (61%, with 34% grade 1 and 27% grade 2) or small lymphocytic lymphoma (39%). In addition, stage II patients (21%) were included, and 23% had B symptoms. Patients were administered maintenance rituximab every 6 months x 4 or until tumor progression. With rituximab maintenance, the ORR increased to 76%, with a median TTP of 34 months. The report25 also noted that 41% of patients had a high LDH; however, there was no mention of the outcome of these patients compared with those with a normal LDH. The study reported herein did not address the issue of rituximab maintenance. It is not known at this time whether it is better to provide maintenance after successful induction therapy or whether it is equally effective to observe the patient after a single course of rituximab, and re-treat them at the time of disease progression. This is clearly an issue that requires study in a randomized clinical trial, and this is now underway. The current study, in addition to the other two studies mentioned above,24,25 indicate that rituximab immunotherapy is highly active as a single agent in patients with previously untreated NHL. None of these three studies were randomized (ie, rituximab v observation); therefore, it is not known whether providing the rituximab early has any impact on overall survival as opposed to a strategy of observation followed by treatment at the time of active disease. Rituximab seems to be a reasonable alternative for asymptomatic patients with a normal serum LDH who prefer to not be observed.
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. Received more than $2,000 a year from a company for either of the last 2 years: Thomas E. Witzig, Genentech.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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4. Ghielmini M, Schmitz SF, Burki K, et al: The effect of Rituximab on patients with follicular and mantle-cell lymphoma: Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 11:123-126, 2000
5. Igarashi T, Kobayashi Y, Ogura M, et al: Factors affecting toxicity, response and progression-free survival in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma treated with rituximab: A Japanese phase II study. Ann Oncol 13:928-943, 2002
6. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90:2188-2195, 1997 7. Nguyen DT, Amess JA, Doughty H, et al: IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patients with low-grade non-Hodgkin's lymphoma and lymphoproliferative disorders: Evaluation of response on 48 patients. Eur J Haematol 62:76-82, 1999[Medline] 8. Igarashi T, Ohtsu T, Fujii H, et al: Re-treatment of relapsed indolent B-cell lymphoma with rituximab. Int J Hematol 73:213-221, 2001[Medline]
9. Davis TA, Grillo-Lopez AJ, White CA, et al: Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: Safety and efficacy of re-treatment. J Clin Oncol 18:3135-3143, 2000 10. Koh LP, Lim LC, Thng CH: Retreatment with chimeric CD 20 monoclonal antibody in a patient with nodal marginal zone B-cell lymphoma. Med Oncol 17:225-228, 2000[Medline] 11. Buckstein R, Imrie K, Spaner D, et al: Stem cell function and engraftment is not affected by "in vivo purging" with rituximab for autologous stem cell treatment for patients with low-grade non-Hodgkin's lymphoma. Semin Oncol 26:115-122, 1999[Medline] 12. Flinn IW, O'Donnell PV, Goodrich A, et al: Immunotherapy with rituximab during peripheral blood stem cell transplantation for non-Hodgkin's lymphoma. Biol Blood Marrow Transplant 6:628-632, 2000[CrossRef][Medline]
13. Magni M, Di Nicola M, Devizzi L, et al: Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: Evidence for a role of both chemotherapy and rituximab infusion. Blood 96:864-869, 2000
14. Cheson B, Horning S, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphoma. J Clin Oncol 17:1244-1253, 1999 15. Duffy D, Santner T: Confidence intervals for a binomial parameter based on multistage tests. Biometrics 43:81-93, 1987[CrossRef] 16. Kaplan E, Meier P: Nonparametric estimation for incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]
17. Travis LB, Curtis RE, Glimelius B, et al: Second cancers among long-term survivors of non-Hodgkin's lymphoma. J Natl Cancer Inst 85:1932-1937, 1993
18. Travis LB, Curtis RE, Stovall M, et al: Risk of leukemia following treatment for non-Hodgkin's lymphoma. J Natl Cancer Inst 86:1450-1457, 1994 19. Kyle RA, Greipp PR, Gertz MA, et al: Waldenstrom's macroglobulinaemia: A prospective study comparing daily with intermittent oral chlorambucil. Br J Haematol 108:737-742, 2000[CrossRef][Medline] 20. Micallef IN, Apostolidis J, Rohatiner AZ, et al: Factors which predict unsuccessful mobilisation of peripheral blood progenitor cells following G-CSF alone in patients with non-Hodgkin's lymphoma. Hematol J 1:367-373, 2000[CrossRef][Medline]
21. Gallagher CJ, Gregory WM, Jones AE, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4:1470-1480, 1986
22. Johnson P, Rohatiner A, Whelan J, et al: Patterns of survival in patients with recurrent follicular lymphoma: A 20-year study from a single center. J Clin Oncol 13:140-147, 1995
23. Cabanillas F: Can we cure indolent lymphomas? Clin Cancer Res 3:2655-2659, 1997
24. Colombat P, Salles G, Brousse N, et al: Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: Clinical and molecular evaluation. Blood 97:101-106, 2001
25. Hainsworth JD, Litchy S, Burris HA 3rd, et al: Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma. J Clin Oncol 20:4261-4267, 2002 26. Hainsworth JD, Litchy S, Morrissey L, et al: Rituximab as first-line and maintenance therapy for indolent non-Hodgkin's lymphoma (NHL): long-term follow-up of a Minnie Pearl Cancer Research Network Phase II trial. Blood 102, 2003 (abstr 1496) Submitted December 9, 2003; accepted June 16, 2004.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
