Originally published as JCO Early Release 10.1200/JCO.2005.05.004 on January 4 2005

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Rituximab Plus Short-Duration Chemotherapy As First-Line Treatment for Follicular Non-Hodgkin’s Lymphoma: A Phase II Trial of the Minnie Pearl Cancer Research Network

From the Sarah Cannon Cancer Center and Tennessee Oncology, PLLC, Nashville; Thompson Cancer Survivor Center, Knoxville, TN; Northwest Georgia Oncology Centers, Marietta, GA; Consultants in Blood Disorders and Cancer, Louisville, KY.

Address reprint requests to John D. Hainsworth, MD, 250 25th Ave N, Suite 110, Nashville, TN 37203; e-mail: jhainsworth{at}tnonc.com

	ABSTRACT

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PURPOSE: To evaluate the feasibility and efficacy of rituximab with short-duration chemotherapy in the first-line treatment of patients with follicular non-Hodgkin’s lymphoma (NHL).

PATIENTS AND METHODS: Patients with previously untreated stage II-IV follicular NHL, grade 1 or 2, were eligible for this multicenter phase II trial. All patients received four weekly doses of rituximab (375 mg/m² intravenous), followed by three courses of combination chemotherapy (either cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP], or cyclophosphamide, vincristine, and prednisone [CVP]) plus rituximab. Patients were evaluated for response after completing treatment, and were then followed up at 3-month intervals.

RESULTS: Between January 2000 and July 2001, 86 patients were treated. Eight-two patients (95%) completed treatment; no patient was withdrawn due to toxicity. The overall response rate was 93%, with 55% complete responses. After a median follow-up of 42 months, the 3- and 4-year actuarial progression-free survivals were 71% and 62%, respectively. Five patients (6%) died from lymphoma; the overall actuarial survival at 3 years was 95%. Grade 3/4 leukopenia occurred in 53% of patients, but only six patients (7%) had neutropenia or fever. Grade 3/4 nonhematologic toxicities were uncommon.

CONCLUSION: Rituximab plus short-course chemotherapy is well tolerated as first-line treatment for patients with follicular NHL. The overall and complete response rates are similar to those reported with chemotherapy/rituximab combinations of longer duration. The actuarial progression-free survival of 62% at 4 years is encouraging, but further follow-up is necessary. Rituximab plus short-course chemotherapy may prove to be as effective as longer-duration chemotherapy and currently provides an attractive option for first-line treatment of elderly patients and others who tolerate chemotherapy poorly.

	INTRODUCTION

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Although many standard chemotherapeutic agents and combinations are active in the treatment of patients with follicular non-Hodgkin’s lymphoma (NHL), the large majority of these patients remain incurable. In recent years, rituximab has become a standard component of first-line therapy, either as a single agent or in combination with chemotherapy.^1-6 However, many patients with follicular NHL are elderly, and delivery of a full 6 to 8 courses of combination chemotherapy is often difficult due to treatment-related toxicity. The addition of rituximab to combination chemotherapy may allow a shorter course of chemotherapy to be administered while retaining a high complete response rate and a long progression-free survival. In addition, this treatment approach would be expected to minimize chemotherapy-related hematologic toxicity as well as cumulative nonhematologic toxicities such as fatigue, neuropathy, and cardiotoxicity.

In this multicenter, community-based phase II trial, we evaluated the feasibility, toxicity, and efficacy of rituximab plus short-duration chemotherapy in the first-line treatment of patients with follicular NHL. Patients received an initial 4-week course of single-agent rituximab, followed by three courses of chemotherapy with rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) at standard doses. Patients thought to be poor candidates for CHOP chemotherapy were allowed to receive rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) chemotherapy instead. In the present article, we present results of this phase II trial, now with a median follow-up of 42 months.

	PATIENTS AND METHODS

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Accrual to this phase II trial began in January 2000. This trial was conducted in the Minnie Pearl Cancer Research Network, a multicenter, community-based collaborative clinical trials group (Appendix).

Patient Eligibility
Eligible patients were required to have biopsy-proven follicular B-cell NHL of either small cleaved cell or mixed small-cleaved/large-cell subtype (grade 1 or 2) as defined by the revised European-American Lymphoma Classification. Patients with stages II, III, and IV lymphoma were eligible, as were patients who had previously presented with early-stage disease (stages I or II) and relapsed after treatment with radiation therapy alone. No previous chemotherapy or monoclonal antibody therapy was permitted. Additional eligibility requirements included: measurable or assessable disease; Eastern Cooperative Oncology Group performance status of 0, 1, or 2; age 18 years; WBC count 3,000/µL; platelet count 100,000/µL; and adequate liver and kidney function. Patients with small lymphocytic lymphoma or other subtypes of indolent NHL were ineligible. Patients who had CNS involvement (parenchymal brain or meningeal) were ineligible. All patients were required to provide written informed consent before entering this clinical trial. This study was approved by the institutional review board at Centennial Medical Center and by the institutional review boards of all participating network sites.

Initial Staging Evaluation
Before beginning therapy, all patients underwent staging procedures including complete history, physical examination, CBC, chemistry profile, computed tomography of the chest and abdomen, and bone marrow aspiration/biopsy. Measurement of cardiac ejection fraction using a nuclear medicine scan was required in all patients who were older than 60 years old or who had a history of cardiac disease.

Peripheral blood and bone marrow were evaluated for the presence of bcl-2 gene rearrangements using polymerase chain reaction (PCR) methodology. In this multicenter study, it was not feasible to perform analysis for bcl-2 rearrangements centrally, so methodology varied depending on the laboratory used. In the majority of patients (79%), the DNA amplification method allowed detection of a clonal population equivalent to one malignant cell in 10,000 normal cells. Rearrangements detected by this methodology were limited to those located in the major breakpoint region (mbr) of the bcl-2 gene.

Treatment
The treatment administered in this clinical trial is diagrammed in Figure 1. All patients initially received rituximab 375 mg/m², by slow intravenous (IV) infusion, administered weekly for 4 consecutive weeks. Beginning in week 5, patients received rituximab 375 mg/m² plus combination chemotherapy. Patients who were considered appropriate candidates received CHOP chemotherapy (cyclophosphamide 750 mg/m² IV, day 1; doxorubicin 50 mg/m² IV, day 1; vincristine 1.4 mg/m² IV, day 1 [maximum 2.0 mg]; prednisone 100 mg PO day 1 through 5). Patients who were felt to be poor candidates for CHOP chemotherapy, due either to cardiac problems or general debility, received CVP chemotherapy (cyclophosphamide 1,000 mg/m² IV, day 1; vincristine 1.4 mg/m² IV, day 1 [maximum 2.0 mg]; prednisone 100 mg PO days 1 to 5). All patients received three courses of chemotherapy plus rituximab, administered at 21-day intervals. After completion of chemotherapy, patients received two additional doses of rituximab (375 mg/m²) during weeks 14 and 15.

View larger version (9K): [in this window] [in a new window]   Fig 1. Treatment regimen. (*), Patients who were poor candidates for CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone) received CVP chemotherapy (cyclophosphamide 1,000 mg/m2 intravenous [IV], day 1; vincristine 1.4 mg/m2 [maximum 2.0 mg] IV, day 1; prednisone 100 mg PO days 1 to 5); R-, rituximab plus.

During the chemotherapy plus rituximab portion of the treatment, chemotherapy dose reductions were based on blood counts measured on the day of scheduled treatment. Nadir blood counts were not used as a basis for dose modification. On the day of treatment, if WBC was 3,000/µL and platelets 100,000/µL, full doses of all chemotherapeutic agents were administered. If WBC count was 2,000 to 3,000/µL or platelets count was 75,000 to 100,000/µL, 75% doses of all myelosuppressive agents were administered, while retaining full doses of the nonmyelosuppressive agents (ie, vincristine, prednisone). If WBC count was less than 2,000/µL or platelets count was less than 75,000/µL, all chemotherapy and rituximab was withheld for 1 week, and treatment continued with 75% doses of myelosuppressive agents after an increase in WBC to more than 3,000/µL, and platelets to more than 100,000/µL. Patients who required hospitalization for treatment of neutropenia and fever received 75% doses of myelosuppressive agents during subsequent courses. Cytokines were not routinely prescribed during the first course of therapy; however, prophylactic use of cytokines according to standard guidelines was permitted during subsequent courses at the discretion of the treating physician.

Patients experiencing reversible grade 3 or 4 nonhematologic chemotherapy-related toxicity (with the exception of nausea, vomiting, or alopecia) had a delay in dosing until resolution of toxicity to grade 1 or less. Chemotherapy was then reinstituted using a 75% dose of the offending agent or agents. Patients with irreversible nonhematologic toxicity, or toxicity that resulted in a treatment delay of 3 weeks, were removed from study.

Determination of Response
Patients were evaluated for response 3 weeks after completing all therapy. Restaging included physical examination, CBCs, chemistry profile, computed tomography of the chest and abdomen, and bone marrow aspiration and biopsy (if involved before treatment). Additional radiologic and/or endoscopic procedures were performed if necessary to re-evaluate sites of known lymph node or extranodal involvement. All patients who were bcl-2–positive in the blood or bone marrow at the beginning of therapy and who achieved a clinical complete response (CR) or unconfirmed CR (CR_u) were required to have a repeat determination after completion of treatment.

All patients were assigned a response category based on restaging after completion of treatment. Responses were categorized according to the International Standardized Response Criteria for non-Hodgkin’s lymphoma.⁷ CR required the disappearance of all detectable clinical and radiographic evidence of disease, disappearance of disease-related symptoms, and normalization of biochemical abnormalities (lactate dehydrogenase levels). All adenopathy on computed tomography scans must have regressed to normal size ( 1.5 cm). CR_u was defined as complete disappearance of all detectable clinical and radiographic abnormalities of disease, with the exception that residual adenopathy larger than 1.5 cm was present, as long as the size of adenopathy had decreased by more than 75%. Residual bone marrow abnormalities that included increased number or size of lymphoid aggregates without definite cytologic evidence of persistent lymphoma could also be present in patients with the CR_u response category. Partial response was defined as a greater than 50% decrease in the sum of products of the greatest diameters of the largest dominant nodes or nodal masses. Patients with stable disease had any response less than a partial response or increase in the size of measurable lesions by less than 25%, with no new lesions appearing. Progressive disease was defined by an increase of more than 25% in the size of measured lesions, as determined by the sum of products of the greatest perpendicular diameters of measurable lesions, or the appearance of new lesions.

In addition to assessing clinical response, the presence of abnormal levels of bcl-2 protein was assessed in all patients before beginning therapy and at the end of therapy. In patients who initially had detectable bcl-2 abnormalities, molecular CR was defined as the achievement of a clinical CR or CR_u, in conjunction with disappearance of detectable bcl-2 abnormalities from the blood and bone marrow.

Patient Follow-Up
After completion of treatment and restaging, patients with objective response were followed without further treatment. Patients were seen and examined by their physicians every 3 months, and complete restaging was performed at 6-month intervals. Restaging included physical examination, CBCs, chemistry profile, and repeat computed tomography scanning of all areas of previous lymphoma involvement. Repeat bone marrow aspiration or biopsy was not performed as a routine part of each restaging.

At the time lymphoma progression was documented, patients were removed from study, and further treatment was at the discretion of the treating physician.

Statistical Methods
This nonrandomized phase II trial was conducted for the purposes of evaluating the feasibility, toxicity, and efficacy of this novel treatment regimen. All patients who received at least one dose of therapy were included in the evaluation of toxicity. Treatment-related toxicities were graded using the National Cancer Institute Common Toxicity Criteria version 2.0.

The primary efficacy end point was the rate of clinical CR. Previous phase II studies using full courses of chemotherapy plus rituximab (ie, 6 to 8 courses) have reported CR rates ranging from 21% to 92%, with most results in the 40%-to-50% range.^2-6 Therefore, achievement of a CR rate more than 50%, with median progression-free survival greater than 36 months, was considered indicative of further development of this short-duration treatment approach. This trial used the Simon two-stage optimal design, assuming an improvement in CR rate to 55% v 40% for historical controls. In stage I, 11 complete responses were required in the first 26 patients treated. When this goal was reached (13 of 26 CR), accrual was continued to a target of 84 assessable patients, providing an level of .05 and a power of .81.

Progression-free survival was measured from the first day of treatment to the day of documented lymphoma progression. Overall survival was measured from the first day of treatment until the date of death. Actuarial survival curves were constructed using the method of Kaplan and Meier.⁸ Comparisons of survival for various subsets of patients were accomplished using two-sided log-rank analysis.⁹

	RESULTS

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Patient Characteristics
Between January 2000 and July 2001, 86 patients entered this multicenter phase II trial. Patient characteristics are listed in Table 1. The median age was 57 years; all patients had good performance status, and 86% had either stage III or IV lymphoma. Sixty-two percent of patients had follicular small-cleaved histology, while 38% had follicular mixed small-cleaved/large-cell lymphoma. The majority of patients (84%) had either low or low-intermediate Follicular Lymphoma International Prognostic Index risk scores.

Treatment Received
Eighty-two (95%) of 86 patients completed the entire course of treatment and were assessable for response. Four patients were withdrawn from treatment before completing the planned treatment course for the following reasons: intercurrent illness (cholecystitis, pneumonia) in two patients; progression of lymphoma in one patient; poor compliance/patient decision in one patient.

Sixty (70%) of 86 patients received CHOP chemotherapy, while 25 patients (29%) received CVP. One patient was withdrawn from protocol treatment during initial rituximab and received no chemotherapy. Sixty-one (74%) of 82 patients who completed three courses of chemotherapy received more than 90% of scheduled chemotherapy doses without any treatment delays. The remainder of the patients completing chemotherapy received at least 75% of the total cumulative planned doses of chemotherapy. All patients received full rituximab doses.

Efficacy
As expected, this regimen was highly active and produced objective responses in 80 (93%) of 86 patients who entered this trial. Forty-seven patients (55%) had CR or CR_u at the time of restaging. Only one patient had progression while on treatment and was removed from protocol study before completing the course of chemotherapy.

Twenty patients who achieved a clinical CR or CR_u had evidence of bcl-2 overexpression at the time treatment was initiated. Fifteen of these 20 patients had PCR analysis for bcl-2 abnormalities following completion of treatment, and 12 (80%) had a molecular CR.

After a median follow-up of 42 months, 58 patients (67%) remained progression free, 27 patients developed progressive lymphoma, and one patient died of an unrelated illness while in remission. The median progression-free survival has not been reached, and the actuarial progression-free survival at 3 years was 71% (Fig 2). For the subgroup of patients who achieved CR or CR_u, the actuarial 3-year progression-free survival is 79%.

View larger version (8K): [in this window] [in a new window]   Fig 2. Actuarial progression-free survival for all patients (N = 86). The 3- and 4-year progression-free survival rates were 71% and 62%, respectively.

View larger version (7K): [in this window] [in a new window]   Fig 3. Overall survival of the entire group. The 3-year survival rate was 95%.

Toxicity during the R-CHOP (or R-CVP) chemotherapy is detailed in Table 2. The major toxicity, as expected, was myelosuppression. Ten patients (12%) had grade 4 leukopenia, and six patients required hospitalization for treatment of fever associated with neutropenia. Thrombocytopenia was uncommon, and no patient had any bleeding complications. In general, nonhematologic toxicity was mild to moderate, and only a few patients had any grade 3/4 nonhematologic toxicities. There were no treatment-related deaths during this trial. Five patients (6%) received cytokine support with G-CSF or GM-CSF, and 10 patients (12%) received treatment with erythropoietin agents.

	DISCUSSION

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In designing the phase II trial reported here, we hoped to preserve the high level of activity seen with rituximab/chemotherapy combinations, while substantially reducing the toxicity of therapy. By reducing the length of treatment from the standard six to eight courses to only three courses of chemotherapy, we felt that overall toxicity could be markedly reduced. In particular, cumulative toxicities such as fatigue, peripheral neuropathy, myelosuppression, and cardiotoxicity could be limited. Most of these toxicities are particularly problematic in elderly patients. In this trial, we also included an initial 4-week course of single-agent rituximab, before initiating chemotherapy. The inclusion of the initial 4-week rituximab course was based on (1) preclinical observations of enhanced chemosensitivity in cells following exposure to rituximab,¹⁷ (2) clinical observations of the high first-line single-agent response rate to this drug,^10,11 and (3) concerns regarding inadequate exposure to rituximab if only three doses were administered concurrently with the three courses of chemotherapy.

The results of this multicenter phase II study, now with a median follow-up of 42 months, confirm a high level of activity with this first-line combination regimen. The clinical CR rate of 55% is similar to the CR rates reported in other phase II and phase III studies of chemotherapy/rituximab regimens, using full courses of chemotherapy.^2-6 In addition, this brief-duration chemotherapy/rituximab treatment produced a substantial molecular CR rate in patients obtaining a clinical complete remission, as reported with longer-duration combination regimens. Although further follow-up is necessary, the progression-free survival achieved in this group of patients is also comparable to the results from other combination regimens using longer treatment duration.

One of the major goals of this short-duration treatment was to minimize treatment-related toxicity. Neutropenia is the most frequent severe toxicity related to CHOP (or R-CHOP) chemotherapy and accounts for a majority of the treatment-related hospitalizations and deaths. The incidence of grade 3/4 neutropenia in patients receiving CHOP (or R-CHOP) chemotherapy ranges from 24% to 42%, and episodes of neutropenia/fever/infection range from 4% to 25%.^2,6,14,19,20 The incidence of neutropenia reported in different trials may be influenced by multiple factors, including cytokine use, policies regarding dose reductions, timing and frequency of blood count monitoring, and patient selection. However, the incidence of infectious complications associated with neutropenia was relatively low (7%) with this brief duration treatment compared with other reports. In addition, most trials with CHOP (or R-CHOP) report a 2% to 5% incidence of septic death; no treatment-related deaths occurred in our study.

Several cumulative, nonhematologic toxicities, including cardiotoxicity, peripheral neuropathy, nausea/vomiting, and fatigue, were clearly reduced with this short-duration treatment. Clinically significant cardiotoxicity is reported in 2% to 8% of patients receiving full-course CHOP, with occasional deaths. A similar incidence of grade 3/4 neuropathy is observed with six courses of CHOP. In our trial, no cardiac events occurred, and only one patient had grade 3 neurotoxicity. Although not usually reported in detail, worsening levels of fatigue, malaise, and anorexia are common clinical observations during the fourth through sixth treatment courses.

Although the ability to lengthen survival in patients with follicular lymphoma has not yet been definitively demonstrated with any first-line treatment, the increased clinical and molecular CR rates, as well as the markedly prolonged progression-free survivals now documented with rituximab/chemotherapy combinations provide a great deal of optimism along these lines. Ongoing studies in first-line treatment of follicular lymphoma should focus on continuing to improve clinical and molecular CR rates. To this end, a number of active new agents are available, and their successful incorporation into combination regimens is a priority. In our current clinical trial for first-line treatment of patients with follicular NHL, we have added a dose of ⁹⁰Y ibritumomab tiuxetan (Zevalin; Biogen Idec, San Diego, CA) following the rituximab/short course chemotherapy regimen reported here. Preliminary results from this ongoing clinical trial indicate a high clinical CR rate, with frequent improvement in response following treatment with ⁹⁰Y ibritumomab tiuxetan.¹⁸

Treatment with rituximab followed by short-course chemotherapy/rituximab as reported here provides a highly effective treatment option for patients with follicular NHL. Although the comparative efficacy of this short-duration regimen compared with a full six to eight courses of rituximab/chemotherapy awaits definition, this treatment approach may prove practical in elderly and/or debilitated patients who are likely to experience difficulties tolerating a full course of chemotherapy. With the increased use of newer, less toxic targeted agents, it is likely that the role of traditional chemotherapy in lymphoma treatment will be further modified in the future. The prospect of more effective, less toxic treatment for NHL seems a real possibility. The next 10 years should continue to be an active and exciting time for the development of improved therapy.

	Appendix

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Minnie Pearl Cancer Research Network Participating Sites: Tennessee Oncology, PLLC Nashville, TN; Northwest Georgia Oncology Centers Marietta, GA; Consultants in Blood Disorders and Cancer Louisville, KY; Thompson Cancer Survivor Center Knoxville, TN; The Cancer Center at Providence Hospital Mobile, AL; Tyler Hematology Oncology Tyler, TX; South Texas Oncology and Hematology San Antonio, TX; University Oncology & Hematology Associates Chattanooga, TN; Columbia Oncology Columbia, TN; Oncology/Hematology Group of South FL Miami, FL; Graves-Gilbert Clinic Bowling Green, KY; Oncology Associates of Western KY Paducah, KY; Mary Bird Perkins Cancer Center Baton Rouge, LA; Louisiana Oncology Associates Lafayette, LA; Upstate Carolina CCOP Spartanburg, SC; McLeod Cancer and Blood Center Johnson City, TN; Greenview Regional Hospital Bowling Green, KY; Northeast Georgia Medical Center Gainesville, GA; Medical Oncology, LLC Baton Rouge, LA.

	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. Received more than $2,000 a year from a company for either of the last 2 years: John D. Hainsworth, Genentech, Bigein Idec.

	NOTES

 
Supported in part by grants from Genentech Inc, IDEC Pharmaceuticals, and the Minnie Pearl Foundation.

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors’ Disclosures of... REFERENCES

 
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5. Marcus R, Imrie K, Belch A, et al: An international multi-centre, randomized, open-label, phase III trial comparing rituximab added to CVP chemotherapy to CVP chemotherapy alone in untreated stage III/IV follicular non-Hodgkin’s lymphoma. Blood 102:28a, 2003 (abstr 81)

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13. Ghielmini M, HsuSchmitz SF, Cogliatti SB, et al: Maintenance treatment with 2-monthly rituximab after standard weekly x 4 rituximab induction significantly improves event-free survival in patients with follicular lymphoma. Ann Oncol 13:18, 2002 (abstr 112)

14. Peterson BA, Petroni GR, Frizzera G, et al: Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: A study of the Cancer and Leukemia Group B. J Clin Oncol 21:5-15, 2003[Abstract/Free Full Text]

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Submitted May 2, 2004; accepted November 15, 2004.

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