Originally published as JCO Early Release 10.1200/JCO.2005.12.191 on January 18 2005

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Maximizing Therapeutic Benefit of Rituximab: Maintenance Therapy Versus Re-Treatment at Progression in Patients With Indolent Non-Hodgkin's Lymphoma—A Randomized Phase II Trial of the Minnie Pearl Cancer Research Network

From the Sarah Cannon Cancer Center and Tennessee Oncology PLLC, Nashville, TN; Northwest Georgia Oncology Centers, Marietta, GA; Jackson Oncology Associates, Jackson, MS; and Consultants in Blood Disorders and Cancer, Louisville, KY

Address reprint requests to John D. Hainsworth, MD, 250 25th Avenue North, Sarah Cannon Cancer Center, Suite 110, Nashville, TN 37203; e-mail: jhainsworth{at}tnonc.com

	ABSTRACT

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PURPOSE: To compare the benefit of maintenance rituximab therapy versus rituximab re-treatment at progression in patients with previously treated indolent non-Hodgkin's lymphoma.

PATIENTS AND METHODS: Between June 1998 and August 2002, 114 patients who had received previous chemotherapy for indolent non-Hodgkin's lymphoma were treated with a standard 4-week course of rituximab. Patients with objective response or stable disease were randomly assigned to receive either maintenance rituximab therapy (standard 4-week courses administered at 6-month intervals) or rituximab re-treatment at the time of lymphoma progression. The duration of rituximab benefit was measured from the date of first rituximab treatment until the date other treatment was required.

RESULTS: Ninety (79%) of 114 patients had objective response or stable disease after initial rituximab treatment, and were randomly assigned to treatment. Progression-free survival was prolonged in the maintenance group (31.3 v 7.4 months; P = .007). Final overall and complete response rates were higher in the maintenance group. Duration of rituximab benefit was similar in the maintenance and re-treatment groups (31.3 v 27.4 months, respectively). More maintenance patients remain in continuous remission, and more are currently in complete remission. Both treatment approaches were well tolerated.

CONCLUSION: In patients who have objective response or stable disease with single-agent rituximab therapy, duration of rituximab benefit is substantially prolonged with either scheduled maintenance treatment or rituximab re-treatment at the time of progression. At present, the magnitude of benefit with either approach appears similar. However, additional follow-up of this trial is required, and completion of phase III randomized trials is necessary to definitively answer this question.

	INTRODUCTION

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Rituximab is a highly active agent in the treatment of patients with indolent non-Hodgkin's lymphoma. When administered to patients with refractory disease or those experiencing relapse, a standard 4-week course of rituximab produces a response rate of approximately 50% and median progression-free survival of approximately 12 months.¹ Recently, it became evident that many patients are able to derive additional benefit from rituximab beyond that produced by a single 4-week course. When patients with initial response to rituximab are re-treated at the time of lymphoma progression, second responses occur in 40%, and the median duration of second responses is 18 months.² The duration of remission produced by rituximab can also be prolonged by using scheduled, intermittent re-treatments (ie, maintenance therapy).^3,4 In a randomized trial, patients with follicular lymphoma who responded to initial treatment and then received scheduled doses of rituximab every 2 months (months 3, 5, 7, and 9) had a longer remission duration than did patients who received a standard 4-week course alone (22.4 v 13.4 months, respectively).⁴ In a group of 62 previously untreated patients, median progression-free survival was 37 months when 4-week courses of rituximab were administered at 6-month intervals.³

Given that treatment with rituximab is associated with fewer adverse effects than other available options, optimization of the duration of benefit is an important clinical issue. In this randomized phase II trial, we compared the efficacy of rituximab maintenance therapy versus rituximab re-treatment at progression in patients with previously treated, indolent non-Hodgkin's lymphoma. All patients entering onto this clinical trial first received a standard 4-week course of rituximab; those with objective response or stable disease were randomly assigned to receive maintenance therapy with rituximab versus re-treatment at progression. We report the results of this randomized, multicenter, community-based clinical trial after a median follow-up of 41 months.

	PATIENTS AND METHODS

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Accrual to this randomized phase II trial began in June 1998. The trial was conducted in the Minnie Pearl Cancer Research Network, a multicenter, community-based collaborative clinical trials group (see Appendix).

Initial Staging Evaluation
Before beginning rituximab therapy, all patients underwent staging procedures including history, physical examination, CBCs, chemistry profile, and computed tomography (CT) of the chest and abdomen. Women of potential childbearing age were required to have a negative pregnancy test before study entry. Bone marrow aspiration or biopsy was recommended, but was not required in patients who had previously demonstrated involved bone marrow at the time of initial diagnosis.

All areas of lymphoma involvement were documented. Tumor measurements and assessment before treatment, and at the time of restaging, were performed using the Cheson criteria.⁵

Initial Treatment
The design of this clinical trial is illustrated in Fig 1. All patients received initial treatment with rituximab 375 mg/m² administered weekly for 4 consecutive weeks. Rituximab was administered by slow intravenous (IV) infusion using standard guidelines. Premedication included oral acetaminophen 650 mg and diphenhydramine 50 mg administered 30 minutes before rituximab infusion. Dexamethasone or other corticosteroids were not routinely administered as premedications in this study.

View larger version (11K): [in this window] [in a new window]   Fig 1. Study design. All patients initially received a standard 4-week rituximab course (375 mg/m2/wk); patients with response or stable disease at week 6 were randomly assigned to treatment. CR, complete response; PR, partial response.

Randomization
All patients were evaluated for response 2 weeks after completing initial treatment with rituximab. All measurable or assessable tumor sites were re-evaluated by physical examination and repeat of appropriate radiologic studies. Repeat bone marrow examination was required only if necessary to document a complete remission. On the basis of this restaging, all patients were assigned a response category based on the Cheson criteria.⁵ All patients with objective responses (partial response or complete response) and patients with stable disease remained on study and were randomly assigned to treatment, whereas patients with lymphoma progression were removed from study. Random assignment for all patients was performed at the central data site at the Sarah Cannon Cancer Center, using a random card system.

Patients were randomly assigned to received maintenance rituximab therapy or to be re-treated with rituximab only when lymphoma progression was documented (Fig 1). Patients in the maintenance group received standard courses of rituximab (375 mg/m² IV weekly for 4 consecutive weeks) at 6-month intervals, until lymphoma progression or for a total of four rituximab courses. Patients who had no evidence of lymphoma progression after completing the fourth course of rituximab were then observed without additional treatment. Patients randomly assigned to receive re-treatment at the time of progression were reassessed at 3-month intervals, and received a repeat 4-week course of rituximab when lymphoma progression was documented. Patients in the re-treatment group could continue to receive re-treatment with rituximab as long as a remission or a period of disease stability 3 months resulted from each treatment.

Follow-Up and Assessment of Treatment Effect
After initial restaging and random assignment, all patients were seen and re-evaluated at 3-month intervals. Routine follow-up included repeat physical examination with tumor measurements, CBCs, and chemistry profile every 3 months, and repeat CT scans at least every 6 months. CT scans were performed before the 6-month interval if physical examination or new symptoms suggested lymphoma progression. For patients in the maintenance rituximab group, repeat re-evaluation with CT scans was performed before each subsequent course of rituximab maintenance therapy was administered. In addition to the initial clinical response, the best response for each patient, according to Cheson criteria, was recorded.

For patients in the maintenance rituximab group, follow-up continued at 3-month intervals, with repeat scans at 6-month intervals, after completion of the four courses of maintenance rituximab. Patients in the re-treatment group continued to be eligible for additional treatment with rituximab, as long as continued benefit was observed (ie, objective response or stable disease of 3 months duration after each re-treatment course).

Statistical Methods
The primary end point for efficacy in this clinical trial was the duration of rituximab benefit, as measured from the date of first treatment until the date that patients developed progressive lymphoma and required other treatment. Patients were considered to benefit from rituximab if they had either ongoing objective response or stable disease (maintenance group), or continued to achieve objective response or stable disease for more than 6 months duration after each rituximab course (re-treatment group). Secondary end points included progression-free survival, objective response rate, and complete response rate. Actuarial progression-free survival curves and duration of rituximab benefit curves were constructed using the method of Kaplan and Meier.⁶ Comparisons of actuarial progression-free survival and duration of rituximab benefit between the two groups was accomplished using two-sided log-rank analysis.⁷

At the time this randomized trial was initiated, no data from any completed trials of maintenance rituximab were available. However, it was estimated that the median duration of rituximab benefit in the re-treatment group would be approximately 18 months (12-month median response duration after the initial 4-week course, plus added benefit for 40% of patients attaining a second remission after re-treatment). To demonstrate a prolongation of the duration of rituximab benefit by 50% (ie, 18 to 27 months) required random assignment of 50 patients to each study group. We estimated that 75% of patients entering this study would be randomly assigned, whereas 25% would be ineligible for random assignment because of the lack of response to the initial course of rituximab. Therefore, a total of 135 patients would be required to enter this trial.

	RESULTS

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Patient Characteristics
Between June 1998 and August 2002, 114 patients were entered onto this clinical trial by 24 participating sites in the Minnie Pearl Cancer Research Network. Accrual to the trial was discontinued before meeting the original goal of 135 patients because of declining enrollment. This decline was probably the result of the increasing use of rituximab as part of first-line therapy for indolent non-Hodgkin's lymphoma, and the reporting of favorable data regarding the efficacy of maintenance rituximab.

Ninety (79%) of 114 patients who entered the trial and received rituximab had either objective response (32 patients; 28%) or stable disease (58 patients; 51%) when re-evaluated at week 6, and were subsequently randomly assigned to treatment. The clinical characteristics of these 90 patients are summarized in Table 1. Patients in this trial had good performance status and had received a mean of 1.6 previous treatment regimens (range, one to four). The median interval between previous treatment and enrollment onto the trial was relatively long (22 months), and the majority of patients had low or low-intermediate International Prognostic Index risk scores. Prognostic factors were relatively well balanced between the two treatment groups. The percentage of patients with SLL was slightly higher in the re-treatment group (39% v 23%); however, this difference was not statistically significant. The distribution of responses to initial rituximab therapy was also similar between the two groups. Overall, 17 patients (39%) in the maintenance group had an initial objective response to rituximab, whereas 15 patients (33%) in the re-treatment group had objective response. The remaining patients (61% of maintenance patients and 67% of re-treatment patients) had stable disease after the initial course of rituximab.

To date, a total of 117 rituximab courses (468 doses) have been administered in the maintenance group versus 83 courses (332 doses) in the re-treatment group. Four patients in the maintenance rituximab group are continuing with scheduled maintenance courses, whereas 14 patients in the re-treatment group remain on study, and may receive additional re-treatment courses.

Treatment Efficacy
The efficacy of rituximab maintenance therapy versus re-treatment is summarized in Table 3. With maintenance rituximab treatment, six additional objective responses occurred, so that the objective response rate improved from 39% at study entry to a best response rate of 52%. In addition, the complete response rate in the maintenance group increased from 9% at study entry to 27%. In contrast, patients who were re-treated at the time of progression had minimal change in overall response rate (33% to 35%), and only two patients in the re-treatment group (4%) had complete response at any time during treatment.

View larger version (12K): [in this window] [in a new window]   Fig 2. Actuarial progression-free survival (PFS). Median PFS was longer in the maintenance group (31.7 months) than in the re-treatment at progression group (7.4 months; P = .007).

View larger version (12K): [in this window] [in a new window]   Fig 3. Actuarial duration of rituximab benefit. After median followup of 41 months, maintenance and re-treatment groups have similar benefit (median 31.7 v 27.4 months, respectively).

View larger version (13K): [in this window] [in a new window]   Fig 4. Actuarial survival curves: 3-year actuarial survival for the maintenance versus re-treatment groups are 72% and 68%, respectively.

	DISCUSSION

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Rituximab is a highly active single agent in the treatment of patients with relapsed or refractory indolent non-Hodgkin's lymphoma. In this patient population, a 4-week course of rituximab has consistently produced response rates of approximately 50%, and median progression-free survival of approximately 12 months.^1,8–10 In previously untreated patients, response rates are higher (70% to 75%) and median progression-free survival is approximately 18 months.^4,11 However, it is evident that many of these patients benefit from additional treatment with rituximab. Re-treatment of rituximab responders, at the time of progression, produces second remissions in 40% of patients.² Maintenance treatment with rituximab also prolongs the duration of remission, producing a median progression-free survival of 22.4 months in a group of predominantly previously treated patients with follicular lymphoma.⁴ Results with maintenance therapy were even more impressive in patients who had received no previous treatment; in two trials, median progression-free survivals were 35.6 and 36.8 months, respectively.^3,4 However, the relative benefit of maintenance rituximab therapy versus rituximab re-treatment at progression has not been addressed previously in clinical trials.

The results of this randomized, phase II trial provide confirmation of several previous observations regarding the efficacy of rituximab when used as initial treatment and as maintenance therapy. When they entered onto this trial, all patients received a standard 4-week course of rituximab; the majority of patients had either objective response (28%) or stable disease (51%) and were subsequently randomly assigned to treatment. The objective response rate to initial treatment with rituximab is somewhat lower than in previous reports; this may have been due to the relatively early time of re-evaluation (6 weeks) or to the inclusion of patients with SLL. This trial also provided the first opportunity to confirm the efficacy of maintenance rituximab, administered every 6 months, in a group of previously treated patients. Results were similar to our previous phase II trial: overall and complete response rates improved with maintenance, and the median progression-free survival (31.3 months) was similar to that seen in patients treated with first-line rituximab (36.8 months).⁴ Finally, the large difference in progression-free survival in the maintenance versus re-treatment groups (31.3 v 7.4 months; P = .007) confirms results from the randomized trial by Ghielmini et al.³

In addition to these confirmatory results, this trial provides the first direct comparison of the efficacy of rituximab maintenance versus re-treatment at progression in previously treated patients with indolent lymphoma. After a median follow-up of 41 months, the median duration of rituximab benefit is similar for patients in the maintenance versus re-treatment group (31.3 v 27.4 months, respectively). Therefore, re-treatment with rituximab substantially extended the duration of benefit in the re-treatment group, in which a single 4-week course of rituximab produced a median progression-free survival of only 7.4 months. At present, patients in the re-treatment group have received 29% fewer doses of rituximab than have the patients in the maintenance group. Given that patients in the re-treatment group remain on study (14 v four, respectively), this disparity may decrease with additional follow-up.

Despite the similar duration of rituximab benefit between the two groups, several differences must also be emphasized. First, patients receiving maintenance rituximab had better responses to treatment than did patients in the re-treatment group. Although the difference in overall response rate did not reach statistical significance (52% v 35%; P = .14), the complete response rates were markedly different (27% v 4%; P = .007). Second, more patients in the maintenance group had continuous remissions during therapy (45% v 24%; P = .05). When assessed in patients with metastatic breast cancer, maintaining continuous remission (v re-treatment at progression) decreased cancer-related symptoms and improved quality of life, even when the treatment involved moderately toxic chemotherapy.¹² Improvements in these parameters may be even more striking with a relatively nontoxic therapy. However, such comparisons have not been performed in patients with indolent non-Hodgkin’s lymphoma. Given that these patients often have asymptomatic tumor progression, re-treatment may provide comparable palliative benefit. These issues require prospective study in randomized trials. Finally, the number of patients currently in complete remission is higher in the maintenance group (23% v 2%, P = .03). Therefore, it is possible that differences may emerge between these two treatment approaches with additional follow-up.

Although the results of this randomized phase II trial provide a preliminary comparison of these treatment strategies, confirmatory trials are necessary before the optimal strategy can be defined with certainty. When our trial was designed and initiated, minimal information regarding the results of either of these treatment strategies was available, and single-agent rituximab had not been used as first-line therapy. Therefore, we limited the eligible patient population to those who had received previous chemotherapy but had never received rituximab. Accrual to the trial decreased markedly during the final 2 years of the study, probably reflecting the near-universal use of rituximab as part of first-line treatment. Because of this particular difficulty, as well as the fact that the benefits of rituximab maintenance treatment appear larger in the first-line setting,^3,4 confirmatory trials will likely need to be performed in a previously untreated patient group.

In addition to the relatively small number of patients included in our trial, several other issues may affect interpretation of results. First, more patients in the maintenance group were withdrawn during the first 6 months because of lymphoma progression (30% v 17%, respectively). Because none of these patients received additional rituximab, this imbalance could have adversely affected the results in the maintenance group. Second, the larger number of SLL patients in the re-treatment group may have adversely affected results with this strategy. Recent results have confirmed lower response rates in SLL patients, as well as shorter progression-free survival with maintenance therapy.^1,9,13 Finally, our arbitrary decision to limit the duration of maintenance therapy (but not the number of re-treatment courses in responsive patients) may result in underestimation of the benefit of maintenance treatment in some patients.

In summary, the results of this study confirm that the duration of rituximab benefit can be prolonged either by using scheduled re-treatment (ie, maintenance), or by re-treating patients at the time of lymphoma progression. To provide optimal palliative treatment for patients with indolent lymphoma, one of these rituximab treatment strategies should be considered in all patients who have an initial objective response or stable disease more than 6 months. Additional follow-up of this trial will be important to determine if any late differences in the relative benefit of these two approaches emerge. Successful completion of the recently initiated Eastern Cooperative Oncology Group trial comparing these two strategies is also critical to clarify this issue. Several other important questions regarding maintenance rituximab are also unanswered. The best dosing schedule and duration of therapy are unclear. The role of maintenance rituximab in B-cell malignancies other than follicular lymphoma has just started to be evaluated. Probably the most important question in the treatment of indolent lymphoma is whether current therapy can prolong survival. The improved molecular complete response rates and longer progression-free survivals obtained with chemotherapy and rituximab combinations have produced optimism that survival improvements may now be possible. Maintenance rituximab after first-line chemotherapy and rituximab may also play a role in therapy designed to extend survival; results of the ongoing trials addressing this issue are eagerly awaited.

	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. Performed contract work within the last 2 years: John D. Hainsworth, Genentech, IDEC Pharmaceuticals; F. Anthony Greco, Genentech, IDEC Pharmaceuticals. Received more than $2,000 a year from a company for either of the last 2 years: John D. Hainsworth, Genentech, IDEC Pharmaceuticals.

	NOTES

 
Supported in part by grants from Genentech Inc 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 Authors' Disclosures of... REFERENCES

 
1. McLaughlin P, Grillo-Lopez AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825–2833, 1998[Abstract]

2. 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[Abstract/Free Full Text]

3. Hainsworth JD, Litchy S, Burris HA, et al: Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin's lymphoma. J Clin Oncol 20:4261–4267, 2002[Abstract/Free Full Text]

4. 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)

5. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244–1255, 1999[Abstract/Free Full Text]

6. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef]

7. Mantel N, Haenszel W: Statistical aspects of the analysis of data from the retrospective study of disease. J Natl Cancer Inst 27:719–748, 1959

8. Maloney DG, Grillo-Lopez AJ, White CA, et al: IDEC-C2B8 (Rituximab) anti-CD20 antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90:2188–2195, 1997[Abstract/Free Full Text]

9. Foran JM, Rahatiner AZS, Cunningham D, et al: European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma and small B-cell lymphocytic lymphoma. J Clin Oncol 18:317–324, 2000[Abstract/Free Full Text]

10. Witzig TE, Gordon LI, Cabanillas F, et al: Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed at refractory low-grade follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 20:2453–2463, 2002[Abstract/Free Full Text]

11. Columbat 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[Abstract/Free Full Text]

12. Coates A, Gebski V, Bishop JF, et al: Improving the quality of life during chemotherapy for advanced breast cancer: A comparison of intermittent and continuous treatment strategies. N Engl J Med 317:1490–1495, 1987[Abstract]

13. Hainsworth JD, Litchy S, Barton JH, et al: Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 21:1746–1751, 2003[Abstract/Free Full Text]

Submitted December 30, 2003; accepted May 20, 2004.

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S. J. Horning Optimizing Rituximab in B-Cell Lymphoma</