Single-Agent Rituximab in Patients with Follicular or Mantle Cell Lymphoma
Abstract & Commentary
By Stuart M. Lichtman, MD, FACP, Associate Attending, Memorial Sloan-Kettering Cancer Center, Commack, NY. Dr. Lichtman reports no financial relationship to this field of study.
Synopsis: This study defined the characteristics predicting response and EFS to rituximab. Prolonged treatment results in longer EFS at the cost of a longer reduction in B cell and IgM levels, but without additional clinical toxicity.
Source: Ghielmini M, et al. Single agent rituximab in patients with follicular or mantle cell lymphoma: clinical and biological factors that are predictive of response and event-free survival as well as the effect of rituximab on the immune system: a study of the Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol. 2005;16:1675-1682.
Follicular (FL) and mantle cell lymphomas (MCL) are usually considered incurable diseases. Even though aggressive interventions such as autologous or allogeneic transplantation may prolong survival or eventually cure some patients, in the majority of cases treatment is aimed at relieving or preventing symptoms. Many treatment options are now available, ranging from relatively simple and well tolerated single-agent regimens to complex and possibly toxic combination chemotherapies. In this mainly palliative setting, many physicians believe that the optimal treatment is one producing the least side-effects while obtaining a long time without symptoms of disease.
Single-agent rituximab is one of these options, having been shown to cause little toxicity and to obtain, given at a prolonged schedule and, in some patient subsets, remissions that are comparable to what is obtained with multi-agent regimens. The efficacy of antibody treatment was shown to differ among lymphoma subtypes, but the reason why some histologies respond better than others has not been clarified. Due to the different mechanisms of action of monoclonal antibodies, it is possible that some mechanisms are more effective against some tumor types than against others, but it could as well be that certain histologies are more associated with biological or clinical characteristics of the patient that influence treatment response.
This trial analyzed an important number of characteristics of 306 patients with FL or MCL and of their disease that could predict benefit from treatment with single-agent rituximab. The short and long-term major side effects are discussed. This exploratory analysis intended to identify potential factors that are associated with response, event-free survival (EFS) and toxicity.
Commentary
This trial consisted of 2 subtrials: one for FL and one for MCL patients. Patients were initially treated with rituximab 375 mg/m2 per week for 4 weeks (‘induction’ phase). Patients with stable disease or in partial or complete response at week 12 (from treatment start) were randomized in a 1:1 ratio into 2 groups: no further treatment (arm A, standard treatment) or treatment with a single infusion of rituximab 375 mg/m2 at week 12, and again at months 5, 7, and 9 (arm B, prolonged treatment). The randomization was stratified according to status of disease at trial entry (first presentation vs refractory or relapsed), response to induction treatment (stable disease vs response), and center.
The main characteristics of the 306 patients were balanced. Thirty-two patients were retrospectively judged ineligible: 27 because the pathology review could not confirm the follicular or the mantle cell histology and 5 because the disease was not measurable according to protocol criteria. One patient was not evaluable because he died before the trial treatment could be initiated.
Of the 273 eligible and evaluable patients, 61 were not randomized to the second phase of the study because of disease progression or major toxicity during the induction phase.
The response rate to rituximab induction in the 273 eligible and evaluable cases was 44% (38% partial response and 6% complete response). Among 33 factors assessed, 15 were found potentially predictive for response. The favorable factors finally selected by the stepwise procedure were disease bulk < 5 cm, follicular histology, normal hemoglobin, and low blood lymphocyte count (CTC toxicity grade > 1), all determined at treatment start.
At a median follow-up of 4.5 years, the EFS for the 212 randomized patients was 11.2 months in arm A and 17.9 months in arm B (P = 0.005). The preliminary univariate analyses showed that 14 baseline characteristics and 5 characteristics at randomization have a potentially significant impact on EFS. Favorable factors finally selected by the stepwise procedure, after taking the treatment arm into account, were: having responded to rituximab induction, Ann Arbor stage I-III, having received not more than one previous line of therapy, disease bulk < 5 cm and high blood lymphocyte count (CTC toxicity grade #1) at randomization.
The unfavorable baseline clinical characteristics selected by a stepwise procedure in the training set of 206 patients were: MCL histology, stage IV, bulky disease, previous chemotherapy, and low hemoglobin (CTC toxicity grade > 0). As suggested by the EFS data, patients could be classified into 3 groups: high-benefit group with score 0-1, intermediate-benefit group with score 2-3 and low-benefit group with score 4-5. By applying such grouping to the whole population of 212 randomized patients, the median EFS in arm A was 19.8 months in the high-benefit group, 11.0 months in the intermediate-benefit group and 5.1 months in the low-benefit groups. For arm B the corresponding median values were 42.3, 17.2, and 7.3 months. The benefit of prolonged rituximab treatment seems to be noticeable only in patients with fewer unfavorable characteristics. Data on lymphocyte subsets at baseline are available on 129 of 212 randomized patients, and on fewer cases at later time points during the study. The baseline levels of T-helper, T-suppressor, NK, and B lymphocytes were lower than the normal ranges in almost half of the patients. T-helper, T-suppressor and NK cells remained stable all along the study in both arms, while circulating B cells showed a reduction to median level 20% of baseline after 8-12 weeks from treatment start (P < 0.0001). After 1 year, the tendency of B-cell recovery was seen in arm A (median level, 81% of baseline; n = 22) but not in arm B (median level, 50% of baseline; n = 35); this latter group took 6 months longer to recover to baseline values.
This is the largest study on clinical and biological predictive factors for activity of single-agent rituximab. Some of our predictive factors are common predictive factors in all cancer patients undergoing chemotherapy: parameters associated with the amount of disease (stage and disease bulk), with the impact of the disease on patient homeostasis (hemoglobin level) or with the extent of previous treatment (number of previous therapy regimens). The lower chance of response in MCL patients compared with FL patients also reflects what is known for chemotherapy in general, and the observation that responders do better than non-responders is common as well. Compared with other studies of single-agent rituximab, they confirmed the favorable role of FL histology for response. The data also showed a relatively long immunosuppression caused by the prolonged schedule of rituximab, but not associated with an increase of clinically relevant immunosuppression-associated pathologies as infections or second tumors.
In conclusion, for patients with FL and not suitable for an aggressive treatment, single-agent rituximab is confirmed to be a valid option, particularly if patients present with a low tumor load and normal blood counts. In these cases prolonged treatment results in significantly longer EFS. Some of these patients may be managed by a watch and wait policy, and studies are ongoing comparing these 2 strategies in this favorable population. Even though the extended schedule causes a more prolonged reduction of B cell and IgM levels, no additional toxicity is seen.
This study defined the characteristics predicting response and EFS to rituximab. Prolonged treatment results in longer EFS at the cost of a longer reduction in B cell and IgM levels, but without additional clinical toxicity.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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