Rituximab Retreatment Research Articles

Optimizing Rituximab in B-Cell Lymphoma

In this issue of the Journal of Clinical Oncology, three groups report their results with rituximab monotherapy in B-cell lymphoma. Following the approximately 50% response rate in recurrent or refractory indolent lymphoma reported in the pivotal trial, investigators have studied alternate dosing schedules in untreated and previously treated patients and have proposed both host and tumor characteristics that may predict the quality of response. How are the reports in the current issue of the Journal informative for current practice and clinical investigations? Witzig et al administered four weekly rituximab infusions to 36 previously untreated, follicular grade 1 lymphoma patients who, in their judgment, required no immediate therapy. Although the primary objective was to estimate the response rate, an important secondary end point was the time to initiating chemotherapy after rituximab treatment. The alternative of rituximab to the conservative approach of observation alone as initial management for selected patients may be considered advantageous if quality of life is improved or if the time to requiring chemotherapy is prolonged. The overall response rate in the North Central Cancer Treatment Group study was 72%, with a median time to progression of 2.2 years from registration—longer than previously reported in treatment-naive patients. The time to subsequent chemotherapy was, however, unexpectedly brief, at just 2.3 years after rituximab or approximately 2.4 years after registration. In two prior randomized phase III studies comparing observation to immediate therapy, time to initiating treatment was 2 and 2.4 years, respectively, after initial observation. In the study by Brice et al, the time to treatment failure was 3.6 years following 3 months of initial interferon alfa. Clearly, it can be hazardous to draw conclusions from a small patient sample, as reported by Witzig et al, in a disease as heterogeneous as follicular lymphoma. Perhaps these patients had more biologically aggressive disease than predicted at diagnosis, or perhaps the treating physicians had a lower threshold for administering chemotherapy, as the North Central Cancer Treatment Group did not establish standard criteria for initiating chemotherapy. It is also important to recall that the time to progression or time to initiating chemotherapy may be as much a function of the underlying biology of indolent lymphoma as the effect of prior treatment. Finally, the potential therapeutic benefit of rituximab was not maximized by the study design used by Witzig et al, which did not include re-treatment of responding patients. Previously, a 40% response rate was reported in follicular lymphoma patients with disease progression after initial response to rituximab and were subsequently re-treated weekly for 4 weeks. The goal, therefore, of rituximab monotherapy might then be best expressed as prolonging the time to requiring alternate therapy, allowing for rituximab re-treatment. Hainsworth et al studied this end point in a prospective trial in previously treated, but rituximab-naive, indolent B-cell lymphoma patients. The trial was a randomized phase II study, in which patients received four weekly rituximab infusions, with assessment of response at 6 weeks and random assignment of stable or responsive patients to maintenance rituximab delivered as four weekly treatments every 6 months, for a maximum of four courses or re-treatment (standard 4-week course) on disease progression. The purpose of this type of study is to evaluate various approaches so that the most promising can be selected for further study. Randomized phase II studies do not have adequate statistical power for definitive treatment comparisons, but seek to estimate treatment effect and toxicity in each arm, without patient selection bias. The primary study end point, duration of rituximab benefit as defined by the administration of alternative treatment, was not different between the two approaches in this trial. However, these results are only estimates, and imbalances in histology and the number of patients progressing before either maintenance or re-treatment may have influenced the results. In addition, rituximab benefit was based on a subjective end point—the requirement for alternate therapy—rather than an objective definition of response or duration of response. As in the Witzig et al JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 6 FEBRUARY 2

Radioimmunotherapy with I131 Tositumomab in Relapsed and Transformed Low-Grade (LG) Non-Hodgkin's Lymphoma (NHL): Long-Term Follow-Up of a Single Institution Experience.

Background: Tositumomab and Iodine I 131 Tositumomab (BEXXAR®) is approved for the treatment of recurrent LG or transformed CD20+ NHL refractory to Rituximab or relapsed after chemotherapy. In 5 trials and an expanded access program (>995 pts), response rates were 47%–68% (durable CRs in up to 30%) with median response durations of 12–18 months. Most pts who relapsed post-BEXXAR tolerated subsequent cytotoxic regimens, stem cell transplant, localized radiation, Rituximab, and Bexxar re-treatment.Methods: A retrospective analysis of 49 pts with relapsed/refractory LG NHL and transformed NHL treated at Rush U. Medical Center (1998–2001) evaluated treatments pre-Bexxar, responses to BEXXAR, and treatments post-BEXXAR. All pts received BEXXAR as previously described (JCO. 19:3918). Median age was 57 yrs (range, 28–88 yrs); 88% had stage III/IV disease, and 49% had bone marrow involvement. Median time from diagnosis to Bexxar treatment was 31 mo (range, 8–204 mo); median prior treatments was 3 (range, 1–7). Prior therapies included anthracycline/ anthracenedione-based therapy in 36 (73%) pts, fludarabine in 22 (45%) pts, both in 16 (33%) pts, and Rituximab in 22 (45%) pts. Median time from last treatment failure or relapse was 3 mo (range, 1–15 mo).Results: Overall response rate to BEXXAR was 63%, with CR in 16 (33%) pts, and PR in 15 (30%) pts. Four (8%) pts had SD. Median duration of response was 11 mo (range, 3–41 mo). Of 16 CRs, 12 (75%) were durable (TTF >12 mo). After a median follow-up of 5.3 yrs (range, 2.7–6.1 yrs), 24 (77%) of 31 responders were alive. Of the 18 nonresponders, 14 died within 1 year, and 4 pts were alive after subsequent therapy. Overall, 19 pts died from progressive disease and 2 from other causes (lung cancer and MDS/AML). Relapse After BEXXAR. 17 pts relapsed after BEXXAR and received other therapies: 11 of 12 patients who received monoclonal antibodies (Rituximab or BEXXAR) have responded and were alive at last follow up (Table 1).Retreatment With BEXXAR. After a median follow-up of 3.4 yr since BEXXAR re-treatment, 3 pts remained in CR (2 with no further therapy); 2 were alive with disease. Interestingly, CR duration after Bexxar re-treatment compared favorably with the first Bexxar treatment in 3 pts (Table 2).Conclusion: Radioimmunotherapy (RIT) is one of the most efficacious treatments for relapsed LG NHL and is delivered over a single week with tolerable toxicity, most of which is hematologic and reversible. Our results suggest that pts who relapse after RIT can be safely and effectively treated with various therapies and responses comparable to pts without prior RIT. We have shown that BEXXAR re-treatment may lead to significantly longer duration of remission compared to initial BEXXAR therapy.Table 1. Relapsed Patients:Treatment After BEXXARTreatmentAliveDeadNo Further Treatment20Rituxan alone30BEXXAR50RT only10Rituximab/Chemo/RT21Rituximab/Chemo/BMT10Chemo01Chemo for Lung Ca01Table 2. Response to Retreatment With BEXXAR (All Received Fludarabine Prior to Bexxar)PatientResponse, Bexxar #1# TreatmentsResponse, Bexxar #21CR 7 mo0CR 3.5 years to date2CR 13 mo0CR 3 years to date3CR 6 mo1CR 3 years, alive with disease4CR 12 mo2CR 9 mo, alive with disease5CR 10 mo2PR 3 mo, alive with disease

Monoclonal antibodies for the treatment of hematologic malignancies: clinical trials in Japan.

Of 12 patients with relapsed CD20(+) B-cell non-Hodgkin's lymphoma (B-NHL) enrolled in a phase I study of rituximab, 11 were eligible, and of these 2 achieved a complete response and 5 a partial response. The elimination half-life of rituximab was 445+/-361 h, and serum rituximab levels were detectable at 3 months. In a phase II study, 90 patients with relapsed indolent B-NHL or mantle cell lymphoma (MCL) were treated with infusions of rituximab 375 mg/m(2) once weekly for four doses. The overall response rate in indolent B-NHL and MCL was 61% (37/61, 95% CI 47-73%) and 46% (6/13, 95% CI 19-75%), respectively. The median progression-free survival (PFS) was shorter in MCL patients, in those with extranodal disease, and in those who had received two or more prior chemotherapy regimens ( P<0.01). Rituximab retreatment was well tolerated in 13 patients with relapsed indolent B-NHL and there were no grade 3/4 nonhematologic toxicities. Partial response was observed in five (38%, 95% CI 14-68%) patients, and the median PFS after retreatment was 5.1 months. In a single-agent phase II study of infusions of rituximab 375 mg/m(2) once weekly for eight doses against relapsed aggressive B-NHL showed, 21 (37%, 95% CI 24-51%) of the 57 eligible patients responded. In conclusion, rituximab is a highly effective agent in relapsed indolent and aggressive B-NHL and MCL with acceptable toxicities. Yttrium-90 provides advantages over iodine-131 because it delivers higher beta energy. In 2002, we initiated a feasibility study of yttrium-90-labeled ibritumomab tiuxetan for relapsed indolent B-NHL in Japan. Gemtuzumab ozogamicin (CMA-676) is a calicheamicin-conjugated humanized anti-CD33 monoclonal antibody. Of 20 patients with relapsed or refractory acute myeloid leukemia enrolled in a "bridging" phase I/II study, 7 showed an objective response. It is concluded that monoclonal antibodies will have play a significant role in the treatment of hematologic malignancies in the future.

Monoclonal antibody therapy for B-cell lymphoma: clinical trials of an anti-CD20 monoclonal antibody for B-cell lymphoma in Japan.

Twelve patients with relapsed CD20+ B-cell non-Hodgkin's lymphoma (B-NHL) were enrolled in a phase I study of rituximab; 4 received rituximab 250 mg/m2 and 8 received rituximab 375 mg/m2 once weekly for 4 weeks. Grade 1 or 2 infusion-related toxicity was observed. Of the 11 eligible patients, 2 achieved complete responses and 5 achieved partial responses. The elimination half-life (T1/2) of rituximab was 445 +/- 361 hours, and serum rituximab levels were detectable at 3 months. Thereafter, 90 relapse patients with indolent B-NHL or mantle cell lymphoma (MCL) were enrolled in a phase II study and treated with rituximab at 375 mg/m2 per infusion in 4 weekly infusions. Sixteen patients were ineligible in protocol compatible analyses. The overall response rates (ORR) in indolent B-NHL and MCL were 61% (37 of 61 patients) and 46% (6 of 13 patients), respectively. Factors affecting response and progression-free survival (PFS) were analyzed for 77 patients whose histopathology was centrally confirmed as indolent B-NHL or MCL. The ORR in patients receiving 1 prior chemotherapy regimen was higher than the ORR in those receiving > or = 2 regimens (P < .05). The median PFS was shorter in MCL patients, in those with extranodal disease, and in those receiving > or = 2 prior chemotherapy regimens (P < .01). The PFS of patients with higher serum rituximab levels (> or = 70 microg/mL) immediately before the third infusion was longer than that of other patients (P < .01). Several pretreatment factors and serum rituximab levels are useful for predicting the efficacy of rituximab monotherapy. Rituximab re-treatment was well tolerated in 13 patients with no grade 3 or 4 nonhematological toxicities. A partial response was observed in 5 patients (38%), and the median PFS after re-treatment was 5.1 months. In conclusion, rituximab is a highly effective agent in relapsed indolent and aggressive B-NHL and MCL and has acceptable toxicities.