Commentary on Abstracts #3504, #2526, #836, and #2533

Radioimmunotherapy is another promising area of lymphoma therapy. The two radioimmunoconjugates (RICs) that have been the most widely studied in patients with follicular, low-grade NHL are tositumomab/iodine-131 tositumomab (Bexxar) and yttrium-90 ibritumomab tiuxetan (Zevalin). Both have demonstrated a high level of activity in patients who have failed chemotherapy and rituximab (Witzig et al: J Clin Oncol 17:3793-3803, 1999; Kaminski et al: J Clin Oncol 19:3918-3928, 2001).

Ibritumomab tiuxetan has been compared with rituximab in a randomized, multicenter phase III trial including 143 patients with relapsed or refractory low-grade/follicular or transformed NHL (Witzig et al: Blood 96:831a[abstract 3591, 2000). Ibritumomab tiuxetan was more active, with an overall response rate of 80% compared with 56% for rituximab (P = .002); with 34% CR/CRu with the RIC and 20% with the unconjugated antibody. Surprisingly, there was no difference in the median response duration (10.9+ and 11.5+ months). The time to next therapy, which was not yet reached for ibritumomab tiuxetan, was 15.2 months for the control group.

Both ibritumomab tiuxetan and tositumomab/iodine-131 tositumomab appear to be highly effective in patients who have failed rituximab. Witzig et al (Blood 96:507a[abstract 2183], 2000) reported on ibritumomab tiuxetan therapy for 54 patients refractory to rituximab, defined as not responding to the drug or relapsing within 6 months of its administration, for relapsed or refractory follicular/low-grade NHL. The overall response rate was 54%, with 15% CRs. The median duration of response of 7.7+ months compared favorably with 6.5 months following the prior chemotherapy response. The median time to progression had not been reached. Toxicities included a median absolute neutrophil count nadir of 700/µL and platelets of 50,000/µL.

Horning et al (Blood 96:508a[abstract 2184, 2000) treated 21 patients with iodine-131 tositumomab, most with a follicular grade I or II NHL. The overall response rate was 57% with 14% complete remissions, lasting a median of 16 months. The median time to progression for all patients and for responding patients was 6 and 19 months, respectively. The median neutrophil nadir was 1,200/µL, and platelets were 90,000/µL. The high salvage rate of rituximab failures with RIC and their greater toxicity supports the use of rituximab prior to RIC therapy.

Nevertheless, where RICs best fit into the treatment paradigm for NHL is an active area of clinical investigation. Response rates with RICs inversely correlate with the extent of prior therapy, while the likelihood of toxicity increases (Leonard et al: Blood 96:728a[abstract 3148], 2000). One approach has been to sequence these agents with chemotherapy. Leonard et al (Blood 94:90a[abstract 393], 1999) treated patients with follicular/low-grade NHL received fludarabine followed by tositumomab/iodine-131 tositumomab as initial therapy, with high response rates.

At the ASH meeting, Press et al from SWOG (abstract #3504) reported their experience with six cycles of CHOP followed by tositumomab/iodine-131 tositumomab in responding patients. The response rate of 80% was impressive, but, as with the results of Leonard and coworkers (Blood 94:90a[abstract 393], 1999), consistent with what has been reported with the RIC alone in this setting (Kaminski et al: Proc Am Soc Clin Oncol 17:2a[abstract 6], 1998). Press et al were appropriately cautious in noting that the study demonstrated that this approach was feasible, but a demonstration of efficacy required a randomized trial. This regimen is one of the three arms of the previously described ongoing Intergroup (SWOG/CALGB) comparison, the other two being CHOP and R-CHOP.

However, whether patients respond to treatment following RIC therapy and how well they tolerate subsequent therapies is as yet unknown. Two abstracts presented at ASH attempted to address these issues. Kaminski et al (abstract #2526) described their experience with 76 patients who had received tositumomab/iodine-131 tositumomab as initial treatment for follicular NHL. Of the 28 who relapsed, 22 received subsequent therapy with at least one chemotherapy regimen, rituximab with or without chemotherapy, or stem cell transplantation. A single patient had therapy discontinued as a result of cytopenias. Although about 6% of patients treated with iodine-131 tositumomab for relapsed or refractory disease develop MDS/AML (Kaminski et al: J Clin Oncol 19:3918-3928, 2001; Kaminski et al: Blood 96:1259-1266, 2000), there were no such events in the present patient group.

Ratanatharathorn et al (abstract #836) described 12 patients who underwent an autologous or allogeneic stem cell transplant after therapy with tositumomab/iodine-131 tositumomab. All five patients who underwent an autologous transplant relapsed and died, as did one of the allografted patients. Another patient died from a treatment-related cause. Thus, only five patients are alive, four without evidence of disease, and with short follow-up. This study demonstrates that whereas transplantation is feasible, it is often complicated in heavily pretreated patients with indolent NHL.

Ansell et al (abstract #2533) conducted a retrospective analysis of 53 patients treated with yttruim-90 ibritumomab tiuxetan after a median of two prior chemotherapy regimens, 34 of whom went on to subsequent chemotherapy or stem cell transplant. Although a single patient required a dose reduction because of persistently low blood counts after RIC therapy, 13 needed growth factor support and 10 required hospitalization for neutropenic fever and/or thrombocytopenia. Clearly, problems may be encountered in patients treated following RIC therapy. However, whether these are more severe than if the patients were treated with additional chemotherapy instead is not known.