Commentary on Abstracts #387, #2806, #386, and #393

At the 1999 ASH meeting, Vose et al (abstract #387) analyzed the overall multicenter experience with iodine-131 tositumomab in 179 patients as a function of histologic subtype. The overall response rate was 81%, with 39% CRs. The median time to progression for responders was 13 months, with a median duration of response of 11 months, although the median duration of CRs was 57 months. The response rates for the follicular small cleaved cell NHL and follicular mixed (follicular grades I and II) were similar (83% and 78%, respectively), as were the CR rates (38% and 39%, respectively). These histologies have shown similar responses to various chemotherapy regimens in most studies.

Zelenetz et al (abstract #2806) presented the composite experience with iodine-131 tositumomab in the subset of 49 patients with transformed low-grade NHL who had been entered into one of four clinical trials. These patients had been heavily pretreated with a median of four prior regimens; although it is unclear how many of those regimens were administered before or after transformation; however, almost half of patients had not responded to prior therapy. Responses to iodine-131 tositumomab, as evaluated by the investigator, included a CR rate of 33% and an overall response rate of 53%. The median duration of response was 12.7 months, with a median duration of CR of 36.5 months. Human antimouse antibody (HAMA) reactions developed in five patients.

Not all transformed low-grade NHLs are the same, however. Outcome is significantly better in patients whose histologic progression is identified early, often as part of surveillance, than in those who present with rapidly enlarging nodes, an elevated lactic dehydrogenase (LDH) level, and disease-related symptoms (Yuen et al: J Clin Oncol 13:1726-1733, 1995). The relative proportions of these populations greatly influence the response rate and duration of response in various series.

As discussed earlier in this supplement , patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who are treated with the recommended dose and schedule of rituximab respond less frequently than do patients with follicular NHL. Phase I studies with iodine-131 tositumomab conducted by Kaminski et al (abstract #386) included 14 patients with SLL who had received a median of four prior chemotherapy regimens. Nine of these patients (64%) responded to the antibody, including three who had a CR. The median duration of response had not been reached after 25.7 months. No patient developed a HAMA reaction.

This agent needs to be studied in additional SLL patients to confirm these promising findings. A phase I trial is being planned to evaluate the safety and efficacy of iodine-131 tositumomab in CLL patients with extensive bone marrow involvement.

Radioimmunoconjugates often incorporate murine antibodies to facilitate clearance of the isotope from the blood. A potential complication is the development of HAMA. This immune response occurs with greater frequency in previously untreated patients than in those who have already received cytotoxic, immunosuppressive agents.

Based on in vitro synergy data, Leonard and coworkers studied the combination of the purine analog fludarabine followed by iodine-131 tositumomab (abstract #393). Since fludarabine is immunosuppressive, a second goal was to determine whether they could reduce the frequency of HAMA development in response to iodine-131 tositumomab. Patients received three courses of fludarabine every 5 weeks, with an infusion of iodine-131 tositumomab 6 to 8 weeks later.

Only 1 of the 14 patients evaluable for response developed a HAMA reaction, in contrast to the expected rate of about 40%. In addition, a very high response rate was reported (100%) with 71% CRs. Following fludarabine, there were 2 CRs and 11 PRs. After iodine-131 tositumomab, 4 of the PRs became CRs, and a patient with stable disease was converted to a partial responder. Nevertheless, this response rate is comparable to rates previously reported with iodine-131 tositumomab alone, although the durability of these responses has yet to be determined (Kaminski et al: Proc Am Soc Clin Oncol 17:2a [abstract 6]. 1998).