Commentary on Abstracts #2482, #2477, #3148, and #4758

Other active unconjugated antibodies are in various stages of their clinical development. CAMPATH-1H has recently been approved for the treatment of refractory chronic lymphocytic leukemia (Keating et al: Blood 94:705a[abstract 3118], 1999). Another promising agent is the anti-CD22 epratuzumab (hLL2 [LymphoCide]) (Leonard et al: Blood 94:92a[abstract 404], 1999). Leonard et al (abstract #2482) presented an update of a phase I/II study including previously treated patients with indolent and aggressive NHL. Responses were observed in 5 of 17 (29%) patients with diffuse large B-cell non-Hodgkin’s lymphoma, including 2 (11%) CRs. Additional patients experienced significant shrinkage of tumor, but not sufficient to be categorized as a PR. Also in development are Hu1D10, directed at an epitope of HLA-DR (Link et al: Proc Am Soc Clin Oncol 19:24a[abstract #86], 2000), and bevacizumab, an anti-VEGF antibody. Extremely promising data were presented using a Pseudomonas exotoxin anti-CD25 immunotoxin in purine analog refractory hairy cell leukemia (abstract #2477).

Considerable interest has been expressed in the use of antibodies conjugated to radioisotopes such as iodine-131 or yttrium-90. The two most widely studied radioimmunoconjugates (RICs) are tositumomab/iodine-131 tositumomab (Bexxar) and yttrium-90 ibritumomab tiuxetan (Zevalin). Kaminski et al, from the University of Michigan, recently updated (Kaminski et al: Blood 96:1259-1266, 2000) their experience including 53 patients demonstrating a response rate of 71%, including 34% CRs. A higher response rate was noted in low-grade or transformed NHL (83%) compared with that for those with de novo large cell NHL (41%). The median progression-free survival for responders was 12 months, and that for complete responders was 20.3 months.

Sixteen patients were re-treated after relapse following tositumomab/iodine-131 tositumomab therapy; in this group there were nine responses, including five complete remissions with a median progression-free survival of 11.4 months. Only 17% of patients in the entire series developed human antimouse antibodies. Five patients developed myelodysplasia 1.2 to 7.5 years after tositumomab/iodine-131 tositumomab therapy, all of whom had received previous alkylating agents (median: four regimens). Cytogenetic abnormalities suggested that the myelodysplasia was secondary to prior treatment.

At the ASH 2000 meeting, Leonard et al (abstract #3148) described the multicenter experience with tositumomab/iodine-131 tositumomab in 269 patients with relapsed or refractory low-grade NHL, which included the University of Michigan patients noted above. Most patients had received a substantial amount of prior therapy, with 42% having one to three prior regimens and an additional 33% with four or more prior regimens; 25% were previously untreated prior to tositumomab/iodine-131 tositumomab therapy. Patient characteristics included 89% with stage III or IV disease, almost half with bone marrow involvement (but less than 25% infiltration), and almost a third with bulky disease.

The CR rate of 28% directly correlated with the extent of prior treatment and responsiveness to that therapy; there was a 58% CR (44% confirmed) as front-line therapy, and a comparable rate of 29% and 22% for one to three and four or more prior regimens, respectively. In addition, there was a longer duration of CR in the previously untreated group (median not reached at 1.5 years median follow-up). There was also a significant correlation between CR rate and duration and responsiveness to the last chemotherapy, and the presence of bulky disease. Tositumomab/iodine-131 tositumomab is a very active agent that provides meaningful clinical benefit, especially in patients who achieve a CR. This report emphasizes the need to ensure that patients are stratified by risk category, and that uniform response definitions are used when interpreting and comparing data among clinical trials since numerous variables can influence patient outcome (Cheson et al: J Clin Oncol 17:1244-1253, 1999).

An expanded access protocol was activated to make tositumomab/iodine-131 tositumomab available for patients who were either not eligible for, did not wish to participate in, or did not have ready access to a clinical trial. Gregory et al (abstract #4758) reported 74 patients who had relapsed after or were refractory to prior chemotherapy. Most of the patients had a follicular histology (79%), 4% were small lymphocytic lymphoma, and 18% had transformed from a low grade to an aggressive NHL. Most patients (94%) had advanced-stage disease. Other adverse features included bulky disease in 30% and an elevated LDH in 18%; 45% had evidence of bone marrow involvement, although less than 25% replacement. The results included a 76% response rate, including 32% CRs. The overall median duration of response was 19 months. Grade IV neutropenia or thrombocytopenia were noted in 8.5% and 3% of patients, respectively. Patients accrued to such protocols tend to be more representative of the patients seen in general oncology practice than those entered onto clinical trials.

Ibritumomab tiuxetan is a murine anti-CD20 monoclonal antibody co-valently bound to tiuxetan, which chelates the yttrium-90. The unconjugated antibody is the murine version of rituximab. In the initial phase I/II trial (Witzig et al: J Clin Oncol 17:3793-3803, 1999), the overall response rate in 32 patients with follicular/low-grade NHL was 82%, including 26% complete remissions. In the 14 patients with an intermediate-grade NHL, the response rate was 43%, with 29% complete remissions. There were no responses in three patients with mantle cell lymphoma. Response could be predicted by tumor grade, tumor bulk, and whether or not the bone marrow was involved by lymphoma. The median time to progression was 12.9+ months and the response duration was 11.7+ months. The major toxicity associated with administration of this agent was myelosuppression, with median granulocyte and platelet nadirs of 1,100/µL and 49,500/µL, respectively, occurring at 50 and 43 days and with an additional 10.5 and 14 days to recovery. Human antimouse antibodies developed in fewer than 2% of patients.