131 I-Tositumomab Therapy as Initial Treatment for Follicular Lymphoma

Authors: Mark S. Kaminski, M.D., Melissa Tuck, M.A., Judith Estes, M.S.N., N.P., Arne Kolstad, M.D., Ph.D., Charles W. Ross, M.D., Kenneth Zasadny, Ph.D., Denise Regan, B.S., Paul Kison, B.S., Susan Fisher, B.A., Stewart Kroll, M.A., and Richard L. Wahl, M.D.
Source: New England Journal of Medicine. Vol 352:441-449, 2005
Affiliation: University of Michigan Medical Center, Ann Arbor

Background

• Follicular lymphoma (FL) is an indolent disease
• However it is often incurable when disseminated, which it usually is at presentation
• External beam radiation can cure Stage I and II FL
• Previous studies have shown that Bexxar ( 131I labeled anti-CD20 antibody) can induce responses in patients with recurrence, even after they have been treated with "cold" anti-CD20 antibody (Rituxan)

Methods

• Design: Phase 2, single-group, open-label, single-center study conducted between June 1996 and April 1999

• Patients: 76 consecutive, previously untreated patients with stage III or IV follicular lymphoma
  • The patients are young, with median age of 49 years, and only 7 patients over 60
  • 43% had at least one mass >5 cm
  • o64% had BM involvement, but limited per eligibility
• Eligibility:
• • < 25% bone marrow involvement (for safety reasons to limit potential hematologic toxicity to an overly packed marrow)
  • absolute neutrophil count (ANC) > 1500
  • platelets (Plt) > 100,000
  • at least one lesion measuring minimum of 2 by 2 cm
• Treatment:
• • 1. Dosimetric dose of cold anti-CD20 followed by 131I-labeled anti-CD20 on Day 0.
  • 2. Therapeutic dose of cold anti-CD20 followed by 131I-labeled anti-CD20 to deliver 75 cGy total body irradiation on Day 7-14.
• Follow-up: Regular CT scans, PE, restaging bilateral bone marrow biopsies at 6 and 12 months after treatment, then yearly.
• • Median follow-up = 5.1 years
• Definitions of Endpoints:
• • Complete remission (CR) = disappearance of all disease for > 1 month or no change in minimal residual radiographic abnormalities for > 6 months.
  • Clinical CR = resolution of all disease-related symptoms for > 1 month
  • Partial remission (PR) = reduction by at least 50% in the sum of the products of the largest perpendicular diameters of all measurable lesions for at least 1 month.
  • Progression = increase of at least 25% in the sum of the products of the largest perpendicular diameters from nadir, or a new lesion larger than 2 cm by radiography or 1 cm by PE, positive BM
  • Molecular Response: PCR for t(14;18) translocation of BM biopsies at baseline and 3 following

Results

• Total Responses = 95%
• CR = 75%
• Median progression-free survival (PFS) = 6.1 years
• Bulky (>5 cm) disease and positive bone marrow decreased chance of CR, but did not affect PFS if CR was attained
• Positive bone marrow decreased PFS on multivariate analysis
• 80% molecular response (t(14;18) translocation of BCL2 gene) in CR patients
• Of patients with CR, PFS was better if they also had a molecular response at 6 mos
• Adverse Events:
• • hematologic toxicity was common, but none required transfusion or growth factors
  • hypothyroidism in 10%
  • lower B-cell counts, but no effect on Ig
  • flu-like illness after infusion
  • development of human anti-mouse antibodies (HAMA) that fight the therapeutic drug, observed in 63% of patients (higher than the normally observed ~10% seen in heavily pretreated patients)
  • no cases of MDS (yet)

Discussion

• Compared with historical controls, the complete response rate was excellent and durable.
• • R-CHOP, which is more toxic and takes longer to give (12 weeks vs. 2 weeks) has total response rate of 100%, CR rate of 58%, and median progression free survival of 6.9 years
• The increased rate of HAMA is possibly due to the fact that without heavy pretreatment, the hosts are more immune competent.
• • This may have impacted PFS, as 23 patients had >5 times detectable HAMA, and post-hoc analysis showed that the 5-year rate of PFS was 35%, as compared with 70% for the others (P=0.003).
  • The authors suggest that efficacy may be improved with a humanized antibody, but this may be more toxic.
• Timing of Bexxar with other regimens needs to be tested. The authors note that a randomized phase 3 study (SWOG and CALGB) is comparing concomitant R- CHOP vs. CHOP followed by Bexxar therapy. The authors suggest that future studies should evaluate whether chemotherapy has any additive benefit to Bexxar alone.

Comments

• The CR rate and durability of responses are significant compared with historical controls.
• The fact that FL is curable by external beam radiation when it is limited in volume and can be encompassed by treatment portals suggests that diffuse antibody-directed radiotherapy may result in some cures of advanced stage FL. This is supported by a hint of survival curve flattening, although long term data are needed in this indolent disease, and more mature data will hopefully be reported in the future.
• Bexxar treatment up front seems to promise a shorter, easier regimen for patients, resulting in possibly superior CR and PFS. However, this concept should be properly tested in a randomized trial, especially since these patients may represent a more favorable population.