Phase I Trial of Combination Therapy with ⁹⁰Y Ibritumomab Tiuxetan (Zevalin) and Gemicitabine in Patients with Non-Hodgkin’s Lymphoma.

Y90-ibritumomab tiuxetan radioimmunotherapy, or Zevalin (Y90-RIT), is an effective therapy against CD20+ lymphoma. While it is approved for use in patients with relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma (NHL), it is not curative and ways to enhance its efficacy would be useful. Gemcitabine (G) is a potent radiation sensitizer that also is active against NHL. Its radiation sensitizing ability and activity against NHL provide the rationale for our ongoing phase I trial to assess the safety of concomitant administration of Y90-RIT and gemcitabine in patients with NHL. Nine patients in three cohorts have been treated with 250 mg/m² of gemcitabine IV on days 1 and 8 of the Y90-RIT treatment program of rituximab + In 111-ibritumomab on day 1 and rituximab + Y90 ibritumomab on day 8, with Y90 at 0.2, 0.3 or 0.4 mCi/kg respectively. Subsequent cohorts only accrued after all patients in the prior cohort had resolution of hematologic toxicities to grade 0–2 or after 60 days from the date of the last treated patient in the previous cohort. One patient has been treated with 300mg/m² of G and 0.4 mCi/kg of Y90-RIT. No DLTs have been observed so far. The dose of G is continuing to be escalated according to a Bayesian based system. Response evaluation is by standard criteria. Eligibility criteria include: any histology of recurrent B cell NHL (not candidates for high dose therapy), platelets ≥ 150,000/ul; < 25% bone marrow involvement by lymphoma; prior radiation to <25% of bone marrow and no prior bone marrow or stem cell transplant. Ten patients have been treated thus far, five with follicular (FL), four with diffuse large B cell (DLBCL) and one with marginal zone NHL. Median age is 70 (range 55–82). The median number of prior treatments is 2 (range 1–6). Patients 1–3 received Y90 at 0.2 mCi/kg, patients 4–6 at 0.3 mCi/kg and patients 7–9 received standard 0.4 mCi/kg of Y90, all with 250 mg/m² of gemcitabine on days 1 and 8. Patient number 10 has received full dose of Y90 and G at 300 mg/m². Grade 3 or 4 toxicities have consisted only of: one grade 3 neutropenia, three grade 3 leukopenia and six grade 3 and three grade 4 lymphopenia. One grade 3 infection occurred, unrelated to the protocol or the study drugs. Grade 3 or 4 non-hematologic toxicities have included one case each of increased bilirubin, increased GGT and increased calcium. In follow up, responses have included: 2 stable disease (one patient each with FL and marginal zone NHL, mean duration of response: 7.2 months), 2 CRu and one CR all in patients with FL (mean duration of response: 17.5 months), one PR and 4 progression of disease (DLBCL). One patient with CRu, and one with SD have ongoing responses. Three additional patients have met the protocol defined criteria for progression but have not had a need for initiation of any other treatments. One patient was diagnosed with a new lung cancer after achieving a PR.

Conclusion: Our findings demonstrate that Y90-RIT (Zevalin) at the standard dose of 0.4 mCi/kg can be safely combined with gemcitabine at 250 and 300 mg/m² days 1 and 8 in the treatment of patients with NHL. Accrual to cohorts with 0.4 mCi/kg of Y90-RIT and escalating doses of gemcitabine is continuing.