90Yttrium Ibritumomab Tiuxetan as First Line Treatment for Follicular Lymphoma. First Results from an International Phase II Clinical Trial

The international FIT Trial (ASH 2007) had shown that Radioimmunotherapy (RIT) with 90Yttrium Ibritumomab Tiuxetan (Zevalin®) significantly improves the remission rate in follicular lymphoma (FL) if given as consolidation after chemotherapy. Since high remission rates are achieved in combination with both mild and aggressive chemotherapy regimens we asked whether chemotherapy is needed at all before applying RIT.

Previously untreated patients with follicular lymphoma Grade I-IIIA from 7 centers in Austria, Germany, Italy, and Sweden have entered a prospective phase II clinical trial. Patients received 90Yttrium Ibritumomab Tiuxetan at the standard single dose of 15 MBq/kg (0.4 mCi/kg). Only stage III and IV FL patients older than 50 y (as required by radiation safety agency) and with clinical need for treatment (tumor lesions increasing at least 50% in the last 6 months, B-Symptoms, bulky disease up to 10cm) were allowed to enter the protocol. The primary end point was the clinical and molecular remission rate six months after primary treatment with 90Yttrium Ibritumomab Tiuxetan. Secondary end points were time to progression as well as safety and tolerability of 90Yttrium Ibritumomab Tiuxetan.

59 of 60 planned patients have been recruited between July 2007 and June 2010. Treatment was well tolerated without severe acute toxicity and with only grade I-II adverse events. Hematological toxicity was modest: 24 patients exhibit Thrombocytopenia (in one case Grade 4, in 13 cases Grade 3) and Neutropenia, (Grade 3 in 13 cases, no grade 4), Anemia (only grade 1–2) was noticed in 5 patients, other side effects were grade 1 or 2. Febrile episodes were not observed after RIT.

At the first follow-up 6 months after RIT 25 patients were in complete remission (45%) and 22 patients were in partial remission (40%) adding up to an ORR of 85%. One year after therapy, the response rate is 72% with 52% CR and 20% PR. Among the 33 patients who have reached a follow up of more than 18 months, 52% continue to stay in complete remission, 9% are still in partial remission while 36% of the patients progressed and are off study, either in observation or with a new treatment. At a median follow-up of 23 months the PFS is 17.9 months.

2 Deaths occurred during observation time, both patients had been off study because of progressive disease: one patient died of progressive lymphoma after several lines of salvage chemotherapy, pancreas carcinoma was the cause of death in a further patient about 10 months after lymphoma progression. While 3 more cases of non-hematological cancers (colon adenocarcinoma, oral cavity squamous carcinoma, renal cancer) were recorded during the study, reevaluation of the CT scans done before RIT revealed in 2 of these patients lesions that were preexisting but missed or misinterpreted as lymphoma. In addition, the short latency between RIT and cancer diagnosis makes a causal relationship unlikely in the remaining two cases. Progression to high-grade lymphoma occurred in 3 patients so far.

49% of the patients (n = 28/57) had evidence of BCL2-IgH translocation in peripheral blood and/or bone marrow by PCR analysis. Of 26 patients evaluated 6 months after treatment 19 have turned negative (molecular remission rate MR = 73%). 9 of these MR patients had only achieved partial remission at clinical evaluation, 3 of them achieved a complete remission later during observation while 3 progressed. Ancillary PET studies were performed in 2 centers including sequential evaluation after therapy. Preliminary evaluation suggests that positivity of PET predicts relapse before this becomes clinically evident.

Radioimmunotherapy with 90Yttrium Ibritumomab Tiuxetan was very safe and well accepted by patients, it induces high percentages of both clinical and molecular responses when given as first line treatment to patients with advanced stage follicular lymphoma. Remission rates are similar to those achieved by standard chemoimmunotherapy protocols, but absence of infectious episodes and the limited severity of side effects compares extremely well with the toxicity of chemotherapy regimens. Duration of remission will be a crucial issue for final comparison. Our study suggests first line RIT as a valuable option, particularly for older and/or frail patients with FL in need of therapy.

No relevant conflicts of interest to declare.