⁹⁰Yttrium-Ibritumomab Tiuxetan as First Line Treatment for Follicular Non-Hodgkin Lymphoma. 5 Year Results from an International Multicenter Phase II Clinical Trial

Purpose

Updated 5 year results are presented from the multicenter phase II trial of ⁹⁰Yttrium-Ibritumomab-Tiuxetan (⁹⁰YIT) as first line stand-alone therapy for patients with follicular lymphoma (FL).

Patients and Methods

59 patients with CD20-positive FL grade 1 to 3a in stages II with bulky disease (n=12), III (n= 26), or IV (n=21), and in need for therapy, were enrolled between 05/2007 and 06/2010. They received ⁹⁰YIT according to standard procedure (rituximab 250 mg/m² days -7 and 0, then ⁹⁰YIT 15 MBq/kg (0.4mCi/kg) day 0; patients with platelet counts below 150.000/ul but above 100.000/ul received only 11 MBq/kg). Primary end point was the clinical and molecular remission rate. Secondary end points were time to progression, safety, and tolerability. Results at 5 years after therapy with ⁹⁰YIT are presented.

Results

Clinical remission rate (CR, Cru) 6 months after treatment with ⁹⁰YIT was 56% (33 patients), while 31% had achieved a PR (18 patients). Median follow-up was 5 years with 8 patients lost to follow-up. Progression free survival was 2.6 years. Of the 26 patients who were in CR 12 months after ⁹⁰YIT 57% were still without progress after 5 years, PFS after ⁹⁰YIT was not reached versus 1.13 years for patients without CR 12 months after treatment (P =0.025, HR 2.474). Elevated LDH predicted a shorter PFS (4.0 years vs. 1.3 years, P=0.056). Some of the patients had extensive disease at time of treatment. Ann Arbor stadium did not differ significantly in response rate and 5 year PFS (II with bulky disease 50%, III 42.3%, IV 33.3%, P=0.12). Median time to next treatment (TTNT) for the whole population was 3.95 years (5-year TTNT-free, 50%). 5 year overall survival since treatment with ⁹⁰YIT was 80%. Cause of Death was progressive disease (1 patient), secondary malignancy (3 patients) and others (6 patients).

As previously reported, most common toxicities were transient thrombo- and leukocytopenia. Non-hematologic toxicities never exceeded grade II (CTCAEv2.0). No unexpected toxicities emerged during 5 year follow-up. Secondary malignancies occurred in 5 patients within 5 years after treatment with ⁹⁰YIT (8%, oropharyngeal cancer, pancreatic cancer, lung carcinoma, cerebellar tumor, adenocarcinoma of the colon). All these cases had occurred shortly after therapy, suggesting pre-existing morbidity (retrospectively confirmed in 2 cases) or chance association (3 cases). Cases of acute myeloid leukemia were not reported. Transformation occurred in 8 patients (14%) with an annual transformation rate of 2.7%.

Conclusion

⁹⁰YIT is well tolerated and achieves a 5 year PFS of 40%. Considering that this treatment is a very short procedure (two outpatient drug applications one week apart) this appears remarkable. While patients with elevated LDH tend to relapse early, individuals who continue to be in CR 1 year after ⁹⁰YIT achieve significantly long responses with a 5 year PFS of 59%. Secondary malignancies and transformation rate were not elevated after 5 years of follow up. ⁹⁰YIT can be considered for the initial treatment of FL in patients who are unable or unwilling to tolerate standard therapy.