A Phase I Study of ⁹⁰Y-Ibritumomab-Tiuxetan (⁹⁰Y-It) in Children with Recurrent/Refractory CD20 Positive Lymphoma: A Cog Phase I Consortium Study.

More than 98% of newly diagnosed childhood B-NHL expresses CD20 (Perkins/Cairo, Clin Adv Hem/Onc 2003). The prognosis for children and adolescents with recurrent CD20 positive NHL, particularly DLBCL and BL, is dismal (Cairo et al, Am J Hem, 2003, Cairo et al, Br J Hem, 2003). A radiolabeled anti-CD20 antibody, ⁹⁰Y-IT, has recently received FDA approval for adults with recurrent indolent CD20+ B-NHL. The dose limiting toxicity in adults has been myelosuppression (Witzig et al, JCO, 2003). Through the COG Phase I Consortium, we evaluated the safety of ⁹⁰Y-IT in Pts with refractory childhood and adolescent CD20+ lymphoma: DLBCL (n=3) 1^st relapse (n=1), 2^nd relapse (n=2); refractory BL (n=1); refractory PTLD (DLBCL) (n=1); M:F ratio 4:1, median age 12 yrs (5–18). Pts (n=5) had a minimum of 2 x 10⁶ CD34/kg cryopreserved PBSC. Pts (n=5) received Rituximab 250 mg/m² IV on Days 0 and 7 and Indium 5 mCi IV on Day 0. Gamma imaging scans and peripheral blood dosimetry studies were performed on Days 0, 1, 3, and 6. Immediately following Rituximab on Day 7 (n=4) or approximately 24 hrs post Rituximab on Day 8 (n=1), Pts received ⁹⁰Y-IT if dosimetry studies demonstrated ≤2000 cGy exposure to all solid organs and ≤300 cGy to red marrow based on a dose escalation schema stratified by marrow reserve and Plt; 0.4 mCi/kg (dose level 1) (n=3), 0.1 mCi/kg (dose level 1) (post BMT) (n=2). One Pt progressed prior to DLT evaluation. No evaluable pts (n=4) experienced non-hematologic DLT defined as any Grade III or IV non-hematologic toxicity attributable to the investigational agent or hematologic DLT defined as Grade IV ANC or Grade IV thrombocytopenia of > 7 days duration, and an ANC that did not reach ≥500 mm³ and/or platelet count that did not recover to ≥20,000/mm³ by Day 35. The incidence of HAMA/HACA was 0% (n=0). Toxicities related to the ⁹⁰Y-IT included Grade I muscle pain/abdominal cramping (n=2), Grade III Plts (n=1), Hgb (n=1), infection (n=1), and Grade IV ANC (n=2), Plts (n=1). One Pt experienced Grade II infusion related chills associated with Rituximab. Mean organ radiation exposure (cGy) was as follows: kidneys 341 (112–515), liver 345 (83–714), lungs 309 (155–519), red marrow 46 (20–78), spleen 565 (161–816), and total body 3.7 (2.1 – 4.8). Mean serum quantitative immunoglobulins (mg/dl) at Day 35 were as follows: IgA 65, IgG 394, and IgM 32. 5/5 Pts experienced progressive disease and went on to receive further therapy. In conclusion, ⁹⁰Y-IT appears to be well tolerated in children and adolescents with recurrent/refractory CD20+ lymphoma and associated with low exposure of radiation to solid organs and marrow. Based on these findings, an investigator-initiated limited institutional Phase II study is planned to further evaluate the safety, tolerability, and response rate with dose stratification based on marrow reserve and Plt: 0.4 mCi/kg (no prior BMT and Plt ≥ 150k), 0.3 mCi/kg (no prior BMT and Plt 100-149 k), 0.2 mCi/kg (prior BMT and Plt ≥ 100k).