Chemoimmunotherapy for ALK+ Relapsed/Refractory ALCL

Brief Background: A multitude of chemotherapeutic regimens have been evaluated for the treatment of de novo ALK+ ALCL. Unfortunately, no chemotherapeutic regimen has improved the 20-30% treatment failure rate. Given the ubiquitous cell surface expression of CD30 on ALK+ ALCL, the anti-CD30 antibody drug conjugate (ADC) brentuximab vedotin (BV) is a rational therapeutic agent for ALK+ ALCL. 16. In the most recent Children's Oncology Group (COG) trial for de novo ALK+ ALCL (ANHL12P1), BV was combined with ALCL99 chemotherapy and demonstrated the best reported outcomes with a 2-year event free survival and overall survival of 79% and 97% respectively. Immune checkpoint inhibition with antibodies that block the inhibitory immune receptors CTLA-4, PD-1, and PD-L1 have improved the outcomes for many patients with cancer by dramatically enhancing the anti-tumor activity of the immune system. Iwafuchi et al. demonstrated that elevated PD-1/PD-L1 expression was associated with a poor prognosis in pediatric ALK+ ALCL 22. Three different case reports have described dramatic responses (CR, CR, CR) to PD-1 inhibitors in heavily pre-treated patients with R/R ALK+ ALCL. The combination of BV and NIVO has been extensively tested in both pediatric and adult patients with R/R Hodgkin lymphoma and R/R primary mediastinal B-cell lymphoma with robust safety and efficacy. Given the frequent expression of both CD30 and PD-L1 in ALK+ ALCL, the impressive single agent therapeutic efficacy of both BV and NIVO, and the tolerability of the combination of BV and NIVO in other patients with lymphoma, investigating the safety and efficacy of BV and NIVO in R/R ALK+ ALCL is warranted. For pediatric patients with relapsed or refractory ALK-positive ALCL, remission can be achieved through the use of chemotherapy and/or immune therapy. However, the optimal treatment strategy for consolidative therapy in pediatric patients with relapsed or refractory ALK- positive ALCL remains to be determined. The literature reports High-risk patients with CD3-positive ALCL experiencing relapse at any time after first-line therapy achieved 5-year EFS and OS rates of 62 and 73%, respectively after reinduction therapy followed by best available donor allogeneic stem cell transplantation. Very high-risk patients with progression during first-line therapy achieved EFS and OS rates of 41 and 59%, respectively after reinduction therapy followed by best available donor allogeneic stem cell transplantation. For all evaluable patients, the 5-year EFS and OS rates were 53 and 78%, respectively. A major barrier to survival for pediatric patients with relapsed or refractory ALCL is progression of disease during reinduction therapy prior to stem cell transplantation, highlighting the importance of effective re-induction therapy. Limited toxicity associated with immune therapy in comparison to traditional cytotoxic chemotherapy may contribute to more rapid recovery, reduction in time to stem cell transplantation and improvement in performance score prior to stem cell transplantation. Through the use of allogeneic stem cell transplantation and donor lymphocyte infusion, a graft versus lymphoma effect has been suggested for pediatric patients with relapsed or refractory ALCL.