Abstract
Introduction:
Despite excellent survival outcomes, significant chronic health conditions occur among pediatric, adolescent, and young adult (CAYA) classic Hodgkin lymphoma (cHL) survivors as a result of current chemotherapy and radiation regimens. Targeting both the tumor microenvironment (TME), as well as tumor-specific antigens has proven to be an effective and safe approach for the treatment of CAYA cHL patients. Here we report on our cHL immunotherapy treatment protocols over the past 13 years. Our approach combines the use of the antibody-drug conjugat,e brentuximab vedotin (Bv), targeting Reed-Sternberg (RS) cells, along with the anti-CD20 antibody rituximab (RTX) and checkpoint inhibitor nivolumab (N) targeting the TME, added to risk-adapted chemotherapy in newly diagnosed CAYA cHL patients. This chemoimmunotherapy approach allows for anthracycline dose reduction and radiation sparing in intermediate and high-risk patients.
Methods:
Our early cHL clinical trial enrolled patients 3-39yr old who received a backbone of brentuximab vedotin, doxorubicin, vinblastine, dacarbazine, and rituximab (Bv-AVD-R) given on Day 1, 2 and Day 15,16 of each cycle. Early response utilizing FDG-PET scan was performed following 2 cycles of therapy (PET2) with PET2 negativity defined as Deauville score of 1, 2 or 3. Rapid early responders (RER) or slow early responders (SER) received an additional 2 to 6 cycles of treatment based on risk assignment and early response. Following completion of our initial trial, subsequent patients were enrolled on our follow-up study evaluating the addition of nivolumab beginning with cycle 3 of therapy and omitting further anthracycline (Bv-NVD-R). This limited the total anthracycline dose to 100mg/m2 per patient. Radiation therapy was initially planned for high-risk patients with slow responding lesions. Subsequently, on our current study, only patients not achieving metabolic CR by FDG-PET at the completion of all chemoimmunotherapy receive radiation therapy.
Results:
A total of 54 patients completed therapy with a median age of 17yrs (4-25yrs). Thirty-four patients received Bv-AVD-R for all cycles and 20 patients are enrolled on our follow up study and received Bv-AVD-R followed by Bv-NVD-R (total doxorubicin dose 100mg/m2). All 54 patients achieved a CR to therapy at a rate of 100%. Early PET2 negativity was achieved in 47 patients (87%). Due to excellent overall rapid response, only four patients have required radiation therapy and no patient received radiation therapy in the follow-up study. The EFS and OS is 100% with a median follow up time of >90 months (range 2-159 months). Accrual is ongoing for the current trial. Adverse events (AEs) included grade IV myselosuppression in the majority of patients, supported with growth factor. There have been no admissions for fever and neutropenia and no infectious complications with either regimen. Among all patients, a total of four (7%) experienced grade 3 or greater non-hematological AEs. These included two (3.7%) grade 3 neuropathy, one (1.9%) grade 3 allergic reaction to Bv, and one (1.9%) grade 3 mucositis. Immune profiles at a median of 18 months of follow-up post-rituximab have demonstrated normal IgG, absolute CD19 and absolute CD3 levels. We have completed the nivolumab safety run in for the follow-ups study in the current trial. There have been no unexpected AEs related to therapy and no dose limiting toxicities with the addition of nivolumab to the immunochemotherapy backbone.
Conclusions:
The addition of immunotherapy to a reduced-intensity chemotherapy backbone is safe, effective and well tolerated. Targeting the HRS cell as well as the TME via the PD1/PD-L1 axis is a promising approach in CAYA with cHL and allows for reduction in both anthracycline and radiation exposure. This is important in limiting short- and long-term adverse effects. The use of rituximab added to this approach may have contributed to the excellent response observed in this CAYA cHL cohort.
