Response-Adapted Therapy with Nivolumab and Brentuximab Vedotin (BV), Followed By BV and Bendamustine for Suboptimal Response, in Children, Adolescents, and Young Adults with Standard-Risk Relapsed/Refractory Classical Hodgkin Lymphoma

Abstract

Introduction: Classical Hodgkin lymphoma (cHL) is among the most common malignancies in adolescents and young adults. High-dose chemotherapy (HDCT) and autologous hematopoietic stem cell transplantation (ASCT) are standard for most patients with relapsed/refractory (R/R) disease. Current salvage therapies are associated with excessive toxicity and variable complete remission rates (Harker-Murray et al, Pediatr Blood Cancer 2014). Novel regimens that increase remission rates and reduce late effects of therapy are needed, particularly for young patients. Nivolumab (nivo) is a fully human IgG4 anti-programmed death-1 monoclonal antibody. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate. In a phase 1/2 study of adults with R/R cHL, the combination of nivo + BV was well tolerated, with a high response rate as first salvage regimen (Herrera et al, Blood 2018). CheckMate 744 (AHOD1721; NCT02927769) is the first risk-stratified, response-adapted, phase 2 study of nivo + BV, followed by BV + bendamustine for suboptimal response, in children, adolescents, and young adults with R/R cHL with low or standard risk of relapse. Here we report preliminary, investigator (INV)-assessed results from the standard-risk (R2) cohort. Methods: This open-label study enrolled patients aged 5-30 years with pathologically confirmed cHL, excluding nodular lymphocyte-predominant HL, after failure/non-response to first-line therapy and without prior ASCT. Stratification to R2 was based on refractory disease or early relapse; B symptoms, extranodal disease, or extensive disease with radiation therapy (RT) contraindicated at relapse; relapse in a prior RT field; or stage IIIB or IV at initial diagnosis. Patients in R2 received induction (IND) with 4 cycles of nivo + BV. Patients without complete metabolic response (CMR; Deauville score 1-3) received intensification (INT) with 2-4 cycles of BV + bendamustine. Patients with CMR after IND or INT discontinued study treatment, proceeded to HDCT/ASCT, and entered follow-up. Tumors were assessed by INV and blinded independent central review (BICR) per Lugano 2014 criteria (Cheson et al, J Clin Oncol 2014) every 2 treatment cycles. Treatment decisions were based on BICR assessment. The primary endpoint was CMR rate by BICR prior to HDCT/ASCT. Secondary endpoints included INV-assessed response and safety. Results: At database lock (DBL), 32 patients in R2 had entered IND. Median age was 16 y (range 9-30), 78% were aged <18 y, and 72% were male. Fifteen patients (47%) had relapsed disease and 17 (53%) refractory; 14 (44%) had B symptoms or extranodal disease at relapse. At DBL, 25 patients (78%) had completed IND (4 cycles of nivo + BV); 7 ongoing. At the end of IND, INV-assessed responses were 16 (64%) CMR, 4 (16%) partial metabolic response, and 1 (4%) progressive metabolic disease; 4 (16%) were pending tumor assessment. Based on BICR assessment, 6 patients entered and completed INT; all achieved CMR after 2 cycles of BV + bendamustine. Overall, all evaluable patients achieved CMR by INV after completing IND or INT. At DBL, 18 patients had proceeded to HDCT/ASCT. During IND, 29 patients (91%) had ≥1 adverse event (AE) due to any cause; 7 (22%) grade 3-4. The most common AEs were nausea (53%), diarrhea (31%), and pyrexia (28%). Six patients (19%) had infusion-related reactions (IRRs); 1 (3%) grade 3-4. Four patients (13%) had drug-related serious AEs; 2 (6%) grade 3-4 (1 IRR and 1 activated partial thromboplastin time prolonged). Two patients (6%) had immune-mediated AEs, including 1 grade 3-4 IRR noted above; none had immune-related serious AEs. During INT, 3/6 patients (50%) had AEs; none grade 3-4; most common were nausea (33%) and vomiting (33%); 1 patient (3%) had grade 1 IRR. Overall, no AEs led to discontinuation and there were no deaths. Conclusion: For children, adolescents, and young adults with standard-risk R/R cHL prior to ASCT, this risk-stratified, response-adapted approach using nivo, BV, and bendamustine resulted in high CMR rates and was well tolerated, making it a promising novel salvage therapy. Most evaluated patients achieved CMR with IND (nivo + BV); all 6 who went to INT (BV + bendamustine) achieved CMR. Updated results based on a planned interim analysis including more patients and BICR-assessed response data will be presented. Study support: Sponsored by Bristol-Myers Squibb in collaboration with Children's Oncology Group (COG) and EuroNet group. Disclosures Leger: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Brugieres:Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: Financial support for SIOP meeting in 2016. Galderisi:Seattle Genetics: Employment, Equity Ownership. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Jou:Bristol-Myers Squibb: Employment, Other: company stock ownership.

Epidemiology, outcome, targeted agents and immunotherapy in adolescent and young adult non‐Hodgkin and Hodgkin lymphoma

“…An international phase II trial of nivolumab and Bv for children, adolescents and young adults with classic HL after failure to frontline therapy, followed by Bv and bendamustine for participants with a suboptimal response has recently been started (NCT02927769) (Table ). The recruitment of the standard risk cohort is already completed; the first encouraging interim results, which compared very well with the results reported by Herrera et al () (ORR 91% and CMR 82%), were presented at the American Society of Hematology meeting 2018 (Harker‐Murray et al , ). The toxicity profile of these compounds is related to immune‐mediated inflammatory reactions, which constitute a new class of adverse events as a consequence of the restored host T‐cell activation.…”

Combination brentuximab vedotin and bendamustine for pediatric patients with relapsed/refractory Hodgkin lymphoma

“…Early results are promising with all patients (n=6) with residual metabolically active disease following initial reinduction with nivolumab and BV achieving CMR following BVB. 27 Most recently, McMillan et al published their single center experience with BVB in pediatric and young adult patients, in which the median age of patients treated was 21 years old and CMR and OR rates were 79% and 83%, respectively. 17 Our study represents the first multicenter effort evaluating the safety and efficacy of BVB in a true pediatric cohort of patients (median age at time of BVB was 16 years old).…”

Invasive Fungal Diseases in Children with Hematological Malignancies Treated with Therapies That Target Cell Surface Antigens: Monoclonal Antibodies, Immune Checkpoint Inhibitors and CAR T-Cell Therapies

“…Substitution of vincristine with Bv in the OEPA-COPDAC chemotherapy regimen for children with HL resulted in tenuous and insignificant decrease in severe neutropenia rates (81.3% versus 81.5%) [ 105 ]. Preliminary results from an open-label study of Bv and nivolumab, followed by Bv and bendamustine, in 32 pediatric patients with r/r HL and no AHSCT recorded promising outcomes and zero severe infection incidence [ 106 ]. A retrospective study from Italy involving patients aged from 12 to 66 years old treated with Bv for r/r HL reported one case of IPA (1.5%) and only three cases of severe neutropenia (4.6%) [ 107 ].…”