Prednisone, Vinblastine, Doxorubicin and Bendamustine (PVAB) Regimen in First Line Therapy for Older Patients with Advanced-Stage Classical Hodgkin Lymphoma: Results of a Prospective Multicenter Phase II Trial of the Lymphoma Study Association (LYSA)
Authors: Ghesquieres Herve , Casasnovas Olivier , Nicolas-Virelizier Emmanuelle , Gandhi Laurent Damaj , Delwail Vincent , Touati Mohamed , Le Du Katell , Morschhauser Franck , Bonnet Christophe , Waultier-Rascalou Agathe , Orsini-Piocelle Frederique , André Marc , Ben Boutieb Myriam , Morand Fabienne , Damotte Diane , Traverse-Glehen Alexandra , Quittet Philippe , Brice Pauline 
Published: November 2019

Introduction: Older patients with an age above 60 years with classical Hodgkin lymphoma (cHL) represent a proportion of 20% to 30% of all cHL. Older cHL patients are characterized by unfavorable prognostic factors with an aggressive disease, a poor tolerance to chemotherapy resulting to a significant reduced survival as compared to younger patients. In relapsed and refractory HL, prospective and retrospective studies showed that bendamustine in monotherapy provided interesting efficacy with 30% of complete response with an acceptable toxicity profile. We developed the PVAB (Prednisone, Vinblastine, Doxorubicin and Bendamustine) regimen in first line therapy to improve prognosis of older HL with advanced stage.
Methods: In this prospective phase II, we recruited newly diagnosed classical HL patients age of 61 years or older with an advanced stage (Ann Arbor stage III, IV, IIB with risk factors). Inclusion criteria were: baseline 18-FDG PET scan performed before any treatment with at least one hypermetabolic lesion; ECOG performance status 0-2; adequate cardio-pulmonary function with LVEF ≥ 50%; adequate renal function with creatinine clearance ≥ 40 mL/min; HIV negative; For patients aged 70 years old and more, a Mini Nutritional Assessment (MNA) ≥ 17. Treatment consisted of 6 cycles of prednisone (40mg/m2 D1-5), vinblastine (6mg/m2, D1), doxorubicin (40mg/m2, D1) and bendamustine (120mg/m2, D1) every 21 days. A first evaluation was performed after 4 cycles by CT scan and a final evaluation by PET scan after 6 cycles. No radiotherapy was applied in this protocol. The primary endpoint was the complete metabolic response (CMR) rate after 6 cycles of study treatment or at premature treatment discontinuation according to Lugano Classification. The main analysis for the CMR rate was based on a Simon's phase II design. We selected P0 and P1 to be 70% and 85%, respectively for CMR rate. A total of 79 patients provided nominal power of 80% at the nominal one-sided 5% significance level. Using a drop-out rate of 10%, 90 patients should be included in this trial.
Results: Between July 2015 and July 2018, 89 patients who signed the consent form and received at least one PVAB cycle corresponding to intention to treat (ITT) group were included in 34 LYSA centers. Among them, four patients did not respected major inclusion criteria (one patient had a nodular lymphocyte predominant subtype after histological review and three patients ≥ 70 years had no MNA evaluation at inclusion) corresponding to the modified ITT group (N=85). The median age of the 89 patients was 68 years (range, 61-88) with 35 patients ≥70 years old (39%) and 58 male (65%). According to the central review, the main histological subtype was nodular sclerosis cHL (66%). Ann Arbor stages were as follows: II (n=3, 3%), III (n=30, 34%), IV (n=56, 63%). B symptoms were present in 57% of patients and 70 patients (80%) had IPS≥3. 78 patients (88%) completed the 6 cycles of PVAB. In ITT, the CMR rate corresponding to the primary endpoint of the study was 77.5% (95%CI, 67-86) with 69 patients in CMR; 8 patients were in partial metabolic response; 2 and 5 patients had a stable and progressive disease, respectively and 5 were not evaluable. In the modified ITT group, the CMR rate at this end of treatment was 77.6% (95%CI, 67-86). With a median follow-up of 23 months (0.5-40.3), 25 patients relapsed or progressed (28%). The 2-year progression survival rate (PFS) rate was 61.3% (95%CI, 49-72). For the 69 patients achieving CMR, the 2-year disease free survival (DFS) rate was 73.3% (95%CI, 61-82). At the date of analysis (December 2018), 17 patients (19%) died: 7 cHL, 4 treatment toxicity, 3 second cancers, 3 other causes. The 2-year overall survival rate was 84.1% (95%CI, 73-91). For toxicity, 4 patients presented toxic death during treatment: one cardiogenic shock (71y, >cycle 1) one septic shock (70y, >cycle 1), one brain hematoma with grade 4 thrombocytopenia (76y, >cycle 1), one fungal infection (86y, >cycle 4). At least one serious adverse events (SAE) were presented by 28 patients (31.5%) mainly infections (13 patients, 15%), blood (11 patients, 12%) and cardiac disorders (4 patients, 4.5%).
Conclusions: Six cycles of PVAB regimen provided high CMR (77.5%) with acceptable toxicity in older cHL patients with advanced stage. Patients with CMR at the end of treatment had a particular favorable outcome but long term follow-up is needed for a better evaluation of survival endpoints.

Disclosures
Morschhauser: Roche/Genentech: Consultancy; Celgene: Honoraria; Servier: Consultancy; Gilead: Consultancy; Janssen: Honoraria; BMS: Honoraria. André:Celgene: Other: Travel grants, Research Funding; Chugai: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel grants, Research Funding; Amgen: Other: Travel grants, Research Funding; Johnson & Johnson: Research Funding; Takeda Millenium: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Brice:Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding; BMS: Honoraria.

OffLabel Disclosure:
Bendamustine is off-label drug use in Hodgkin lymphoma