Multicenter Study with Mbvd Regimen in Elderly or Younger Patients with Cardiac Disorders Affected By Hodgkin’s Lymphoma. a Phase II Study on Behalf of the Fondazione Italiana Linfomi (FIL)
Authors: Salvi Flavia , Spina Michele , Pulsoni Alessandro , Storti Sergio , Tucci Alessandra , Chiozzotto Marianna , Massidda Stefania , Alvarez Isabel , Stelitano Caterina , Liberati Anna Marina , Lenti Valentina , Ceccarelli Manuela , Levis Alessandro 
Published: October 2019

Abstract
Backgrounds: ABVD is considered the standard of care for Hodgkin’s Lymphoma (HL) patients; however few prospective studies have evaluated his efficacy and safety in elderly patients. Moreover anthracycline-based chemotherapy is not feasible in patients with moderate/severe concomitant heart disease. In comparison with conventional doxorubicin, non–pegylated liposomal doxorubicin (TLC-D99; Myocet ™) has shown a selective uptake and a reduced clearance by the tumor cells resulting in improved cardiac safety.
Purpose: Aim of the study was to investigate efficacy and safety of an ABVD-like regimen with non-pegylated liposomal doxorubicin (TLC-D99; Myocet ™) instead of conventional doxorubicin.
Patients and Methods : From March 2010 to January 2013, 41 non-frail elderly (age³ 70) and 6 younger cardiopathic patients with untreated HL were enrolled by 22 FIL centers. “Non-frail” definition was based on less than 3 grade CIRS-G co-morbidities, no grade 4 CIRS-G and no geriatric syndrome at diagnosis. Cardiac disorder was defined according to the presence of at least one of the following: left ventricular ejection fraction (LVEF) < 50%, left ventricular hypertrophy, uncontrolled moderate/severe arterial hypertension, history of ischemic cardiopathy, clinically significant ventricular arrhythmia, atrial fibrillation, pulmonary hypertension, moderate/severe mitral valvular disorder, moderate aortic valvular disorder. For advanced disease (IIB-IV) the treatment plan was 6 courses of MBVD ( Myocet 25 mg/m2; bleomycin 10 mg/m2; vinblastine 6 mg/m2; dacarbazine 375 mg/m2) plus radiotherapy (RT) on bulky disease or residual PET positive area; for early stages (I-IIA) the treatment plan was 3 courses of MBVD plus RT involved field (IF). Preventive use of granulocyte growth factors was recommended in elderly patients; erythropoietin treatment was considered for all patients if the haemoglobin value was < 11 gr/dl. The two primary objectives of the study were to evaluate the complete remission (CR) rate according to international criteria (Cheson 2007) and the rate of cardiac events (CE) defined as a reduction of LVEF ³ 15% from baseline or the occurrence of any significant cardiac disorder.
Results. Patients’ median age was 75 (range 46–84); thirteen patients (28%) were in early stage and the remaining 34 (72%) in advanced stage. According to CGA-G scale one or more G2-3co-morbidities were present in 28 patients (60%). All the 13 early stages patients regularly ended the three planned courses of chemotherapy in an outpatients setting without complications; 1 of them refused subsequent RT IF. Among the advanced stage, 13 out 34 patients (38%) interrupted their treatment, mainly from course three to six, for the following reasons: 9 for severe toxicity; 1 for disease progression; 2 for poor compliance or consent retirement; 1 for lung cancer. Fifty-one % of patients experienced at least one episode of grade 3-4 haematological toxicity; severe infections were reported in 3 patients (6%); grade 4 acute cardiac toxicity in only 1 patient. A LVEF reduction ³ 15% from baseline was never documented. The final CR rate was 100% in early stage and 68% in advanced stage patients. At a median follow-up of 28 months all patients with early disease are alive and in CR. In advanced stage patients the 30 months actuarial OS rate is 62%, while the 30 months actuarial PFS rate is only 34% with a median PFS of 20 months. So far, 10 advanced patients have died: 3 of HL; 3 of acute toxicity including 1 sepsis, 1 pneumonia and 1 myocardial infarction, resulting in a 6% treatment-related mortality (TRM); moreover 2 patients died of lung cancer diagnosed within 7 months after the end of their treatment; 1 of heart failure and 1 of pneumonia, thrombocytopenia and gastrointestinal bleeding , both 1 year later the end of treatment. Acute and late CE with fatal exit from the study occurred in 2 patients (4%).
Conclusions: In elderly patients with advanced disease MBVD shows an unfavourable toxic profile, not really different from ABVD, even if cardiac toxicity was spared. Prospective studies with baseline definition of comorbidity score and new less aggressive strategies are needed.

Disclosures
Off Label Use: Lenalidomide in MCL. Spina:Teva: Honoraria.