Long Term Results Of a Phase 2 Study Of Vincristine Sulfate Liposome Injection (Marqibo®) Substituted For Non-Liposomal Vincristine In CHOP With Or Without Rituximab For Patients With Untreated Aggressive Non-Hodgkin's Lymphomas

Abstract

IntroductionDespite significant advances over the past decade in the treatment of CD20+ aggressive Non-Hodgkin Lymphomas (NHL), such as Diffuse Large B-cell Lymphoma (DLBCL), outcomes, particularly in older patients with unfavorable prognositic features, remain unsatisfactory. Vincristine sulfate liposome injection (VSLI; Marqibo® M) is active as a single-agent and in combination with rituximab in relapsed and refractory lymphomas, and approved in the United States for relapsed and refractory Ph-negative adult acute lymphocytic leukemia. MethodsWe evaluated VSLI (2.0 mg/m2 without any dose cap) substituted for non-liposomal vincristine (VCR) in R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), creating R-CHMP in 60 patients with untreated DLBCL. The primary endpoint was overall response rate (ORR), defined as the proportion of patients that achieved a complete response (CR), unconfirmed CR (CRu), or partial response (PR). Secondary efficacy endpoints included progression free survival (PFS) and overall survival (OS). ResultsThe ORR was 95% (57/60) including CR in 54 (90%) patients and CRu in 1 (2%) patient. Median PFS and OS were not reached at median follow-up of 8 and 10.2 years, respectively. The 10-year PFS and OS were 64% and 87%, respectively. In the DLBCL patients over the age of 60 years, R-CHMP resulted in an ORR of 91%, 10-year PFS of 48%, and 10-year OS of 65%. In the DLBCL patients age >60 years with an age-adjusted International Prognostic Index (aaIPI) of 2-3, the ORR was 92% (all CR), median PFS was 118 months, and the 10 year PFS and OS were 27% and 50%, respectively.Despite median and maximum cumulative VSLI delivery of VCR of 22.8 mg and 35.2 mg, respectively, the safety profile of R-CHMP was comparable to that reported for R-CHOP. Grade 3 peripheral neuropathy (PN) was reported in 2 (3%) patients, there was no reported Grade 4 PN, and there was no reported Grade 3 or 4 constipation.Progression Free Survival % (95% CI)Overall Survival % (95% CI)Patient Group3 years5 years10 years3 years5 years10 yearsDLBCL Patients (n=60)81 (71-91)81 (71-91)64 (50-77)92 (85-99)87 (78-95)87 (68-89)Age ≤ 60 yrs (n=28)82 (68-96)82 (68-96)78 (63-94)96 (89-100)93 (83-100)93 (83-100)aaIPI 0-1 (n=26)85 (71-99)85 (71-99)81 (65-96)96 (89-100)92 (82-100)92 (82-100)aaIPI 2-3 (n=2)10050501005050Age > 60 yrs (n=32)80 (66-95)69 (52-86)48 (27-69)88 (76-99)81 (68-95)65 (48-82)aaIPI 0-1 (n=19)89 (75-100)70 (48-92)56 (32-81)95 (85-100)84 (68-100)74 (54-94)aaIPI 2-3 (n=13)67 (41-94)67 (41-94)27 (0-67)77 (54-100)77 (54-100)50 (21-79) ConclusionsR-CHMP (M = Marqibo) in patients with untreated DLBCL resulted in a high ORR and encouraging PFS and OS without apparent increased toxicity compared to historical experience with R-CHOP. In particular, elderly DLBCL patients with an unfavorable prognosis, based on aaIPI, experienced remarkable PFS and OS. These data compare favorably with previously reported studies in a comparable patient population. This enhanced activity likely reflects VCR dose intensification, pharmacokinetic optimization, and enhanced delivery afforded by VSLI. A randomized Phase 3 cooperative group trial comparing R-CHMP versus R-CHOP in older patients with untreated DLBCL is ongoing. Disclosures:Off Label Use: Marqibo (VSLI) is approved for adults with Ph- relapsed/refractory acute lymphoblastic leukemia. Deitcher:Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment. Sarris:Inex Pharmaceuticals (nowTekmira): Consultancy. Cabanillas:Inex Pharmaceuticals (nowTekmira): Consultancy.