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

Despite 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.

We 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).

The 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.

R-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.

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.