-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2063 Vincristine Sulfate Liposome Injection (VSLI) with Bendamustine and Rituximab As First-Line Therapy for Indolent B-Cell Lymphomas: A Phase 1 Study

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Poster II
Hematology Disease Topics & Pathways:
Follicular Lymphoma, Biological, antibodies, Adult, Diseases, Marginal Zone Lymphoma, Non-Biological, Mantle Cell Lymphoma, Therapies, Non-Hodgkin Lymphoma, chemotherapy, B-Cell Lymphoma, Lymphoid Malignancies, Study Population, Clinically relevant
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Thomas A Ollila, MD1,2, James Butera, MD1,2, Pamela C Egan, MD1,2, John L Reagan, MD1,2, Anthony G Thomas, DO2,3, Inna Yakirevich, NP4*, Kelsey MacKinnon5*, Jeannine Margolis5*, Valerie Rosati6*, Jessica McMahon, RN7*, Jordan Robison, CRA7* and Adam J Olszewski, MD1,2

1Division of Hematology-Oncology, Rhode Island Hospital, Providence, RI
2Brown University, Providence, RI
3The Miriam Hospital, Providence, RI
4Lifespan Cancer Institute, Providence, RI
5Brown University Oncology Research Group (BrUOG), Providence, RI
6Lifespan Oncology Clinical Research, The Miriam Hospital, Providence, RI
7Lifespan Oncology Clinical Research, Rhode Island Hospital, Providence, RI

Background: The combination of bendamustine and rituximab (BR) is frequently used as treatment for indolent B-cell lymphomas (iBCL; Rummel et al, Lancet 2013; Olszewski et al, Am J Hematol 2019). Its relatively low adverse effect profile and lack of overlapping toxicities suggest the potential for adding vincristine – another highly active anti-lymphoma agent. However, a prior trial found high rates of thrombocytopenia when standard vincristine was combined with full-dose bendamustine (Herold M, et al. J Cancer Res Clin Oncol. 2006). VSLI is a liposome-encapsulated formulation of vincristine designed to improve its activity, therapeutic index, and pharmacokinetic profile. VSLI at an uncapped dose of 2.0 mg/m2 has been successfully combined with cyclophosphamide, doxorubicin, and prednisone (Hagemeister et al., Br J Haematol 2013). The objective of this phase 1 study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of VSLI in combination with standard doses of BR for treatment of iBCL.

Methods: Patients with iBCL otherwise appropriate for BR therapy were eligible for this phase 1 study. Bendamustine was given at 90 mg/m2 on Day 1, 2, and rituximab at 375 mg/m2 on Day 1 of each 28-day cycle, for 6 cycles. VSLI was given on Day 2 of each cycle at a patient-specific dose ranging from 1.8 mg/m2 up to maximum 2.3 mg/m2, as determined by the Escalation with Overdose Control (EWOC) model-based design (Babb et al., Stat Med, 2001). EWOC allows for rapid identification of the MTD using a small sample size and single-subject dose cohorts. Model parameters for this study included target probability of DLT (q) of 0.33 and starting probability of exceeding MTD (a) of 0.25. There was no intra-patient dose escalation. Simulations indicated that n=10 subjects would be sufficient to determine the MTD, and this sample size was set for the study by design. MTD was defined as median of the Bayesian 95% confidence interval (CI) for the VSLI dose, calculated from the model at the end of the study. DLT was defined during cycle 1 only, as grade (G) 4 neutropenia lasting >7 days (or G3 with fever / infection), G4 thrombocytopenia (or G3 requiring transfusion), or any G3/4 non-hematologic toxicity. Secondary objectives included cumulative rates of adverse effects (AE, particularly VSLI-related neuropathy), completion rate of 6 cycles of therapy, overall response rate (ORR), and complete response (CR) rate. This study (BrUOG-326) was conducted by Brown University Oncology Research Group (BrUOG) and registered on clinicaltrials.gov as NCT02257242.

Results: Ten patients received BR+VSLI as first-line therapy. The VSLI dose was escalated from 1.80 to 2.24 mg/m2 (see Table). Median age was 59.5 years; there were 6 (60%) women. Patients had follicular (n=4), marginal zone (n=3), mantle cell (n=2), and small lymphocytic lymphoma (n=1). There was 1 observed DLT (G3 ileus) at VSLI dose 2.04 mg/m2. So far, six patients have completed 6 cycles of BR+VSLI, while two discontinued VSLI and continued on 6 cycles with BR alone (one for DLT in cycle 1, and one for G2 neuropathy after cycle 3). The most common AE included lymphopenia (100%), constipation (60%), nausea, infusion reaction, neutropenia (each 50%), and peripheral neuropathy (40%). The only G3/4 AE were lymphopenia (90%), neutropenia (20%) and ileus (10%). Four patients developed neuropathy: two G1 and two G2. Only one patient (10%) had treatment-related rash (G2 during cycle 5). Using data from all 10 subjects, the MTD for VSLI in combination with BR was estimated to be 2.25 mg/m2 (Bayesian 95% CI, 2.00-2.40 mg/m2).

All patients who completed therapy (n=8) achieved a response, with 50% achieving CR at the end of therapy (i.e. after 6 cycles of BR+VSLI or BR if VSLI was discontinued early). With median follow-up 18 months (range, 2-29), one patient experienced recurrence of a blastoid mantle cell lymphoma, while others remain in remission (see Figure). Estimated 2-year progression-free survival is 80.0% (95% CI, 20.4-96.9%), and all patients remain alive.

Conclusions: VSLI at 2.25 mg/m2 can be safely combined with BR as first-line treatment for iBCL. In this study, the efficient phase 1 EWOC design enabled MTD determination for VSLI in a small cohort. Considering low rate of G3/4 toxicity, BR+VSLI may provide a platform for further combinations in treatment of B-cell lymphomas (including with an anthracycline for aggressive NHL).

Disclosures: MacKinnon: Brown University Oncology Research Group: Current Employment. Margolis: Brown University Oncology Research Group: Current Employment. Olszewski: TG Therapeutics: Research Funding; Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; Spectrum Pharmaceuticals: Research Funding.

OffLabel Disclosure: Vincristine sulfate liposome injection (Marqibo) is indicated for the treatment of adult patients with Philadelphia chromosome‒negative (Ph‒) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following 2 or more anti-leukemia therapies. Bendamustine is indicated for the treatment of patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

*signifies non-member of ASH