MULTI-TARGETED THERAPY WITH VIPOR-P IN RELAPSED/REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA: UPDATED ANALYSIS OF EFFICACY AND MINIMAL RESIDUAL DISEASE

Introduction: Targeted ViPOR therapy leads to durable remissions in R/R non-GCB DLBCL (Melani et al. Blood. 2024). We hypothesized that polatuzumab may improve outcomes and conducted a Phase I/II study of ViPOR-P. Here, we present updated efficacy and new MRD data from our ongoing ViPOR-P study.

Methods: R/R DLBCL pts with adequate organ function were eligible. Polatuzumab 1.8 mg/kg IV D2, venetoclax 800 mg PO D2–14, ibrutinib 560 mg PO D1–14, prednisone 100 mg PO D1–7, obinutuzumab 1000 mg IV D1–2, and lenalidomide 15 mg PO D1–14 were given as previously described (Melani et al. Blood. 2024). ViPOR-P q21d × 6C was given without maintenance or consolidation. All pts received TLS and G-CSF ppx. Baseline CT, PET, BM, and tumor bx was performed with CT scans after C2, 4, and 6 and PET after C6. Surveillance CT was performed q3m × 1y, q4m × 1y, q6m × 1y, and q12m × 2y. MRD was assessed in plasma ctDNA using clonoSEQ at baseline, during tx, and in f/u.

Results: 40 DLBCL pts (15 in Ph 1 & 25 in Ph 2) enrolled. Median (range) age was 55y (23–83) with 73% male. 22 (55%) pts had non-GCB DLBCL, 11 (28%) HGBCL-DH-BCL2, 4 (10%) THRLBCL, 2 (5%) HGBCL-DH-BCL6, and 1 (3%) GCB DLBCL. Stage III/IV disease was seen in 83% with IPI > 3 in 55%. Median (range) prior tx were 2 (1–6), with prior CAR-T in 40% and 53% of pts refractory per SCHOLAR-1.

G3–4 heme AEs (% cycles) included thrombocytopenia (26%), neutropenia (21%), and anemia (13%), with 2 febrile neutropenia events in 145 total cycles. All grade non-heme AEs (% pts) included hypokalemia (97%), diarrhea (76%), elevated LFTs (53%), and nausea (50%). G1–2 neuropathy occurred in 26% with no G3–4 neuropathy seen. 1 uncomplicated TLS event occurred and there was no tx-related mortality. Dose reductions occurred in 32% of pts, and 2 pts prematurely stopped tx due to toxicity.

In 36 evaluable pts off-tx, ORR was 78% (28/36) and CR rate was 56% (20/36). By IHC, CR rate was 67% (16/24) in non-GCB and 33% (4/12) in GCB, with all GCB CRs in HGBCL-DH-BCL2. By RNA-seq, CR rate was 78% (7/9) in ABC, 45% (5/11) in GCB, and 100% (1/1) in unclassified DLBCL. In refractory and post-CAR-T pts, CR rate was 40% (8/20) and 38% (6/16), respectively. In 29 MRD evaluable pts, 66% (19/29) of all pts and 100% (18/18) of PET CR pts were MRD undetectable at EOT (Figure 1A). Undetectable MRD after C1 or at EOT was associated with improved PFS. With a median f/u of 28m, 71% of CRs are ongoing with a 2y PFS and OS of 41% and 53%, respectively. 2y PFS was 49% in non-GCB and 25% in GCB by IHC (Figure 1B), and 67% in ABC and 27% in GCB by RNA-seq. In refractory and post-CAR-T pts, 2y PFS was 22% and 26%, respectively.

Conclusions: ViPOR-P × 6C leads to durable undetectable MRD CRs in R/R DLBCL, especially non-GCB and ABC subtypes, further validating the curative potential of ViPOR-based treatment. Compared to ViPOR, ViPOR-P is safe without significant additional toxicity.

Research funding declaration: Intramural Research Programs of NCI and NCATS.

Keywords: Minimal residual disease; Aggressive B-cell non-Hodgkin lymphoma; Molecular Targeted Therapies

Potential sources of conflict of interest:

A. Jacob

Employment or leadership position: Adaptive Biotechnologies

Stock ownership: Adaptive Biotechnologies

H. Simmons

Employment or leadership position: Adaptive Biotechnologies

Stock ownership: Adaptive Biotechnologies