Page 151 - Haematologica Vol. 110 - January 2025

ARTICLE - R-GemOx+Atezo in R/R transformed DLBCL
T. Othman et al.
ceive CAR T cells achieve long-term disease-free survival.3,5-7 There were small subsets of patients with transformed FL in the pivotal and randomized CAR T-cell studies and there is no clear standard treatment for patients with Richter transformation (RT). Thus, better therapies for transformed DLBCL, including RT, is a clear unmet need.
Atezolizumab is a monoclonal antibody that binds pro- grammed death ligand-1 (PD-L1) to inhibit the interaction between the programmed cell death-1 receptor (PD-1) and PD-L1.8 PD-1 or PD-L1 is overexpressed in several types of non-Hodgkin lymphoma, including DLBCL9, FL, and RT.10-12 Anti-PD-1/PD-L1 monotherapy has demonstrated modest overall response rates ranging from 4-18% in FL and DLB- CL.13 Atezolizumab has been safely combined with several agents in R/R DLBCL, such as polatuzumab vedotin, taze- metostat, and obinutuzumab, but these combinations again demonstrated limited overall response rates ranging from 16-25%.14-16 Preclinical data suggest synergy between immu- nogenic chemotherapy with anti-PD-L1 antibodies, leading to eradication of PD-1/PD-L1 blockade-refractory tumor cells.17 One such immunogenic chemotherapy is oxaliplatin, which increases T- and dendritic cell infiltration, thereby increasing the cytotoxic T-cell:regulatory T-cell ratio and enhancing dendritic cell/macrophage function.17,18 Another example is gemcitabine, which depletes myeloid-derived suppressor cells, increases tumor cell expression of major histocompatibility complex class I, and shifts the polarity of tumor-associated macrophages.19-22
The combination of gemcitabine and oxaliplatin (GemOx) is a commonly used salvage regimen for DLBCL. Transformed DLBCL is an ideal disease in which to evaluate the combina- tion of immunogenic chemotherapy and checkpoint inhibitors given the genomic complexity of transformed FL. PD-1/PD-L1 antibodies exhibit their greatest efficacy in tumors with high genomic instability (i.e., high tumor mutational burden and microsatellite instability).23,24 Transformed DLBCL, and in particular transformed FL, are more genomically complex than the underlying indolent B-cell non-Hodgkin lympho- mas,25,26 and therefore may provide more neo-antigens ripe for recognition by T cells stimulated by checkpoint inhibi- tors. We hypothesized that combining PD-L1 blockade with immunogenic R-GemOx would be safe and could enhance the antitumor activity driven by each type of therapy and lead to a higher response rate than chemotherapy or im- munotherapy alone. We developed a pilot study to combine immunogenic chemotherapy, R-GemOx, with atezolizumab (R-GemOx+Atezo), to assess the safety and preliminary ac- tivity of this combination in patients with R/R transformed DLBCL, including RT, and report our findings here.
Methods
Study design and participants
We conducted a multicenter phase I trial through the Na-
tional Cancer Institute Experimental Therapeutics Clinical Trials Network (NCI ETCTN). Participating centers included City of Hope, University of California Davis, and Emory Uni- versity. All participating sites obtained institutional review board approval. The trial was registered at clinicaltrials. gov (NCT03321643). Eligible patients were ≥18 years old with histologically confirmed transformed DLBCL, including histological transformation from any indolent lymphoma, such as FL, marginal zone lymphoma, lymphoplasmacytic lymphoma or RT of chronic lymphocytic leukemia. Addi- tionally, they must have had documented R/R disease after at least one prior treatment regimen (which did not have to be DLBCL-directed therapy), as defined using the 2014 Lugano classification.27 Other inclusion criteria included an Eastern Cooperative Oncology Group performance status ≤2 and adequate organ function. Exclusion criteria included prior receipt of GemOx, anti-PD1/PD-L1 therapy or alloge- neic HSCT; prior chemotherapy, radiotherapy or systemic immunosuppressive therapy (with the exception of acute, low dose, systemic immunosuppressant medications) within 2 weeks of enrollment; active central nervous system lym- phoma; history of autoimmune disease; and pregnancy. A full list of eligibility criteria is provided in the Online Sup- plementary Appendix.
The study had a six-patient safety lead-in with a dose-lim- iting toxicity (DLT) evaluation. Patients were enrolled in the safety lead-in via the traditional 3+3 method to establish the recommended phase II dose (RP2D). We included a dose de-escalation level in the event that excess toxicity was ob- served at the starting dose level. Once the RP2D had been established, two separate expansion cohorts were enrolled: a cohort of patients with transformed FL and another cohort of patients with transformation of other non-FL indolent lymphomas or RT. The six patients from the safety lead-in portion of the study treated at RP2D were included in the expansion cohort accrual. R-GemOx consisted of rituximab 375 mg/m2 intravenously (IV), gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 on day 1 every 2 weeks. Atezoli- zumab was given at a fixed dose of 840 mg IV every 2 weeks on day 1 starting with cycle 2. Patients could receive up to a maximum of four 21-day cycles of R-GemOx. Responding patients could then receive maintenance therapy with ritux- imab 375 mg/m2 IV plus a fixed dose of atezolizumab 1,200 mg IV (R-Atezo) every 4 weeks until disease progression or unacceptable toxicity (Figure 1A). Patients who achieved a complete response could transition to maintenance thera- py after completing at least two cycles. Patients who were transplant candidates were required to complete at least the first two cycles of study therapy before proceeding to HSCT at the discretion of the treating physician. Positron emission tomography/computed tomography (PET/CT) was performed at baseline, followed by PET/CT (or CT scans once a complete response had been confirmed) after cycles 2 and 4. For those receiving maintenance, PET/CT or CT scans were performed every 12 weeks until 2 years from
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