Smart Stop Trial: Effective Combo for Newly Diagnosed DLBCL

Patients(pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL) faced the same first-line chemoimmunotherapy (CIT). The Smart Start trial challenged this, testing a chemo-free combo (R+L+ibrutinib) before standard CIT. Early results are promising: high response rates, good survival, and even a potential cure without CIT.

A notable case achieved remission post-CR without subsequent CIT for over 4 years. Acalabrutinib (A) and L exhibit synthetic lethality in non-GCB DLBCL models, while CD20 antibody R and CD19 antibody tafasitamab (T) show clinical activity with L in DLBCL pts.

Based on the reported data analysis Jason Westin and his team aimed to evaluate the  Smart Stop trial’s (NCT04978584)  interim findings, emphasizing the potential reduction or omission of CIT cycles post-targeted therapy response, reporting interim results from cohort 1.

The study included pts aged 18 and above with previously untreated DLBCL. Initially, the Hans algorithm was utilized to select non-GCB DLBCL, but this criterion was subsequently removed. Eligible participants exhibit adequate organ and bone marrow function, with exclusion criteria including known CNS involvement of lymphoma, recent thrombosis, or intolerance to prophylactic anticoagulation.

Patients were administered L (25mg on days (d) 1-10), T (12mg/kg IV on d1, 8, and 15), R (375mg/m² IV on d1), and A (100mg PO twice/d) in a 21-day cycle. All pts undergo LTRA for 4 cycles, followed by a PET/CT scan to define complete response (CR) with a 5-point scale (ps) of 1, 2, or 3. In cohort 1, after 4 cycles of LTRA, pts with CR receive 2 cycles of CHOP, while others receive 6 cycles of CHOP. Cohort 2, upcoming in the study, plans to administer no cycles of CHOP to pts with CR after 4 cycles of LTRA.

From the analysis of Cohort 1 comprising 30 pts enrolled between May 2022 and July 2023, to be evaluable for 1A endpoint and 22 pts (73%) evaluable for endpoint 1B by the ASH meeting. The median age was 61 years (range: 32-85), with 30% aged 70 or older and 50% female. Notably, 67% exhibited poor-risk R-IPI, 77% advanced stage, and 83% elevated LDH, predominantly featuring the non-GCB subtype (83%) and 17% had the GCB subtype of DLBCL.

After 4 cycles of LTRA, the cohort demonstrated a 100% overall response rate (ORR) and a 64%  (endpoint 1A, n = 14/22 evaluable at abstract submission) complete response rate(CRR). Following 2 additional cycles of LTRA-CHOP, the ORR and CRR were 100% and 95%, respectively  (n = 18/19 evaluable at abstract submission). At the end of all therapy, the CRR reached 100% endpoint 1B, n = 12), with no cases of progressive lymphoma. To date, no patient has developed progressing lymphoma, including the first six pts who have had 3 and 6 month follow-up scans. Rash was reported in 47% of pts (13% grade 3), and 40% required L dose reduction.

The study concluded that the lenalidomide, tafasitamab, rituximab, and acalabrutinib combination proves highly effective as an initial chemotherapy-free regimen for newly diagnosed DLBCL. This approach may facilitate a response-adapted reduction in chemotherapy. Updated response and time-to-event data will be presented at the meeting. Cohort 2, set to enroll an additional 30 pts, aims to further explore the omission of CHOP cycles for those achieving early CR after 4 cycles of LTRA.

The study was sponsored by M.D. Anderson Cancer Center

Source: https://ash.confex.com/ash/2023/webprogram/Paper180381.html

Clinical Trial: https://clinicaltrials.gov/study/NCT04978584

Westin J, Steiner R E, Chihara D, et al. (2023). ” Smart Stop: Lenalidomide, Tafasitamab, Rituximab, and Acalabrutinib Alone and with Combination Chemotherapy for the Treatment of Newly Diagnosed Diffuse Large B-Cell Lymphoma.” Presented at ASH 2023 (Abstract 856).