Clinical Summary:

• Design/Population: This investigator-initiated phase 2 trial evaluated pirtobrutinib plus venetoclax and obinutuzumab in treatment-naïve patients with chronic lymphocytic leukemia (CLL), including patients with high-risk molecular features. Obinutuzumab was administered for 6 cycles, while pirtobrutinib and venetoclax continued through cycle 13.
• Key Outcomes: Undetectable measurable residual disease (MRD) rates deepened during reatment in both bone marrow and peripheral blood. No patient experienced observed CLL progression, and MRD recurrence after protocol-defined treatment completion was uncommon during follow up. 
• Clinical Relevance: These findings support further evaluation of a fixed-duration frontline strategy combining BTK inhibition with BCL2 and CD20 targeting, with the potential to achieve deep remissions while allowing patients to discontinue therapy. 

Results from the phase 2 PIVOT-CLL trial demonstrated that pirtobrutinib plus venetoclax and obinutuzumab produced high rates of deep undetectable measurable residual disease (MRD) remission among patients with previously untreated chronic lymphocytic leukemia (CLL). 

These results were presented by Nitin Jain, MD, MD Anderson Cancer Center, Houston, Texas, at the Society of Hematological Oncology (SOHO) Annual Meeting in Houston, Texas.

In this investigator-initiated trial, 80 treatment-naïve patients initiated pirtobrutinib and obinutuzumab during cycle 1, followed by standard venetoclax ramp-up beginning in cycle 2. Obinutuzumab was administered for 6 cycles, while pirtobrutinib and venetoclax continued through cycle 13. 

Response assessments according to 2018 International Workshop on CLL criteria were performed after cycles 7 and 13. MRD was assessed by next-generation sequencing in both peripheral blood and bone marrow.

Patients with detectable MRD at a sensitivity of at least 10^-5 at the end of cycle 13 were eligible to continue pirtobrutinib and venetoclax for an additional 12 cycles. After completing therapy, all patients underwent continued peripheral blood MRD monitoring by next-generation sequencing. 

Three patients discontinued the trial early, including 1 patient who required treatment for newly diagnosed head and neck cancer during and 2 patients who discontinued due to travel logistics or insurance denial. The remaining 77 patients continued on study. 

At a median follow-up of 28.2 months,deep MRD responses increased over the course of therapy. Bone marrow undetectable MRD at 10^-6 sensitivity was achieved by 61% of patients after cycle 7 and 74% of patients after cycle 13. Corresponding peripheral blood undetectable MRD6 rates were 75% and 86%, respectively. 

No patients experienced disease progression during follow up. The 2-year progression-free survival (PFS) and overall survival (OS) rates were both 98.6%.

Among 66 patients who completed treatment per protocol at the end of cycle 13, responses were largely sustained after treatment discontinuation. At a median follow-up of 16.6 months after treatment discontinuation, only 1 patient experienced MRD4 recurrence, defined as MRD of at least 0.01% in peripheral blood on 2 consecutive assessments. 

Grade 3/4 neutropenia occurred in 67% of patients, and grade 3/4 thrombocytopenia occurred in 19% of patients. One patient died from infectious complications after completing therapy.

The findings demonstrate that a frontline regimen combining noncovalent BTK inhibition with BCL2 inhibition and CD20-directed therapy can produce deep molecular remissions with a time-limited treatment approach. The persistence of MRD negativity after therapy discontinuation is particularly notable, although longer follow-up will be required to determine the durability of treatment-free remissions.

Source:

Jain N, Ferrajoli A, Swaminathan M, et al. CLL-1265: Pirtobrutinib, venetoclax, and obinutuzumab treatment in first-line CLL (PIVOT-CLL). Presented at the SOHO Annual Meeting; September 9-12, 2026; Houston, Texas. Abstract MDS-812.