Combinations Produced Durable Responses in High-Risk Chronic Lymphocytic Leukemia

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Fixed-duration treatment with obinutuzumab plus venetoclax or ibrutinib can produce durable responses in patients with chronic lymphocytic leukemia (CLL) at high risk of relapse, according to a pooled analysis of phase 2 trials published in Blood.

The analysis included data from 3 multicenter, phase 2 CLL trials (ClinicalTrials.gov Identifier: NCT02345863, NCT02401503, and NCT02689141).

The trials included 51 patients with high-risk genetics — 29 with del(17p) and TP53 mutations, 20 with TP53 mutations only, and 2 with del (17p) only. Most patients also had other risk factors, such as unmutated IGHV (38 patients) or complex karyotype (23 patients).


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There were 27 patients — 15 with previously untreated CLL and 12 with relapsed/refractory CLL — who underwent debulking with up to 2 cycles of bendamustine.

All 51 patients received 6 cycles of induction — 21 patients with ibrutinib-ofatumumab, 13 with ibrutinib-obinutuzumab, and 17 with venetoclax-obinutuzumab. All but 3 patients received maintenance with their assigned combination as well.

The primary endpoint was overall response rate (ORR) at the end of induction (after 8 months of targeted treatment). The ORRs were 81% with ibrutinib-ofatumumab, 100% with ibrutinib-obinutuzumab, and 94% with venetoclax-obinutuzumab.

Minimal residual disease (MRD) was undetectable in the peripheral blood in 0% of patients treated with ibrutinib-ofatumumab, 23% treated with ibrutinib-obinutuzumab, and 82% treated with venetoclax-obinutuzumab.

There were 17 patients who stopped maintenance therapy because they achieved remission with undetectable MRD — 5 who received ibrutinib-obinutuzumab and 12 who received venetoclax-obinutuzumab.

The median progression-free survival (PFS) was 45 months for the entire cohort, and there was no difference in PFS between the treatment groups.

Among patients with MRD-guided treatment discontinuation, the median PFS was 28 months. At a median observation time of 46 months, 35% of patients (6/17) were still in remission. Nine patients had relapsed, 2 died without progressing, and 4 patients died in all.

Taking these results together, the researchers concluded that MRD-guided fixed-duration therapies combining obinutuzumab with venetoclax or ibrutinib can induce “deep and durable remissions” in patients with high-risk genetics, and these remissions can persist after treatment discontinuation.

Disclosures: This research was supported by F. Hoffmann LaRoche, Janssen-Cilag, Novartis, and AbbVie. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Cramer P, Tausch E, von Tresckow J, et al. Durable remissions following combined targeted therapy in patients with CLL harboring TP53 deletions and/or mutations. Blood. 2021;138(19):1805-1816. doi:10.1182/blood.2020010484



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