Adding Umbralisib and Ublituximab (U2) to Ibrutinib in Patients with CLL: A Phase II Study of an MRD-Driven Approach.

Abstract

PURPOSE:

Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an "add on" approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO).

PATIENTS AND METHODS:

Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry, <1 cell in 10-4 cutoff for U-MRD). U2 was added to ibrutinib, and patients were monitored serially for MRD. Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. The primary study objective was rate of U-MRD. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation.

RESULTS:

Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7-67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%.

CONCLUSIONS:

This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up.

• Authors: Lindsey E Roeker, Tatyana A Feldman, Jacob D Soumerai, Victoria Falco, Gail Panton, Colleen Dorsey, Andrew D Zelenetz, Lorenzo Falchi, Jae H Park, David J Straus, Camila Pena Velasquez, Sonia Lebowitz, Yehudit Fox, Kristen Battiato, Carissa Laudati, Meghan C Thompson, Elizabeth McCarthy, Sabrina Kdiry, Rosalba Martignetti, Teja Turpuseema, Michelle Purdom, Dana Paskalis, Hari P Miskin, Peter Sportelli, Lori A Leslie, Anthony R Mato
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 18 Pg. 3958-3964 (09 15 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 35852793 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Heterocyclic Compounds, 4 or More Rings
• Piperidines
• ibrutinib
• umbralisib
• Adenine
• ublituximab

Topics

• Adenine (analogs & derivatives)
• Antibodies, Monoclonal
• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Heterocyclic Compounds, 4 or More Rings
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
• Neoplasm, Residual (drug therapy)
• Piperidines