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Clinical Trial
. 2022 Sep 15;28(18):3958-3964.
doi: 10.1158/1078-0432.CCR-22-0964.

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

Lindsey E Roeker  1 , Tatyana A Feldman  2 , Jacob D Soumerai  3 , Victoria Falco  1 , Gail Panton  1 , Colleen Dorsey  1 , Andrew D Zelenetz  1 , Lorenzo Falchi  1 , Jae H Park  1 , David J Straus  1 , Camila Pena Velasquez  1 , Sonia Lebowitz  1 , Yehudit Fox  1 , Kristen Battiato  1 , Carissa Laudati  1 , Meghan C Thompson  1 , Elizabeth McCarthy  2 , Sabrina Kdiry  2 , Rosalba Martignetti  3 , Teja Turpuseema  4 , Michelle Purdom  4 , Dana Paskalis  4 , Hari P Miskin  4 , Peter Sportelli  4 , Lori A Leslie #  2 , Anthony R Mato #  1
Affiliations
Clinical Trial

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

Lindsey E Roeker et al. Clin Cancer Res. .

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.

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Conflict of interest statement

Disclosure of Conflicts of Interest

LER has served as a consultant for AbbVie, Ascentage, AstraZeneca, Beigene, Janssen, Loxo Oncology, Nurix, Pharmacyclics, Pfizer, TG Therapeutics, served as a CME speaker for DAVA, Curio, and Medscape, holds minority ownership interest in Abbott Laboratories, received travel support from LOXO oncology, and has received research funding (paid to the institution) from Pfizer, Loxo Oncology, and Aptose Biosciences. LAL has served as an advisory board or panel participant, on speaker’s bureau and/or as a consultant for AbbVie, AstraZenca, BeiGene, Celgene/Bristol Myers Squibb, Epizyme, Karyopharm, Janssen, Kite/Gilead Sciences, Merck, Pharmacyclics, Seagen, TG Therapeutics. JDS has received consulting fees from Abbvie, AstraZeneca, Beigene, Biogen, Bristol Myers Squibb, Roche, TG Therapeutics, and Verastem, and research funding from Adaptive Biotechnologies, Beigene, BostonGene, Genentech/Roche, GlaxoSmithKline, MEI Pharma, Moderna, and TG Therapeutics. TAF served on speaker’s bureau for AbbVie, BMS, Celgene, Janssen Biotech, Pharmacyclics, Seattle Genetics, Takeda, and has served as a consultant for AbbVie, ADC Therapeutics, Astrazeneca, Daiichi Sakyo, Genmab, Karyopharm, KITE, MorphoSys. ADZ has served as a consultant for Genentech/Roche, Gilead, BMS/Celgene/JUNO, Janssen, Novartis, Adaptive Biotechnology, MorphoSys, Abbvie, AstraZeneca, MEI Pharma, BeiGene, received research funding from MEI Pharmaceuticals, Genentech/Roche, and Beigene, and was a DMC member for BMS/Celgene/Juno. LF has served as a consultant for Roche-Genentech, Genmab, AbbVie and ADC therapeutics, and has received research funding from Roche-Genentech and Genmab. JHP received advisory or consulting fees from Allogene, Amgen, Artiva, Autolus, BMS, Curocel, Incyte, InnatePharma, Kite Pharma, Kura Oncology, Minerva, Novartis, Pfizer, PrecisionBio, Servier and serves on a data monitoring committee for Affyimmune, BrightPharma, and Intellia. KB has served as a consultant for AbbVie. MCT has received honorarium from: MJH Life Sciences, Curio Science, VJHemOnc, Brazilian Association of Hematology and Hemotherapy (ABHH) and Massachusetts Medical Society. TT, MP, DP, HPM, PS are employed by TG therapeutics. ARM has served as a consultant for AbbVie, AstraZeneca, Beigene, Bristol Myers Squibb Company, Celgene, Genentech, Loxo Oncology, Octapharma, Pharmacyclics, Pfizer, TG Therapeutics, served as a CME speaker for DAVA, Curio, and Medscape, is a member of the medical advisory board for CLL Society and a scientific advisor for Lymphoma Research Foundation. All other authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Swimmer’s plot depicting time on study, specifically time on triple therapy with detectable MRD, time on therapy with U-MRD between sequential assessments, and time in treatment free observation.
Figure 2.
Figure 2.
Swimmer’s plot depicting time on ibrutinib prior to study enrollment and time on study with specification of which patients have achieved U-MRD vs. remain with MRD detectable disease.
Figure 3.
Figure 3.
Absolute MRD levels over time. Solid lines depict time on treatment while dotted lines depict those in treatment free observation. Per protocol, U-MRD is defined as a sensitivity of 10−4.
Figure 4.
Figure 4.
Progression free survival (PFS) (A) from time of study entry and (B) from entering treatment free observation. One progression event has been observed on study, and landmark 12-month PFS from treatment discontinuation is estimated to be 95%.
See this image and copyright information in PMC

References

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