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

As a continuous therapy, ibrutinib has improved progression-free (PFS) and overall survival (OS) when compared with standard of care treatment options for chronic lymphocytic leukemia (CLL) in both the front-line and relapsed/refractory (R/R) settings (1–3). Although effective as approved, ibrutinib is administered as a continuous therapy with a treat-to-progression strategy, and the use of ibrutinib is limited by intolerance and resistance (4, 5). With 7 years of follow-up of the RESONATE-2 study, which examined the use of ibrutinib compared with chlorambucil in the front-line setting, 53% of patients have discontinued ibrutinib, with 23% discontinuing for toxicity (6). For those who remain on drug, continuous drug exposure exerts selective pressure with potential for development of resistance mutations in BTKC481 and PLCG2 (7, 8). Although continuous ibrutinib monotherapy is an excellent choice for many patients with CLL, there may be a subset of patients interested in a time-limited approach. Further, we hypothesize that time-limited ibrutinib-based therapy may curb development of toxicity and resistance.

The combination of ibrutinib and venetoclax has been studied as a time-limited therapy with excellent outcomes. In the CAPTIVATE study, 75% of patients treated with ibrutinib and venetoclax in the front-line setting achieved U-MRD in the peripheral blood. For those who received this combination as a 15 cycle fixed duration therapy, PFS at 2 years remains excellent at 95% (9, 10). Similar results with the combination of ibrutinib and venetoclax were achieved in the R/R setting (11, 12). Although outcomes are excellent, any strategy where all patients are treated uniformly with multiple targeted agents in combination may overtreat a proportion of patients who would do well with sequential monotherapies or with currently approved time-limited options (venetoclax/obinutuzumab). Further, data regarding efficacy of subsequent therapies if both a Bruton tyrosine kinase inhibitor (BTKi) and venetoclax are used in combination are limited and outcomes for patients who have progressed through both BTKi and venetoclax are poor (13, 14). A triplet combination that does not include venetoclax leaves open the possibility of venetoclax for treatment at the time of subsequent disease relapse. Of note, venetoclax containing regimens also require 5-week dose escalations for venetoclax due to the risk of tumor lysis syndrome, which can be cumbersome in clinical practice for both patients and providers.

Umbralisib is a dual PI3K delta (PI3Kδ) and CK1ε inhibitor. Ublituximab is a glycoengineered anti-CD20 mAb. The combination of umbralisib and ublituximab (U2) has been studied in front-line and R/R CLL with a 24-month PFS rate of 77% in the treatment-naïve setting and 41% in the R/R setting (15). Because of its specificity for the delta isoform, many of the PI3K inhibitor autoimmune toxicities associated with this class of agents are observed less frequently with umbralisib. Further, it is hypothesized the CK1e inhibition ameliorates immune-mediated toxicities caused by PI3K inhibition by stimulating regulatory T-cell production via the T-cell transcription factor (TCF-1) and forkhead box P3 (FoxP3) pathway. The most common grade ≥3 adverse events (AE) with U2 included neutropenia (24% in treatment naïve, 40% in R/R), diarrhea (14% in treatment naïve, 10% in R/R), ALT/AST increase (12/8% in treatment naïve, 3/2% in R/R). Colitis and pneumonitis were rare.

Undetectable MRD (U-MRD) with ibrutinib monotherapy is a relatively rare event with trial data demonstrating that only 10.2% of patients have U-MRD in the peripheral blood after 4 years on therapy (16). For ibrutinib-treated patients with CLL with response but persistent MRD, an “add on” approach was designed to increase depth of response with the goal to convert a treat-to-progression continuous therapy to a time-limited one. In this study, we added U2 to ibrutinib in patients with CLL who had detectable MRD and continued triplet therapy until the earlier of achievement of U-MRD or 24 cycles of treatment, and then had patients discontinue therapy and enter a period of treatment-free observation (TFO).

This phase II study included patients with CLL receiving standard of care ibrutinib, acalabrutinib, or venetoclax across three centers in the United States. In this report, we focus on the ibrutinib-treated cohort of patients. The protocol was reviewed and approved by the Institutional Review Board at each center, all patients gave written informed consent, and the study was conducted in accordance with the Declaration of Helsinki. This study is registered at www.clinicaltrials.gov as NCT04016805. Data cutoff for this report is November 12, 2021.

Patients with CLL were eligible if they had received ibrutinib as a monotherapy or in combination with an anti-CD20 mAb in any line of therapy for at least 6 months, had detectable MRD by central laboratory assessment, and were without evidence of progression. Other key eligibility criteria included adequate organ function and ECOG performance status ≤2. Patients with a history of Richter's transformation and/or active infections were excluded from this study.

Following screening, the U2 regimen [umbralisib 800 mg oral every day and ublituximab 900 mg i.v. on days 1/2 (split dose), 8 and 15 of cycle 1, day 1 of cycles 2–6, and then day 1 of every 3 cycles] was added to ibrutinib. MRD assessments were performed on peripheral blood starting on cycle 3 day 1 and every three cycles thereafter for a maximum of 24 cycles. MRD was assessed in a central laboratory using flow cytometry with a cutoff for U-MRD defined as less than one CLL cell per 10,000 leukocytes (10^–4; refs. 17, 18). Once U-MRD was achieved in the peripheral blood, a confirmatory MRD test was performed at least 28 days later. For patients in whom U-MRD was confirmed, patients completed their current cycle of therapy and then entered a period of TFO. Patients could receive a maximum of 24 cycles of triple therapy and then entered TFO, regardless of MRD status. Patients who experienced toxicity requiring drug discontinuation also entered TFO.

While in TFO, patients were monitored with clinical exam and laboratory analyses, and MRD was assessed in the peripheral blood every 12 weeks up to cycle 24 followed by every 24 weeks. Patients in TFO for a minimum of 6 months and experiencing disease progression according to iwCLL criteria (19) were eligible to be retreated with the same combination of ibrutinib, umbralisib, and ublituximab until achieving U-MRD or for a maximum of 24 cycles. Mutational analysis was performed at baseline is planned at time of progression for those retreated per protocol. Patients who experienced progression within 6 months of entering TFO and who had emergence of detectable MRD but did not meet formal iwCLL criteria for disease progression were not eligible for retreatment per protocol.

The primary endpoint for this study was rate of U-MRD for patients receiving triple therapy at any timepoint while on therapy. A rate of MRD eradication of 25% was considered promising. Overall U-MRD rate was defined as the proportion of patients with detectable MRD at baseline who converted to U-MRD in the peripheral blood on two sequential peripheral blood studies at least 4 weeks apart at any time during treatment on protocol. The target sample size was 28 patients to provide an 80% confidence interval with an approximate width of 20% to assess the primary endpoint. Key secondary endpoints included safety of this triple combination, time to achieving U-MRD, PFS, time to progression, OS, and response to retreatment per protocol. Safety analyses are descriptive and graded using the NCI Common Terminology Criteria for Adverse Events version 5.0. Time to achieving U-MRD, PFS, time to progression, and OS were estimated by the Kaplan–Meier method (20). Statistical analyses were performed using SAS version 9.2.

Data generated from this study are available upon request from the study sponsor TG Therapeutics, Inc. (H.P. Miskin).

Twenty-eight patients were enrolled in the ibrutinib cohort of this study between September 25, 2019, and July 29, 2021. All patients were evaluable for safety with a cutoff date of November 2, 2021. Twenty-seven patients were evaluable for efficacy endpoints. See Supplementary Fig. S1 for details regarding patient disposition. The median age of the study cohort was 64 years (range, 48–81). Most patients were male (79%; 22/28) and had excellent performance status with ECOG 0 for 93% (26/28) and ECOG 1 for 7% (2/28). Baseline disease characteristics included IGHV unmutated in 67% (18/27), deletion of chromosome 11q in 21% (6/28), and deletion of chromosome 17p in 7% (2/28). Baseline characteristics are included in Table 1.

Sixty-eight percent (19/28) of patients were receiving ibrutinib as their front-line of therapy, whereas 32% (9/28) were receiving ibrutinib in the relapsed/refractory setting. Ibrutinib was given in combination with an anti-CD20 mAb for 3 patients (16%) in the front-line and 4 patients (44%) with relapsed/refractory disease. For the 9 patients who had received ibrutinib in the R/R setting, the median number of lines of therapy prior to ibrutinib was one (range, 1–2) and all had previously received chemoimmunotherapy. All patients had achieved partial response on ibrutinib (100%) prior to enrollment. The median time on ibrutinib prior to enrollment was 21 months (range, 7–67 months).

Table 2 describes all treatment emergent AEs, regardless of causality, that occurred in ≥10% of the study population. In the safety cohort (n = 28), the observed grade 3/4 AEs included hypertension (7%), diarrhea (4%), increased ALT/AST (4%), and COVID-19 infection (4%). Any grade AEs of special interest were rare, specifically colitis in 4%, pneumonitis in 0%, and increased ALT/AST in 14%. Nine patients experienced any infection while on study of which three were Grade 3. No Grade 4 or 5 infections were observed. Two patients discontinued study treatment due to a treatment emergent AE, of which one patient experienced a grade 2 rash and another experienced grade 3 rash and grade 1 arthralgias. Both patients had U-MRD at the time of treatment discontinuation and AEs resolved with drug discontinuation and supportive care. One patient died due to COVID-19–related complications 103 days after discontinuing study therapy and was not included in subsequent efficacy evaluations as MRD assessments were not performed.

At a median of 14 months of follow up, 52% (14/27) of patients achieved confirmed U-MRD per protocol (two peripheral blood assessments at least 4 weeks apart) while on triple therapy. U-MRD was achieved at least once for 78% (21/27) of patients in this study. The median time to achieving U-MRD was 7.4 months (95% CI, 4.6–10.2). Seventeen of 27 (63%) patients have entered TFO after a median of 6.4 months of triple therapy. At the time of data analysis, 9 patients remain on triple therapy with the potential of achieving U-MRD.

Figure 1 describes the patient experience on study, including time on triple therapy with detectable MRD, time on therapy with U-MRD between sequential assessments, and time in TFO. Figure 2 depicts time on ibrutinib, either in the front-line or R/R setting, prior to study enrollment, as well as time on triple therapy on protocol.

For patients who have entered TFO (n = 17), the median time off therapy is 11 months (339 days) and 6 patients have been in TFO for at least 1 year. In TFO, the median time to recurrence of detectable MRD is 6 months (189 days). Nine of 17 patients (53%) in TFO have maintained U-MRD. MRD kinetics during treatment and TFO are depicted in Fig. 3.

One patient in TFO had quickly recurrent symptoms and required retreatment. As this progression event occurred within 6 months of treatment discontinuation, this patient was not eligible for retreatment per protocol and MRD was not evaluated. However, this patient restarted ibrutinib monotherapy and recaptured a response within one cycle. Notably, patients who have developed detectable MRD during the follow up period have not clinically progressed and have not required therapy per iwCLL guidelines.

Figure 4 demonstrates PFS from time of study entry and time of TFO for the entire study cohort.

Novel agent combination therapy is undoubtably effective in the management of CLL, although the optimal use of novel agent combinations remains an area of active investigation. In this study, we aimed to identify ibrutinib-treated patients with CLL with detectable MRD who were interested in converting their treat-to-progression therapy into a time limited therapy. Using this approach, we explored the ability to convert a continuous therapy into a time limited one with the addition of two novel agents (U2) to ibrutinib. Notably, this combination did not include venetoclax, adding to ease of use in clinical practice without required and TLS monitoring during dose escalation. Importantly, this “venetoclax-sparing” triplet strategy distinguishes itself from other triplets being tested for the treatment of CLL and reserves the use of venetoclax for subsequent lines of therapy.

The triplet combination of ibrutinib, umbralisib, and ublituximab was well tolerated. Grade ≥3 AEs were rare, and the most common low grade AEs included diarrhea, hypertension, anemia, contusion, and fatigue. Only two patients required drug discontinuation for toxicity, both with rash and one with additional arthralgias. Of note, both patients had U-MRD at the time of this toxicity and subsequently experienced a durable TFO. PI3Ki-associated autoimmune-related AEs were rare with one grade 2 colitis event (4%), no observed pneumonitis, and 14% transaminitis (4% grade ≥3 transaminitis). Overall, the toxicity profile of this triplet combination did not appear to differ significantly from that of ibrutinib monotherapy. This is consistent with a previous study of ibrutinib and umbralisib in patients with CLL and MCL, which demonstrated that this combination is generally well tolerated (21). Notably, however, 9 patients remained on treatment at that time of this data cut and will continue to be followed for new safety events, which may accumulate with time.

Efficacy results were promising with 52% of evaluable patients achieving U-MRD confirmed at two sequential time points on triplet therapy per protocol at a median of 6.4 months of triplet therapy. Further, 78% of evaluable patients achieved U-MRD at any time during the study. In the phase III iLLUMINATE study, which compared ibrutinib and obinutuzumab with chlorambucil and obinutuzumab, 30% of patients treated with ibrutinib and obinutuzumab achieved U-MRD in the peripheral blood as best MRD response (22). In the GENUINE study, U-MRD was achieved in the peripheral blood for 42% of patients treated with ibrutinib and ublituximab (23). Although limited by cross-trial comparison, we conclude that the addition of the PI3Ki umbralisib does appear to contribute to efficacy beyond what has been observed with doublet ibrutinib and CD20 mAb.

Utilizing MRD status as the endpoint for therapy in this study demonstrates the potential for tailored time-limited therapy and individualized treatment programs in CLL. Allowing deep responses without excess drug exposure may allow patients to minimize cumulative toxicity and decrease the development of resistance. MRD-guided approaches are being explored with other combination therapies, including ibrutinib/venetoclax (24), ibrutinib/rituximab (25), venetoclax/obinutuzumab (NCT04447768), acalabrutinib/venetoclax/obinutuzumab (26), and zanubrutinib/venetoclax (27) ± obinutuzumab (28). However, an “add on” MRD-guided strategy is unique to this trial and a phase II study of venetoclax added to ibrutinib (29).

This study solely relied on peripheral blood MRD status rather than bone marrow evaluation. This intentional decision was made to provide a patient-centric approach with avoidance of procedures and associated morbidity. The utility of peripheral blood MRD assessment, especially in regimens containing anti-CD20 mAb, remains a topic of study. Reassuringly, utilizing this endpoint did allow for successful discontinuation for most patients included in this study.

Seventeen patients have entered TFO with a median time of treatment observation of 11 months as of this data cut. PFS at 12 months following discontinuation of all therapy was excellent and estimated to be 95%. While in TFO, 9 remain with U-MRD. For those who have developed detectable MRD, median time to MRD conversion was 6 months. Despite MRD conversion, none of these patients have required retreatment suggesting a prolonged interval between MRD conversion and true iwCLL progression.

Per protocol, patients who have had at least 6 months of TFO will be eligible for retreatment with the same triple combination therapy. If this approach proves to be successful, patients may be able to achieve disease control with the same regimen over multiple lines of therapy, thus saving additional effective novel agents, specifically venetoclax, for future lines of therapy.

Novel agent combination therapy likely represents the future of CLL-directed therapy for a subset of patients. However, for whom combination therapy is superior to single agents and the optimal combination of agents remain incompletely understood. Through this study design, we selected patients who had a prolonged “lead in” period of monotherapy to assess response and tolerance. We then utilized a combination of BTKi with PI3Ki and anti-CD20 mAb. These study suggest that this combination of a Pi3Ki, BTKi, and anti-CD20 antibody can be very effective in inducing U-MRD without the need for a venetoclax-based backbone and may allow for use of venetoclax in future lines of therapy.

Notably, U2 is no longer being developed in CLL or other B-cell malignancies. While this particular combination will not be investigated further, this study suggests that an “add on” approach to combination therapy may allow patients to safely and effectively discontinued planned continuous BTKi therapy. Future studies of combination therapy are needed to further explore this strategy, and this study drives the hypothesis that combination therapies need not depend on venetoclax, adding to ease of use in clinical practice given lack of requirement for dose ramp-up.

As CLL continues to be a chronic disease requiring treatment with multiple lines of therapy over time, consideration for effective subsequent lines remains within our patients’ best interest. Through this strategy, we introduce a novel agent combination therapy that effectively induces deep responses and allows for TFO following a biology-driven, time-limited triplet exposure. This study has limitations. As a single arm study, we do not have a comparative continuous strategy or to other time-limited approaches. Second the study included a small number of patients, and utility in a broader patient population remains unclear. Finally, patients have not yet required retreatment per protocol, so the utility of this strategy is unexplored. However, these hypothesis generating data suggest that continuous therapy may be converted to time limited therapy using an “add on” strategy.

L.E. Roeker reports personal fees from AbbVie, Ascentage, AstraZeneca, Beigene, Janssen, Pharmacyclics, TG Therapeutics, DAVA, Curio, and Medscape; grants and personal fees from Loxo Oncology and Pfizer; other support from Abbott Laboratories; and grants from Aptose Bioscience outside the submitted work. T.A. Feldman reports sponsorship by TG therapeutics. J.D. Soumerai reports personal fees and other support from TG Therapeutics during the conduct of the study; other support from Adaptive Biotechnologies, Beigene, BostonGene, Genentech/Roche, GlaxoSmithKline, MEI, and Moderna; and personal fees from AbbVie, AstraZeneca, Beigene, Biogen, Bristol Myers Squibb, and Roche outside the submitted work. A.D. Zelenetz reports other support from TG Therapeutics during the conduct of the study; personal fees from Genentech/Roche, Gilead/Kite, MorphoSys, AbbVie, Novartis, BMS/Celgene/JUNO, Mei Pharma, Beigene, Janssen, and AstraZeneca; and non-financial support from Adaptive Biotechnology outside the submitted work. L. Falchi reports other support from TG Therapeutics during the conduct of the study; personal fees from Genmab, AbbVie, and Roche/Genentech; and other support from ADC Therapeutics outside the submitted work. J.H. Park reports personal fees from Allogene, Servier, Minerva, Autolus, Amgen, Affyimmune, Kite Pharma, Pfizer, Curocel, BMS, Artiva, Umoja, Kura Oncology, Novartis, Intellia, Innate Pharma, and PrecisionBio outside the submitted work. D.J. Straus reports personal fees from Seagen during the conduct of the study. K. Battiato reports personal fees from AbbVie and BeiGene outside the submitted work. C. Laudati reports personal fees from TG Therapeutics outside the submitted work. M.C. Thompson reports other support from MJH Life Sciences, Curio Science, VJHemOnc, Brazilian Association of Hematology and Hemotherapy (ABHH), and Massachusetts Medical Society; and grants from The Lymphoma Foundation outside the submitted work. T. Turpuseema reports personal fees from TG Therapeutics, Inc. during the conduct of the study. M. Purdom reports other support from TG Therapeutics outside the submitted work. D. Paskalis reports other support from TG Therapeutics outside the submitted work. H.P. Miskin reports other support from TG Therapeutics, Inc. during the conduct of the study and other support from TG Therapeutics, Inc. outside the submitted work. P. Sportelli reports other support from TG Therapeutics, Inc. during the conduct of the study and other support from TG Therapeutics, Inc. outside the submitted work. L.A. Leslie reports personal fees from Kite, Beigene, Pharmacyclics, Janssen, AstraZeneca, AbbVie, Epizyme, Karyopharm, TG Therapeutics, Celgene/BMS, Merck, and Seagen outside the submitted work. A.R. Mato reports grants, personal fees, and other support from TG Therapeutics; grants and personal fees from PCYC, AbbVie, Genentech, Eli Lilly, Beigene, and Nurix; and grants from DTRM, Janssen, Octopharma, and Genmab during the conduct of the study. No disclosures were reported by the other authors.

L.E. Roeker: Writing–original draft. T.A. Feldman: Writing–review and editing. J.D. Soumerai: Writing–review and editing. V. Falco: Writing–review and editing. G. Panton: Writing–review and editing. C. Dorsey: Writing–original draft, writing–review and editing. A.D. Zelenetz: Writing–review and editing. L. Falchi: Writing–review and editing. J.H. Park: Writing–review and editing. D.J. Straus: Writing–review and editing. C.P. Velasquez: Writing–review and editing. S. Lebowitz: Writing–review and editing. Y. Fox: Writing–review and editing. K. Battiato: Writing–review and editing. C. Laudati: Writing–review and editing. M.C. Thompson: Writing–review and editing. E. McCarthy: Writing–review and editing. S. Kdiry: Writing–review and editing. R. Martignetti: Writing–review and editing. T. Turpuseema: Writing–review and editing. M. Purdom: Writing–review and editing. D. Paskalis: Writing–review and editing. H.P. Miskin: Writing–review and editing. P. Sportelli: Writing–review and editing. L.A. Leslie: Writing–review and editing. A.R. Mato: Conceptualization, writing–review and editing.

The authors would like to thank all participating patients, their families, and caregivers for their participation in this study. We would also like to thank Sarah Yukelis, Tenzin Nyima, and Monica Shah for their support of this study. This sponsored study was funded by TG Therapeutics. This work was supported in part by NIH/NCI Cancer Center support Grant No. P30 CA008748 and Program Project Grant No. P01 CA023766.

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