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Novel Approaches in Chronic Lymphocytic Leukemia


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To complement The ASCO Post’s continued comprehensive coverage of the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel therapeutic approaches in chronic lymphocytic leukemia (CLL). For full details of these study abstracts, visit ashpublications.org.

Syed Ali Abutalib, MD

Syed Ali Abutalib, MD

Jennifer R. Brown, MD, PhD

Jennifer R. Brown, MD, PhD

Newly Diagnosed and Relapsed or Refractory CLL/SLL

ABSTRACT 543: UNITY-CLL study—Ublituximab/umbralisib (combination referred to as U2; n = 210) is superior to obinutuzumab/chlorambucil (n = 211) in treatment-naive (n = 240) and relapsed or refractory CLL/SLL patients: Results from the phase III study (NCT02612311)1

Background: Ublituximab is a glycoengineered monoclonal antibody that targets a specific epitope on the CD20 antigen found on mature B lymphocytes. Umbralisib (800 mg once daily) is a dual inhibitor of PI3Kδ and CK1ε that exhibits improved selectivity for the delta isoform of PI3K.

Methods: The primary endpoint was independent review committee–assessed progression-free survival.

Results: At a median follow-up of 36.2 months, U2 significantly prolonged progression-free survival vs obinutuzumab/chlorambucil (median, 31.9 months vs 17.9 months; hazard ratio = 0.546, 95% CI = 0.413–0.720, P < .0001). The progression-free survival improvement was consistent across all subgroups examined including treatment-naive patients (median, 38.5 months vs 26.1 months; HR [95% CI] = 0.482 [0.316–0.736]); and relapsed or refractory patients (median, 19.5 months vs 12.9 months; HR [95% CI] = 0.601 [0.415–0.869]). Among previously treated subjects, 26 (6%) received prior ibrutinib (14 on U2, 12 on control arm), with an overall response rate of 57% with U2 vs 25% for the control. There was more regimen discontinuation with U2 (16.5%) vs the control (7.6%). Grade 3 or 4 diarrhea, transaminitis, colitis, and pneumonia were observed in 12.1%, 8.3%, 3.4%, and 2.9% of patients on U2 compared with 2.5%, 2%, 0%, and 0%, respectively, in the control arm.

Clinical Implications: The UNITY-CLL study is the first randomized phase III study in CLL of a PI3K inhibitor vs obinutuzumab/chlorambucil and the first randomized study of a PI3K inhibitor that included treatment-naive CLL. The U2 regimen exhibited a well-tolerated safety profile, albeit likely one with characteristic PI3Kδ inhibitor toxicities, and significantly improved progression-free survival vs obinutuzumab/chlorambucil in treatment-naive and relapsed or refractory CLL. The U.S. Food and Drug Administration (FDA) granted Fast Track designation to the combination of U2 for the treatment of adults with CLL. The U2 combination is also being tested with other active agents in CLL. If the combination receives FDA approval, grade 3 or 4 gastrointestinal, liver, and lung toxicities, as well as a front-line progression-free survival, which is lower than that seen with BTK inhibitors and venetoclax/obinutuzumab, will likely limit its use in the front-line setting. The most likely use of U2 will be after the other two classes, but we still lack significant data on efficacy after BTK inhibitors and/or venetoclax.

Relapsed or Refractory CLL/SLL

ABSTRACT 542: BRUIN study—LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: Results from the phase I/II study (NCT 03740529)2

Background: Despite the marked efficacy of ibrutinib, acalabrutinib, and venetoclax, treatment failure can occur through the development of resistance. In the presence of BTK cysteine binding site (C481) mutations, BTK inhibitors show reduced or no activity. Patients in whom BTK and BCL2 inhibitors fail tend to have a worse prognosis. LOXO-305 has emerged as a new hope for such heavily pretreated patients.

Methods: The aim of the BRUIN trial was to define the safety and early efficacy of LOXO-305 in a relapsed or refractory CLL/SLL cohort (n = 170) and other B-cell non-Hodgkin lymphomas (NHLs). The primary endpoint was to determine the maximum tolerated dose/recommended phase II dose. The median number of prior therapies in the CLL/SLL cohort was four. About 86% of patients had received prior BTK inhibitors, and 69% had received an anti-CD20 antibody, chemotherapy, and a BTK inhibitor. In addition, 21% had received a PI3K inhibitor and 34%, venetoclax.

Results

  • At the efficacy cutoff date, 83 of 88 responding patients (94%) remained on therapy, and 139 patients were evaluable for efficacy. The overall response rate was 63%, which deepened to 83% in patients followed for more than10 months. There were no complete remissions.
  • LOXO-305 demonstrated high oral exposures, with doses of at least 100 mg daily exceeding the BTK IC90 for the entirety of the dosing interval.
  • There were no dose-limiting toxicity or dose reductions. However, the treatment-emergent adverse events regardless of attribution or grade seen in at least 10% of patients (n = 323 included B-cell NHL cohort as well) were fatigue (n = 65, 20%) and diarrhea (n = 55, 17%).

Clinical Implications: LOXO-305 demonstrated promising efficacy in heavily pretreated, poor-prognosis patients with CLL/SLL following multiple prior lines of therapy including a covalent BTK inhibitor and a BCL2 inhibitor, with manageable and minimal adverse event(s). Follow-up remains short, but the activity of LOXO-305 was not restricted to subjects with BTK C481 mutations. A recommended phase II dose of 200 mg daily was selected for future studies, which have initiated. It is important to remember that patients with CLL that has progressed after both BTK and BCL2 inhibitors have a very poor prognosis and need to be considered for chimeric antigen receptor T-cell options, and/or allogeneic transplant, which remains the only curative therapy for these patients.

ABSTRACT 125: MURANO study: 5-year analysis demonstrates enduring undetectable MRD (defined as < 10-4 threshold) in a subset of patients with relapsed or refractory CLL/SLL following fixed-duration (24 months) venetoclax/rituximab (n = 194) compared with bendamustine/rituximab (n = 195) for six cycles (NCT02005471)3

Background: In the previously reported data,4 the 2-year rates of progression-free survival were 84.9% vs 36.3% (HR for disease progression or death = 0.17; 95% confidence interval [CI] = 0.11–0.25; P < .001 by the stratified log-rank test) in patients on venetoclax/rituximab and bendamustine/rituximab, respectively. The rate of clearance of minimal residual disease on the basis of peripheral blood samples was higher with venetoclax/rituximab than bendamustine/rituximab (121 of 194 patients [62.4%] vs 26 of 195 patients [13.3%]). The rate of overall survival was higher with venetoclax/rituximab than bendamustine/rituximab, with 24-month rates of 91.9% and 86.6%, respectively (hazard ratio = 0.48; 95% CI = 0.25–0.90).

Methods: The primary endpoint was investigator-assessed progression-free survival. Subjects were randomly assigned to venetoclax (400 mg daily for 2 years) plus rituximab (with first 6 months) or bendamustine (70 mg/m2) plus rituximab for 6 months. Peripheral blood MRD was analyzed centrally by allele-specific oligonucleotide polymerase chain reaction and/or flow cytometry. MRD conversion was defined as two consecutive assays detecting MRD or progressive disease (not conversion to detectable MRD) in patients who previously had undetectable MRD.

Results

  • Median progression-free survival was 53.6 months (95% CI = 48.4–57.0 months) with venetoclax/rituximab and 17.0 months (95% CI = 15.5–21.7 months) with bendamustine/rituximab.
  • The 5-year overall survival estimates were 82.1% (95% CI = 76.4%–87.8%) with venetoclax/rituximab and 62.2% (95% CI = 54.8%–69.6%) with bendamustine/rituximab.
  • Improved progression-free survival was observed among the patients given venetoclax/rituximab who reached the end of therapy without progressive disease and had undetectable MRD (83 of 118). There was a trend toward a difference in overall survival, with 3-year post–end of therapy estimates of 95.3% (95% CI = 90.0%–100.0%) vs 85.0% (95% CI = 72.8%–97.2%), respectively.
  • Of the 47 of 83 subjects with confirmed MRD positivity conversion, 19 subsequently developed progressive disease by International Workshop on CLL criteria, with a median time to progressive disease from MRD positivity conversion of 25.2 months (95% CI = 19.4–30.4 months).

Clinical Implications: The 5-year data from MURANO continue to demonstrate sustained progression-free survival and overall survival benefit with venetoclax/rituximab over bendamustine/rituximab in relapsed or refractory CLL/SLL. The benefit was maintained across all clinical and biologic subgroups. In addition, with focus on the venetoclax/rituximab cohort, undetectable MRD at the end of therapy was associated with improved progression-free survival, with a trend toward improved overall survival. In the venetoclax/rituximab cohort, unmutated IGHV, del(17p), and complex genotype (at least three cytogenetic abnormalities) were associated with higher rates of MRD positivity conversion and subsequent progressive disease after attaining undetectable MRD at the end of therapy, suggesting these patients are at higher risk of earlier disease progression after discontinuing therapy. Nonetheless, for many of these patients, this 2-year time-limited regimen provides an effective treatment option. It is important to remember that the regimen is planned for 2 years regardless of MRD level, and undetectable MRD at the end of therapy does not equate to cure (but “treatment-free interval”). As yet, there is no clinical role for serial MRD monitoring

Dr. Abutalib is Associate Director of the Hematology and BMT/Cellular Therapy Programs and Director of the Clinical Apheresis Program at Cancer Treatment Centers of America, Zion, Illinois; Associate Professor at the Rosalind Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy. Dr. Brown is Professor at Harvard Medical School, Director of the Chronic Lymphocytic Leukemia Center, and Institute Physician at Dana-Farber Cancer Institute.

DISCLOSURE: Dr. Abutalib has served on an advisory board for AstraZeneca. Dr. Brown has served as a consultant for AbbVie, Acerta, AstraZeneca, BeiGene, Catapult, Dynamo Therapeutics, Eli Lilly, Juno/Celgene/Bristol Myers Squibb, Kite, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Rigel, Sunesis, TG Therapeutics, and Verastem; received research funding from Gilead, Loxo, Sun, TG Therapeutics, and Verastem; and served on data safety monitoring committees for Invectys.

REFERENCES

1. Gribben JG, Jurczak W, Jacobs R, et al: Umbralisib plus ublituximab is superior to obinutuzumab plus chlorambucil in patients with treatment naive and relapsed/refractory chronic lymphocytic leukemia: Results from the phase 3 Unity-CLL study. 2020 ASH Annual Meeting & Exposition. Abstract 543. Presented December 7, 2020.

2. Mato AR, Pagel JM, Coombs CC, et al: LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: Results from the phase 1/2 BRUIN study. 2020 ASH Annual Meeting & Exposition. Abstract 542. presented December 7, 2020.

3. Kater AP, Kipps TJ, Eichhorst B, et al: Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease in a subset of relapsed/refractory chronic lymphocytic leukemia patients following fixed-duration venetoclax-rituximab therapy. 2020 ASH Annual Meeting & Exposition. Abstract 125. Presented December 5, 2020.

4. Seymour JF, Kipps TJ, Eichhorst B, et al: Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 378:1107-1120, 2018.


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