Selected ASH Abstracts on Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Part 2: Relapsed or Refractory Disease

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ABSTRACT 355: MURANO study: Four-year analysis confirms sustained benefit (compared to bendamustine and rituximab; n = 195) of time-limited venetoclax/rituximab (n = 194) in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; NCT02005471)1

Methods: As previously published,2,3 patients were randomly assigned to six cycles of venetoclax/rituximab (n = 174) then venetoclax at 400 mg once daily for a total of 2 years (n = 130) or six cycles of bendamustine/rituximab. Central analysis of minimal residual disease (MRD) status in peripheral blood was performed at cycle 4, at the end of combination treatment, and then every 3 to 6 months. Patients were categorized as having protocol-defined undetectable MRD (< 1 CLL cell/10,000 leukocytes [< 104]), low MRD (≥ 104 to < 102), or high MRD (≥ 10–2).

Results: The progression-free survival benefit of venetoclax/rituximab over bendamustine/rituximab was sustained (hazard ratio [HR] = 0.19, 95% confidence interval [CI] = 0.14–0.25; P < .0001). The 4-year progression-free survival estimates were 57.3% (95% CI = 49.4%–65.3%) vs 4.6% (95% CI = 0.1%–9.2%), respectively. For the patients who completed 2 years of venetoclax (n = 130), the 18- and 24-month post-treatment cessation progression-free survival estimates were 75.5% (95% CI = 67.4%–83.7%) and 68.0% (95% CI = 57.6%–78.4%), respectively. A sustained overall survival benefit was demonstrated with venetoclax/rituximab over bendamustine/rituximab (HR = 0.41, 95% CI = 0.26–0.65; P < .0001; 4-year rate: 85.3% vs 66.8%). There were no new serious adverse events considered related to the study drug.1-3 In the venetoclax/rituximab cohort, improved progression-free survival was observed for patients who had protocol-defined undetectable MRD at the end of treatment. Among patients treated with venetoclax/rituximab who had detectable MRD in peripheral blood at the end of combination therapy, those with low (≥ 10–4 to < 10–2) MRD continued to show improved progression-free survival compared with those who had high (≥ 10–2) MRD, implying that patients who had high MRD should possibly not stop therapy.

Clinical Implications: These follow-up data provide further support for the application of time-limited venetoclax/ituximab over bendamustine/rituximab and establish the prognostic role of monitoring MRD in relapsed or refractory CLL/SLL. The precise role of MRD as a predictive marker would require further evaluation.

ABSTRACT 501: Results from a first-in-human, proof-of-concept phase I trial in pretreated B-cell malignancies for LOXO-305, a next-generation, highly selective, noncovalent Bruton’s tyrosine kinase (BTK) inhibitor (NCT03740529)4

Methods: LOXO-305 is an oral BTK inhibitor that preclinically inhibits wild-type and C481-mutated BTK. The primary endpoint was to establish the maximum tolerated dose and recommended phase II dose. The median age was 65 (range, 51–79 years), and the median number of prior therapies was 3 (range, 2–6). A total of 12 patients (8 with CLL, 4 with mantle cell lymphoma [MCL]) received prior chemotherapy plus an anti-CD20 antibody.

Results: Clinical activity was noted within the first cycle of therapy and at the first dose level of 25 mg daily. The first eight patients were evaluable for initial response, and seven tumor responses (87.5%) were observed: five of five patients with CLL and two of three patients with MCL. Two additional patients with CLL were awaiting initial radiologic assessment but had already demonstrated treatment-induced lymphocytosis. Of 13 patients, 12 remain on therapy, with the longest ongoing at 5+ months.

Clinical Implications: Phase I data with LOXO-305 demonstrate a favorable safety profile and provide proof-of-concept evidence of ef­ficacy in heavily pretreated patients with CLL/SLL (n = 9) and MCL (n = 4), including those with acquired resistance to currently U.S Food and Drug Administration–approved BTK inhibitors and venetoclax.

ABSTRACT 503: Rapid undetectable (10-4) MRD responses in patients with relapsed or refractory CLL/SLL treated with lisocabtagene maraleucel: Updated results from Transcend CLL 004, a phase I/II study including patients with high-risk disease previously treated with ibrutinib (NCT03331198)5

Methods: Eligible patients with CLL/SLL had received at least three (standard-risk disease) or at least two (high-risk disease: del[17p], TP53 mutation, unmutated IGHV, or complex karyotype) prior lines of therapy, including a BTK inhibitor unless contraindicated. After 3 days of lymphodepletion with fludarabine and cyclophosphamide, patients received lisocabtagene maraleucel; two dose levels were tested: DL1 = 50 × 106 and DL2 = 100 × 106 chimeric antigen receptor T cells. Dose-limiting toxicities were evaluated for 28 days after infusion. At data cutoff, 23 patients were evaluable for safety and 22, for efficacy.

Results: Nine patients were treated at DL1 and 14 patients, at DL2. Two patients had dose-limiting toxicities (all at DL2: grade 4 hypertension [n = 1]; grade 3 encephalopathy, grade 3 muscle weakness, and grade 4 tumor-lysis syndrome [n = 1]). The most common grade 3 and 4 treatment-emergent adverse events were cytopenias. Two patients had grade 3 cytokine-release syndrome; five patients had grade ≥ 3 neurotoxicity. The median time to onset of cytokine-release syndrome and neurotoxicity was 4 (range, 1–10) and 4 (range, 2–21) days, respectively. Lymph node tumor burden correlated with neurotoxicity (P = .025).

Among evaluable patients, the best overall response rate was 82%; the best complete response/complete response with incomplete blood cell count recovery rate was 45.5%. Of 22 patients, 15 achieved an objective response by day 30; 78% of responders (7 of 9 patients) with at least 9 months of post-infusion follow-up have remained progression-free. In six patients, responses deepened over time. Among 20 patients evaluable for MRD, most achieved blood and/or bone marrow protocol-defined undetectable MRD.

Clinical Implications: Toxicities associated with lisocabtagene maraleucel were manageable at both dose levels tested. The phase II portion of the study is currently enrolling at DL2. Objective responses, complete response, and MRD (less than 10-4) were achieved in the majority of patients, with durable responses past 6 months.  

DISCLOSURE: Dr. Abutalib has served in a consulting or advisory role board for AstraZeneca and Partner Therapeutics. Dr. Pagel has served in a consulting or advisory role for Actinium Pharmaceuticals, AstraZeneca, Gilead Sciences, and Pharmacyclics.


1. Seymour JF, Kipps TJ, Eichhorst BF, et al: Four-year analysis of MURANO study confirms sustained benefit of time-limited venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia. Blood 134(suppl 1):355, 2019.

2. 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.

3. Kater AP, Seymour JF, Hillmen P, et al: Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival. J Clin Oncol 37:269-277, 2019.

4. Mato AR, Flinn IW, Pagel JM, et al: Results from a first-in-human, proof-of-concept phase I trial in pretreated B-cell malignancies for LOXO-305, a next-generation, highly selective, non-covalent BTK inhibitor. Blood 134(suppl 1):501, 2019.

5. Siddiqi T, Soumerai JD, Dorritie KA, et al: Rapid undetectable MRD responses in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma treated with lisocabtagene maraleucel, a CD19-directed CAR T-cell product. Blood 134(suppl 1):503, 2019.

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