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Selected ASH Abstracts on Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Part 1: Newly Diagnosed Disease


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To complement The ASCO Post’s continued comprehensive coverage of the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel therapies for newly diagnosed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Part 2 of this article (on page 68) includes selected ASH abstracts on new treatments under study in relapsed or refractory CLL and SLL. For full details of these study abstracts, visit ashpublications.org.

ABSTRACT 31: ELEVATE TN: Phase III study of the Bruton’s tyrosine kinase inhibitor acalabrutinib combined with obinutuzumab (n = 179) or alone (n = 179) vs obinutuzumab plus chlorambucil (n = 177) in patients with treatment-naive CLL/SLL and coexisting conditions (Cumulative Illness Rating Scale score > 6, creatinine clearance < 70 mL/min; ClinicalTrials.gov identifier NCT02475681)1

“Perhaps the most important part of this study is the continued apparent favorable toxicity profile of acalabrutinib.”
— Syed Ali Abutalib, MD, and John M. Pagel, MD, PhD

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Methods: The primary endpoint was progression-free survival with acalabrutinib (given until progressive disease) plus obinutuzumab (given for 6 cycles) vs obinutuzumab (given for 6 cycles) plus chlorambucil (given for 6 cycles). Key secondary endpoints included progression-free survival with single-agent acalabrutinib vs obinutuzumab plus chlorambucil, independent review committee–assessed overall response rate, overall survival, and safety. Crossover to acalabrutinib monotherapy was allowed for patients in the obinutuzumab-plus-chlorambucil arm with independent review committee–confirmed disease progression.

Results: At a median follow-up of 28 months, acalabrutinib plus obinutuzumab significantly prolonged progression-free survival vs obinutuzumab plus chlorambucil (median not reached vs 22.6 months; hazard ratio [HR] = 0.10, 95% confidence interval [CI] = 0.06–0.18, P < .0001), reducing the risk of disease progression or death by 90%. Single-agent acalabrutinib also prolonged progression-free survival (median not reached) vs obinutuzumab plus chlorambucil (HR = 0.20, 95% CI = 0.13–0.31, P < .0001).

Adverse reactions led to acalabrutinib dose reduction in 7% and 4% of patients in the acalabrutinib-plus-obinutuzumab and acalabrutinib-monotherapy arms, respectively. Adverse events led to treatment discontinuation in 11% with acalabrutinib plus
obinutuzumab, 9% with acalabrutinib, and 14% with obinutuzumab plus chlorambucil. The rates of atrial arrhythmia, hypertension, and herpes virus infection for those who received acalabrutinib were 3.6%, 5%, and 6%, respectively.

Clinical Implications: The estimated 30-month progression-free survival rates with acalabrutinib plus obinutuzumab, single-agent acalabrutinib, and obinutuzumab plus chlorambucil were 90%, 82%, and 34%, respectively. Based on these data, the U.S. Food and Drug Administration approved acalabrutinib for adults with treatment-naive CLL/SLL. Despite crossover for disease progression in the obinutuzumab-plus-chlorambucil arm (25% of patients), a trend toward improved overall survival was observed in both acalabrutinib arms, although longer follow-up is needed.

Overall, perhaps the most important part of this study is the continued apparent favorable toxicity profile of acalabrutinib. The relatively low rates of atrial fibrillation and hypertension are encouraging, as were the relatively low rates of rash, arthralgias, and other bothersome toxicities. Headache is an apparent unique toxicity to acalabrutinib, which often benefits from caffeine intake, as commonly delivered with soda and coffee.

GUEST EDITORS

Syed Ali Abutalib, MD

Syed Ali Abutalib, MD

John M. Pagel, MD, PhD

John M. Pagel, MD, PhD

Dr. Abutalib is Associate Director, Hematology and Cellular Therapy Program; Director, Clinical Apheresis Program; Cancer Treatment Centers of America, Zion, Illinois; Associate Professor, Roseland Franklin University of Medicine and Science; Founder and Co-Editor, Advances in Cell and Gene Therapy. Dr. Pagel is Chief of Hematologic Malignancies and Director of Hematopoietic Stem Cell Transplantation Program, Swedish Cancer Institute, Seattle.

ABSTRACT 33: Extended follow-up from the E1912 trial: Ibrutinib and rituximab (cycles 3 to 7) provides superior clinical outcome compared to fludarabine, cyclophosphamide, and rituximab (FCR) for up to six cycles in patients aged < 70 years with CLL (NCT02048813)2

Methods: The primary endpoint of the trial was progression-free survival. Patients with deletion 17p were excluded from participating in E1912, given their known poor outcome with FCR therapy.

Results: On subgroup analysis by IGHV mutation status, ibrutinib and rituximab (n = 210) was superior to FCR (n = 71) for IGHV-unmutated patients (HR = 0.28; 95% CI = 0.17–0.48; P < .0001). With a median follow-up of 45 months, 257 of 354 patients (73%) who were randomly assigned to ibrutinib and rituximab remain on ibrutinib. Grade 3 and higher treatment-related adverse events were observed in 70% of patients who received ibrutinib and rituximab and 80% of FCR-treated patients (odd ratio = 0.56; 95% CI = 0.34–0.90; P = .013). With current follow-up, the 3-year progression-free survival difference was not significant with ibrutinib and rituximab (10 events in 70 cases), compared with FCR (8 events in 44 cases) in IGHV-mutated patients (HR = 0.42; 95% CI = 0.16–1.16; P = .086).

Clinical Implications: Less than 7% of ibrutinib-treated patients experienced disease progression while on therapy; it is important to note that roughly one in five patients discontinued ibrutinib for a reason other than disease progression or death.

ABSTRACT 35: Ibrutinib plus venetoclax (3 cycles of ibrutinib ­[“lead-in”] followed by combination therapy for 12 cycles) for first-line treatment of CLL/SLL: Results from the minimal residual disease [MRD] cohort (n = 164) of the phase II CAPTIVATE study (NCT02910583)3

Methods: Investigators reported results from the MRD cohort (age < 70 years) after 12 cycles of combination therapy prior to MRD-guided randomized treatment discontinuation (data not yet available). The key endpoints prior to MRD-guided randomization included protocol-defined undetectable MRD (< 10-4 by 8-color flow cytometry), venetoclax-related tumor-lysis syndrome risk, pharmacokinetics, and adverse events. MRD status was evaluated in peripheral blood after 6, 9, and 12 cycles and in marrow after 12 cycles of ibrutinib plus venetoclax.

Results: In total, 92% of patients completed the 3-month ibrutinib “lead-in” and all 12 cycles of ibrutinib plus venetoclax. Protocol-defined undetectable MRD was achieved at any time after baseline in 75% of patients in peripheral blood and 72% of patients in marrow. The high rates of marrow undetectable MRD were consistent across high-risk subgroups, and the rates of peripheral blood MRD improved over time. In patients with undetectable MRD in peripheral blood with matched marrow samples, 93% had undetectable MRD in both peripheral blood and marrow. With a median follow-up of 14.7 months (range, 0.5–19.9 months), 3 patients (2%) experienced disease progression. No patient developed clinical tumor-lysis syndrome. Adverse events leading to treatment discontinuation were infrequent, occurring in 7% of patients overall (ibrutinib: 5%; venetoclax: 4%).

Clinical Implications: Results from the MRD-guided, randomized treatment discontinuation cohort and fixed duration cohort of the CAPTIVATE trial await further follow-up and are expected to provide evidence to support a time-limited treatment option and impact of MRD on specific outcomes. Also, another presented study (Abstract 32) described that nearly half of patients treated with acalabrutinib plus venetoclax and obinutuzumab achieved a complete response plus protocol-defined undetectable (8-color flow cytometry at a sensitivity of at least 10-4) MRD (NCT03580928).4 In the future, further understanding and refinement of MRD algorithms (eg, kinetics of MRD in different genetic-risk groups) may help guide therapy in an individual patient (eg, discontinuation vs continuation or de-escalation vs escalation of therapy).

“The addition of venetoclax to zanubrutinib to deepen the responses in this high-risk patient population [del(17p) CLL/SLL] may be the next step moving forward.”
— Syed Ali Abutalib, MD, and John M. Pagel, MD, PhD

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ABSTRACT 499: Efficacy and safety of zanubrutinib (160 mg twice daily) in patients (n = 109) with treatment-naive CLL or SLL with del(17p) mutation: Initial results from Arm C of the SEQUOIA trial (NCT03336333)5

Methods: Patients at least 65 years of age or unsuitable for treatment with FCR were eligible. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required. The median age was 70 years (range, 42–86 years), and the median follow-up in the safety analysis set was 6.3 months.

Results: Adverse events reported in at least 10% of treated patients included contusion, rash, upper respiratory tract infection, and nausea. Grade ≥ 3 adverse events were reported in 33 patients. One patient died due to grade 5 pneumonia, which occurred 8 days after the last dose of zanubrutinib. No adverse events of atrial fibrillation were reported. At data cutoff, 90 patients were evaluable for efficacy, with a median follow-up of 7 months; of them, 87 patients remained on study treatment. The overall response rate was 92.2%. Two patients from other study arms had disease progression. No patient with CLL/SLL had experienced disease progression.

Clinical Implications: In this study, investigators have completed enrollment of one of the largest prospective cohorts of treatment-naive patients with del(17p) CLL/SLL. The results were limited by the relatively short follow-up period. The addition of venetoclax to zanubrutinib to deepen the responses in this high-risk patient population may be the next step moving forward. Also, Abstract 500 reported safety, tolerability, and high overall responses with zanubrutinib in patients with treatment-naive and relapsed or refractory CLL/SLL.

DISCLOSURE: Dr. Abutalib has served on advisory boards for AstraZeneca and Partner Therapeutics. Dr. Pagel has served on advisory boards for Actinium Pharmaceuticals, AstraZeneca, Gilead Sciences, and Pharmacyclics.

REFERENCES

1. Sharman JP, Banerji V, Fogliatto LM, et al: ELEVATE TN: Phase III study of acalabrutinib combined with obinutuzumab or alone vs obinutuzumab plus chlorambucil in patients with treatment-naive chronic lymphocytic leukemia. Blood 134(suppl 1):31, 2019.

2. Shanafelt TD, Wang V, Kay NE, et al: Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia: Extended follow-up from the E1912 trial. Blood 134(suppl 1):33, 2019.

3. Tam CS, Siddiqi T, Allan JN, et al: Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the MRD cohort of the phase II CAPTIVATE study. Blood 134(suppl 1):35, 2019.

4. Lampson BL, Tyekucheva S, Crombie JL, et al: Preliminary safety and efficacy results from a phase II study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia. Blood 134(suppl 1):32, 2019.

5. Tam CS, Robak T, Ghia P, et al: Efficacy and safety of zanubrutinib in patients with treatment-naïve chronic lymphocytic leukemia or small lymphocytic lymphoma with Del(17p): Initial results from Arm C of the SEQUOIA trial. Blood 134(suppl 1):499, 2019.

6. Cull G, Simpson D, Opat S, et al: Treatment with the Bruton tyrosine kinase inhibitor zanubrutinib (BGB-3111) demonstrates high overall response rate and durable responses in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma: Updated results from a phase I/II trial. Blood 134(suppl 1):500, 2019.


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Selected ASH Abstracts on Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia Part 2: Relapsed or Refractory Disease

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; ClinicalTrials.gov NCT02005471)1

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