The ASCO Post has offered comprehensive coverage of the 2019 ASCO Annual Meeting. To complement this news coverage, here are featured clinical trials of several treatments in chronic lymphocytic leukemia (CLL). They focus on the monoclonal antibody obinutuzumab in combination therapy in the CLL14 trial, comparison of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the monoclonal antibody ofatumumab in the RESONATE trial, and the newer BTK inhibitor acalabrutinib in ibrutinib-intolerant patients with resistant CLL.
Syed Ali Abutalib, MD
Sonali M. Smith, MD, FASCO
Phase III CLL14 and RESONATE Trials
ABSTRACT 7502: Effect of fixed-duration of therapy with venetoclax plus obinutuzumab (n = 216) and chlorambucil/obinutuzumab (n = 216) on progression-free survival and effect on minimal residual disease (MRD) negativity in previously untreated patients with CLL and comorbidities (Cumulative Illness Rating Scale score > 6 and/or an estimated creatinine clearance < 70 mL/min): Results of multinational, open-label, phase III CLL14 trial (ClinicalTrials.gov identifier NCT02242942)1
Background: The initial treatment of CLL has substantially evolved, with chemoimmunotherapy taking a backseat in most patients with CLL. However, many current front-line nonchemotherapy approaches require indefinite therapy and are not associated with deep remission. The study investigators previously tested (in the CLL11 trial2) a limited-duration regimen of chlorambucil vs chlorambucil/rituximab vs chlorambucil/obinutuzumab in older adults with comorbidities. They found that chlorambucil/obinutuzumab yielded superior progression-free survival (compared with both experimental arms), time to next treatment (compared with both experimental arms), and overall survival (compared with chlorambucil alone). The current CLL14 study compares the “winner” of the CLL11 trial—chlorambucil/obinutuzumab—against venetoclax/obinutuzumab in the same older patient population with comorbidities and/or an estimated creatinine clearance < 70 mL/min.
“Longer follow-up of the venetoclax/obinutuzumab group is required to better understand the effect of MRD negativity on clinical outcomes.”— Syed Ali Abutalib, MD, and Sonali M. Smith, MD, FASCO
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Study Endpoints: The primary study endpoint was progression-free survival. A secondary study endpoint was MRD negativity in peripheral blood or bone marrow 3 months after treatment completion.
MRD Assessment: MRD was analyzed serially from cycle 4 onward every 3 months by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-PCR; cutoff, 10-4) and by next-generation sequencing (cutoffs, 10-4, 10-5, 10-6).
Results: After a median follow-up of 29 months, superior progression-free survival was observed with venetoclax/obinutuzumab vs chlorambucil/obinutuzumab (hazard ratio [HR] = 0.35; 95% confidence interval [CI] = 0.23–0.53; P < .0001). The 24-month progression-free survival rate was 88.2% vs 64.1% favoring venetoclax/obinutuzumab. MRD negativity by ASO-PCR was significantly higher with venetoclax/obinutuzumab than with chlorambucil/obinutuzumab in both peripheral blood (76% vs 35% [P < .0001]) and bone marrow (57% vs 17% [P < .0001]) 3 months after treatment completion. MRD-negative rates by next-generation sequencing confirmed these results. Overall, in the venetoclax/obinutuzumab cohort, 75% of patients were MRD negative in peripheral blood and also in bone marrow vs 49% of patients in the chlorambucil/obinutuzumab cohort.
Clinical Implications: In the CLL14 study of patients with untreated CLL and coexisting conditions, venetoclax/obinutuzumab was associated with longer progression-free survival than chlorambucil/obinutuzumab.3 Longer follow-up of the venetoclax/obinutuzumab group is required to better understand the effect of MRD negativity on clinical outcomes. A fixed-dose schedule of venetoclax/obinutuzumab was approved for CLL and small lymphocytic leukemia (SLL) by the U.S. Food and Drug Administration in May 2019.
“In relapsed or refractory CLL/SLL, extended ibrutinib treatment showed sustained efficacy, including in patients with high-risk genomic disease.”— Syed Ali Abutalib, MD, and Sonali M. Smith, MD, FASCO
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ABSTRACT 7510: Final analysis of phase III RESONATE study: Six-year follow-up in patients with previously treated CLL/SLL on ibrutinib vs ofatumumab for 24 months; NCT015787074
Results: A significant, sustained progression-free survival benefit was observed with ibrutinib vs ofatumumab, with a median progression-free survival of 44.1 vs 8.1 months (HR = 0.15; 95% CI = 0.11–0.20; P < .0001), and it was consistent across baseline subgroups. Median progression-free survival in a high-risk genomic population was 44.1 vs 8.0 months with ibrutinib vs ofatumumab (HR = 0.11; 95% CI = 0.08–0.15). The overall response rate with ibrutinib was 88% (complete remission/complete remission with incomplete hematologic recovery in 11%). Initial ibrutinib treatment conferred better overall survival than ofatumumab when censored for crossover (HR = 0.64; 95% CI = 0.42–0.98). Ibrutinib therapy resulted in hypertension and atrial fibrillation in 21% and 12% of patients, respectively; major hemorrhage occurred in 10% of patients.
Clinical Implications: In relapsed or refractory CLL/SLL, extended ibrutinib treatment showed sustained efficacy, including in patients with high-risk genomic disease. A total of 41% of patients received ibrutinib for more than 4 years. The adverse-event profile with ibrutinib remained consistent with prior reports. Thirty-seven percent of patients discontinued therapy due to progressive disease.
Treatment With Acalabrutinib
ABSTRACT 7530: Phase II study of acalabrutinib in ibrutinib-intolerant patients (n = 60) with relapsed or refractory CLL (NCT02717611)5
Background: The BTK inhibitor ibrutinib improved patient outcomes in CLL; however, some patients experience treatment-emergent adverse events leading to treatment discontinuation. These ibrutinib-related adverse events include atrial fibrillation, arthralgia, rash, diarrhea, and bleeding; they have led to ibrutinib discontinuation in 9% to 14% of patients in clinical studies and approximately 22% of patients in routine clinical practice.6 Acalabrutinib (100 mg orally twice daily in 28-day cycles) is a highly selective, covalent BTK inhibitor with minimal off-target activity.6
“Acalabrutinib is tolerable and effective in ibrutinib-intolerant patients, providing a viable strategy for continuing BTK inhibitor therapy.”— Syed Ali Abutalib, MD, and Sonali M. Smith, MD, FASCO
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Results: The median duration of prior ibrutinib therapy was 6 months (range, < 1–55 months); common adverse events that led to ibrutinib discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%), and rash (12%). At a median follow-up of 19 months (range, 1–31 months), 67% of patients remain on acalabrutinib; treatment discontinuation was mostly due to progressive disease (13%) and adverse events (10%). The overall response rate (> partial response with lymphocytosis) was 77% (95% CI = 64%–87%). Serious adverse events (≥ 2 patients) were pneumonia (10%), anemia (3%), and syncope (3%). Atrial fibrillation occurred in three patients (5%; all grade 1 or 2), and major hemorrhage was observed in two patients (3%; grade 3 hematuria and grade 2 subdural hematoma). Grade 5 adverse events were pneumonia (n = 2), bronchopulmonary aspergillosis (n = 1), and ventricular fibrillation (n = 1), and all were considered not to be related to the treatment.
Clinical Implications: Acalabrutinib is tolerable and effective in ibrutinib-intolerant patients, providing a viable strategy for continuing BTK inhibitor therapy. The efficacy and safety of acalabrutinib in patients with relapsed or refractory CLL who are intolerant to ibrutinib therapy are being further evaluated in an ongoing phase II study in which intolerance is more objectively defined (NCT02717611).
ABSTRACT 7511: Second cancer incidence in patients with CLL (n = 691) receiving BTK inhibitors (ibrutinib or acalabrutinib)7
Rationale: BTK inhibitors are effective for the treatment of CLL and are associated with partial restoration of immune function with ongoing treatment. The impact of BTK inhibitors on secondary primary neoplasia is not well characterized.
Patient Characteristics: The median age was 64 years. The median number of prior lines of treatment was two (20% treatment-naive, 66% had prior chemoimmunotherapy), and 56% were never smokers.
Results: At a median follow-up of 44 months, 68 patients (10%) were diagnosed with secondary primary neoplasia (standard incidence ratio (SIR) = 2.4, CI = 1.9–3.0) including 13 lung (SIR = 3.2, CI = 1.7–5.5), 9 melanoma (SIR = 6.9, CI = 3.1–13), 9 prostate (SIR = 1.4, CI = 0.6–2.6), and 7 bladder (SIR = 5.2, CI = 2.1–10.6) cancers. The cumulative incidence ratio of secondary primary neoplasia at 3 years was 7.6%. Smoking (HR = 2.9, CI 1.7–5.0, P < .01) and a low CD8 count (HR = 0.9 for twofold increase, CI = 0.8–0.9, P < .01) were associated with a higher incidence of secondary primary neoplasm. Richter’s transformation was diagnosed in 58 patients (8%), and nonmelanoma skin cancer was diagnosed in 138 patients (20%). About 179 patients had died, with a 3-year overall survival rate of 79% (CI = 76%–82%); the most common causes of death were CLL/Richter’s transformation (57%) and secondary primary neoplasia (13%).
Clinical Implications: The incidence of secondary primary neoplasia may be increased, compared with the general population, in patients who received BTK inhibitors for CLL. In this retrospective study, the 5-year cumulative incidence ratio of nonmelanoma skin cancer and secondary primary neoplasia was 23% and 12%, respectively. These data support continued consideration of vigilant cancer screening, especially for skin cancers, in patients treated for CLL. ■
DISCLOSURE: Dr. Abutalib is an advisor for AstraZeneca and Partner Therapeutics. Dr. Smith has served as a consultant or advisor for AbbVie/Genentech, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Gilead Sciences, Kite Pharma, Pharmacyclics, Portola Pharmaceuticals, Seattle Genetics, and TG Therapeutics; and has received research funding from Acerta Pharma/AstraZeneca, Celgene, and Pharmacyclics/Janssen.
1. Fischer K, Al-Sawaf O, Bahlo J, et al: Effect of fixed-duration venetoclax plus obinutuzumab on progression-free survival, and rates and duration of minimal residual disease negativity in previously untreated patients with chronic lymphocytic leukemia and comorbidities. 2019 ASCO Annual Meeting. Abstract 7502. Presented June 4, 2019.
2. Goede V, Fischer K, Bosch F, et al: Updated survival analysis from the CLL11 study: Obinutuzumab versus rituximab in chemoimmunotherapy-treated patients with chronic lymphocytic leukemia. 2015 ASH Annual Meeting & Exposition. Abstract 1733.
3. Fischer K, Al-Sawaf O, Bahlo J, et al: Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 380:2225-2236, 2019.
4. Barr PM, Munir T, Brown JR, et al: Final analysis from RESONATE: Six-year follow-up in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma on ibrutinib. 2019 ASCO Annual Meeting. Abstract 7510. Presented June 3, 2019.
5. Rogers KA, Thompson PA, Allan JN, et al: Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. 2019 ASCO Annual Meeting. Abstract 7530. Presented June 3, 2019.
6. Awan FT, Schuh A, Brown JR, et al: Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv 3:1553-1562, 2019.
7. Bond DA, Huang Y, Fisher JL, et al: Second cancer incidence in CLL patients receiving BTK inhibitors. 2019 ASCO Annual Meeting. Abstract 7511. Presented June 3, 2019.