A Review of Selected Presentations From the 61st ASH Meeting • December 7-10, 2019
• Orlando, Florida
ELEVATE TN: Phase 3 Study of Acalabrutinib Combined With Obinutuzumab or Alone vs Obinutuzumab Plus Chlorambucil in Patients With Treatment-Naive Chronic Lymphocytic Leukemia
Ibrutinib is an oral Bruton tyrosine kinase (BTK) inhibitor that is approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).1 Acalabrutinib is an irreversible BTK inhibitor that is more highly selective than ibrutinib.2 The multicenter, open-label, phase 3 ELEVATE TN trial (ELEVATE CLL TN: Study of Obinutuzumab + Chlorambucil, Acalabrutinib [ACP-196] + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL) investigated the safety and efficacy of acalabrutinib alone or combined with obinutuzumab in treatment-naive patients with CLL.3 The control arm was standard treatment with chlorambucil plus obinutuzumab.3 Eligible patients were ages 65 years or older, or younger than 65 years if they had coexisting conditions, such as a Cumulative Illness Rating Scale score higher than 6 or creatinine clearance below 70 mL/min.
Patients were stratified based on chromosome 17p deletion (del[17p]), Eastern Cooperative Oncology Group (ECOG) performance status, and geographic location. They were randomly assigned into 1 of 3 treatment arms. Acalabrutinib monotherapy was administered at a dose of 100 mg, twice daily. Patients in the acalabrutinib plus obinutuzumab arm received the same dose of acalabrutinib plus 6 cycles of obinutuzumab (1000 mg on days 1, 2, 8, and 15 of cycle 2, followed by 1000 mg on day 1 of subsequent cycles). Patients in the control arm received 6 cycles of obinutuzumab (starting with cycle 1) plus chlorambucil (0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles). The primary endpoint was progression-free survival (PFS) with acalabrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab.
The trial enrolled 565 patients into the 3 arms. The median age of the overall study population was 70 years (range, 41-90 years). In the 3 arms, the proportion of patients ages 65 years or older ranged from 80.4% to 86.4%. More than 90% of patients had an ECOG performance status of 0 or 1. Between 44.1% and 48.6% of patients had Rai stage III/IV disease. The median time from diagnosis was 30.5 months (range, 0.4-284.5 months) in the acalabrutinib plus obinutuzumab arm, 24.4 months (range, 0.4-242.6 months) in the acalabrutinib monotherapy arm, and 30.7 months (range, 0.3-247.0 months) in the chlorambucil plus obinutuzumab arm. Across the 3 treatment arms, similar proportions of patients had high-risk features, which included unmutated immunoglobulin heavy chain (IGHV; 57.5%-66.5%), del(11q) (17.3%-18.6%), the TP53 mutation (10.6%-11.9%), the complex karyotype (16.2%-18.1%), and del(17p) (8.9%-9.5%).
One patient (0.6%) in the acalabrutinib monotherapy arm and 8 patients (4.5%) in the control arm did not receive therapy. At the time of the study report, treatment was ongoing in 79.3% of patients in both the acalabrutinib arms vs 0% in the control arm. In the control arm, 77.4% of patients had completed the regimen of chlorambucil plus obinutuzumab. Rates of treatment discontinuation ranged from 18.1% in the control arm to 20.7% in the acalabrutinib/obinutuzumab arm. The most common reasons for treatment discontinuation included adverse events (AEs; 8.9% with acalabrutinib monotherapy; 11.2% with the acalabrutinib plus obinutuzumab combination; and 14.1% with chlorambucil plus obinutuzumab). The median treatment exposure was 27.7 months (range, 2.3-40.3 months) in the acalabrutinib plus obinutuzumab arm, 27.7 months (range, 0.3-40.2 months) in the acalabrutinib monotherapy arm, and 5.6 months in the control arm (range, 0.9-7.4 months).
The interim data analysis was conducted after a median follow-up of 28.3 months. The independently assessed median 2-year PFS was 93% with acalabrutinib plus obinutuzumab (hazard ratio [HR], 0.10; 95% CI, 0.06-0.17; P<.0001 vs the control arm), 87% with acalabrutinib monotherapy (HR, 0.20; 95% CI, 0.13-0.30; P<.0001 vs the control arm), and 47% with chlorambucil plus obinutuzumab (Figure 1). A post hoc exploratory analysis suggested that acalabrutinib plus obinutuzumab was superior to acalabrutinib alone (HR, 0.49; 95% CI, 0.26-0.95). In subgroup analyses, acalabrutinib, either alone or in combination with obinutuzumab, was superior to chlorambucil plus obinutuzumab regardless of age, sex, Rai disease stage, and ECOG performance status. The objective response rate (ORR) was 93.9% with the acalabrutinib combination, 85.5% with acalabrutinib monotherapy, and 78.5% in the control arm (Figure 2). The difference was statistically significant between the acalabrutinib combination vs the control (P<.0001), but not between acalabrutinib monotherapy vs the control (P<.0763). The complete response (CR) rate was 13% with acalabrutinib plus obinutuzumab, 1% with acalabrutinib monotherapy, and 5% with chlorambucil plus obinutuzumab. Median overall survival (OS) was not significantly different for the acalabrutinib combination vs standard therapy (HR, 0.47; 95% CI, 0.21-1.06; P=.0577) or for acalabrutinib monotherapy vs standard therapy (HR, 0.60; 95% CI, 0.28-1.27; P=.1556).
An AE of any grade was reported in 96.1% of the acalabrutinib plus obinutuzumab arm, 95.0% of the acalabrutinib monotherapy arm, and 98.8% of the standard treatment arm. Serious AEs occurred in 38.8%, 31.8%, and 21.9%, respectively. AEs of grade 3 or higher were observed in 70.2%, 49.7%, and 69.8%. Grade 5 AEs occurred in 2.8%, 3.9%, and 7.1%. Serious AEs were observed in 38.8% of patients in the acalabrutinib combination arm, 31.8% of patients in the acalabrutinib monotherapy arm, and 21.9% of patients in the standard treatment arm. Across the 3 arms, the most common serious AEs included pneumonia (6.7% in the acalabrutinib plus obinutuzumab arm), tumor lysis syndrome (4.7% in the chlorambucil plus obinutuzumab arm), and febrile neutropenia (4.1% in the chlorambucil plus obinutuzumab arm).
The study identified several grade 3 to 5 AEs of clinical interest for acalabrutinib. The most common of these events were infections, which occurred in 14.0% of the monotherapy arm vs 20.8% of the combination arm; hypertension, which occurred in 2.2% vs 2.8%; and bleeding, which occurred in 1.7% of each acalabrutinib arm. Secondary primary malignancies (excluding nonmelanoma skin cancer) were reported in 1.1% of patients treated with acalabrutinib monotherapy vs 3.4% of those treated with the acalabrutinib combination. Atrial fibrillation occurred in 0.6% of each acalabrutinib arm.
References
1. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study [published online October 18, 2019]. Leukemia. doi:10.1038/s41375-019-0602-x.
2. Liu D, Zhao J. Frontline therapies for untreated chronic lymphoid leukemia. Exp Hematol Oncol. 2019;8:15.
3. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients with treatment-naive chronic lymphocytic leukemia [ASH abstract 31]. Blood. 2019;134(suppl 1).
Treatment Patterns and Outcomes of 1205 Patients on Novel Agents in the US Veterans Health Administration System: Results From the Largest Retrospective EMR and Chart Review Study in the Real-World Setting
Although nearly 20,000 new cases of CLL are diagnosed every year, limited data are available regarding real-world treatment patterns with newer agents, such as ibrutinib, idelalisib, and venetoclax. The US Veterans Health Administration (VHA) conducted the CLOVER study (CLL Outcomes of Veterans in the Real World) to evaluate treatment patterns and outcomes in a large group of CLL patients who received treatment with novel agents.1 The incidence of CLL is highest in older, white men, making the VHA database an excellent source of information on this patient population. The CLOVER study retrospectively evaluated rates of dose reduction and discontinuation, as well as the reasons for both, in real-world CLL patients who were treated with novel agents at the VHA. The study also evaluated OS and duration of therapy. Variables and outcomes were collected via a structured electronic medical records database and by chart review. Patient baseline information was obtained from as early as October 1993 using International Classification of Diseases 9 and 10 codes. Included patients had CLL and received treatment with a novel agent from October 1, 2013 through March 31, 2018. Among 26,879 CLL patients identified, only 1366 had initiated treatment with a novel agent. The analysis excluded 161 patients. Among the 1205 patients included in the study, 1069 were treated with ibrutinib, 87 with venetoclax, and 49 with idelalisib.
Among the 1069 patients treated with ibrutinib, 328 were treatment-naive and 741 had relapsed or refractory disease. All of the patients treated with idelalisib or venetoclax had relapsed or refractory disease. Across the 4 patient cohorts, patients had a median age of 72 years (range, 45-96 years), and nearly all of the patients were male. Between 5% and 8% of patients had been exposed to Agent Orange. The most common comorbidities at baseline were coronary artery disease (18%-33%), atrial fibrillation (6%-23%), and deep vein thrombosis (3%-14%). Hypertension was present at baseline in 23% of patients who received first-line ibrutinib for CLL, whereas only 3% to 5% of patients in the other 3 cohorts had hypertension at baseline. Among patients with relapsed or refractory disease, the median number of prior CLL therapies was 2 (range, 1-14) in the ibrutinib cohort, 3 (range, 0-7) in the idelalisib cohort, and 3 (range, 1-8) in the venetoclax cohort.
Across the 4 arms, the most common reason for treatment discontinuation was AEs, ranging from 41% in the venetoclax cohort to 64% in the first-line ibrutinib cohort (Figure 3). Among patients receiving first-line ibrutinib, the most common hematologic AE that led to discontinuation was anemia (13%; 8/69). In the cohort of patients receiving ibrutinib in the second-line or later setting, the most common hematologic AEs that led to discontinuation were neutropenia (9%; 14/165) and thrombocytopenia (9%; 14/165). The most common hematologic AE that led to discontinuation was anemia (9%; 2/22) in the idelalisib cohort and neutropenia (45%; 5/11) in the venetoclax cohort. The most common nonhematologic AE that led to treatment discontinuation in the first-line ibrutinib cohort was atrial fibrillation (23%; 15/69). Among the cohorts of patients with relapsed or refractory disease, the most common nonhematologic AEs that led to treatment discontinuation were atrial fibrillation (21%; 33/165) with ibrutinib, infection (23%; 5/22) with idelalisib, and infection (18%; 2/11) with venetoclax.
Median follow-up ranged from a low of 9 months (range, 0-35 months) in the venetoclax arm to 31 months (range, 2-85 months) in patients who received ibrutinib therapy for relapsed or refractory disease. The median duration of treatment, from initiation to discontinuation, was 8 months (range, 0-49 months) in the first-line ibrutinib cohort. Among patients with relapsed or refractory disease, the median duration of treatment was 12 months (range, 0-81 months) with ibrutinib, 5 months (range, 0-50 months) with idelalisib, and 5 months (range, 0-22 months) with venetoclax. Treatment discontinuation rates were higher in the VHA real-world study compared with outcomes from patients in clinical trials.2-5
References
1. Frei CR, Le H, McHugh D, et al. Treatment patterns and outcomes of 1205 patients on novel agents in the US Veterans Health Administration (VHA) system: results from the largest retrospective EMR and chart review study in the real-world setting [ASH abstract 795]. Blood. 2019;134(suppl 1).
2. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study [published online October 18, 2019]. Leukemia. doi:10.1038/s41375-019-0602-x.
3. Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133(19):2031-2042.
4. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.
5. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.
Preliminary Safety and Efficacy Results From a Phase 2 Study of Acalabrutinib, Venetoclax, and Obinutuzumab in Patients With Previously Untreated Chronic Lymphocytic Leukemia
The phase 3 CLL14 study (A Study to Compare the Efficacy and Safety of Obinutuzumab + Venetoclax [GDC-0199] Versus Obinutuzumab + Chlorambucil in Participants With Chronic Lymphocytic Leukemia) demonstrated that fixed-duration therapy with venetoclax plus obinutuzumab yielded a longer PFS compared with chlorambucil plus obinutuzumab in 432 CLL patients with comorbidities.1 After a median follow-up of 28.1 months, estimated 2-year PFS was 88.2% with obinutuzumab plus venetoclax vs 64.1% with standard treatment (HR, 0.35; 95% CI, 0.23-0.53; P<.001). A phase 1b study evaluated the combination of ibrutinib plus venetoclax and obinutuzumab in 12 patients with relapsed or refractory CLL.2 The study yielded an ORR of 92% (95% CI, 62%-100%), with a 42% CR/incomplete CR rate. Six patients had no detectable CLL cells in both the blood and bone marrow at the end of treatment. Infusion reactions were reported in 83.3%. Grade 3/4 AEs included infusion-related reaction (8.3%), neutropenia (33.3%), and hypertension (25%). The combination of acalabrutinib plus obinutuzumab demonstrated efficacy with acceptable tolerability in the first-line setting in the ELEVATE TN trial.3
An open-label, single-arm, investigator-initiated, phase 2 trial evaluated the combination of acalabrutinib, venetoclax, and obinutuzumab as first-line treatment.4 The regimen was administered in a time-limited strategy. Eligible patients had a confirmed diagnosis of treatment-naive CLL/SLL requiring treatment and a maximum ECOG performance status of 2. Acalabrutinib and obinutuzumab were administered at standard doses, and each cycle was 28 days. Patients first received a single cycle of acalabrutinib, with obinutuzumab added in cycle 2. On day 1 of cycle 4, venetoclax was added and escalated from 20 mg (cycle 4, day 1) to 400 mg, for a total of 4 cycles of triple-combination therapy. After 6 months of obinutuzumab, patients could continue to receive acalabrutinib plus venetoclax through cycle 24. However, patients with a CR and undetectable minimal residual disease (MRD) in the bone marrow were allowed to stop therapy after cycle 15. The primary endpoint was the rate of CR with undetectable MRD in the bone marrow.
The 37 enrolled patients were a median age of 63 years (range, 41-78 years), and 27% were female. All of the patients had an ECOG performance status of 0 or 1, and 54.1% had Rai stage III/IV disease. Genomic aberrations of interest included unmutated IGHV (62.2%), TP53 aberrancy (27.0%), del(11q) (29.7%), and complex karyotype (19.0%).
After 8 treatment cycles, the ORR was 100%, with a CR/incomplete CR rate of 25% (8/32). After 16 treatment cycles, the CR/incomplete CR rate was still 25% (2/8; Figure 4). Rates of undetectable MRD in the bone marrow increased over time, from 3.7% (1/27) on day 1 of cycle 4, to 48.3% (15/31) on day 1 of cycle 8, to 75.0% (6/8) on day 1 of cycle 16 (Figure 5). No significant differences in ORR or undetectable MRD rate were observed between patients with vs without mutated IGHV. Among the patients with TP53 aberrancy, the response rate at cycle 8 included 67% (6/9) PRs and 33% (3/9) CRs. The rate of undetectable MRD at cycle 8 was 33% (3/9) in the bone marrow and 78% (7/9) in the blood.
After a median follow-up of 11 cycles (range, 6-16 cycles), the most common nonhematologic toxicities of any grade were fatigue (84%), headache (76%), and bruising (46%). The most common grade 3/4 toxicities were hematologic. They included neutropenia (32%), thrombocytopenia (11%), and anemia (8%). In addition to 3 reports of grade 4 neutropenia, other serious AEs included 2 cases of grade 3 laboratory tumor lysis syndrome, 1 case of grade 4 hyperkalemia, and 1 case of grade 3 elevated cardiac troponin. By starting treatment with 3 cycles of lead-in therapy with acalabrutinib and obinutuzumab, the proportion of patients with a high risk of tumor lysis syndrome was reduced from 30% at baseline to 2% at the time of venetoclax introduction.
AEs of special interest included 7 cases of grade 1/2 infusion-related reactions, plus 1 grade 3 event; 2 cases of grade 1/2 hypertension; and 1 case of grade 3 atrial fibrillation (which developed along with pericarditis during cycle 9). In 1 patient, headaches required 2 dose reductions of acalabrutinib to 100 mg, with subsequent reescalation to the full dose. Another patient required a dose reduction of venetoclax to 300 mg daily owing to grade 4 neutropenia, despite growth factor support. One patient discontinued therapy. This patient, at baseline, had erosive gastritis, duodenitis, and symptomatic splenomegaly, and developed worsening of gastrointestinal symptoms during the study. Although this patient had a partial response (PR) at restaging on day 1 of cycle 4, study therapy was stopped during cycle 5.
An expansion cohort will evaluate the combination of acalabrutinib, obinutuzumab, and venetoclax in patients with TP53 aberrancy. A phase 3 trial will compare the 3-agent combination vs acalabrutinib plus venetoclax or chemoimmunotherapy in approximately 780 patients with treatment-naive CLL.5
References
1. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236.
2. Rogers KA, Huang Y, Ruppert AS, et al. Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia. Blood. 2018;132(15):1568-1572.
3. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients with treatment-naive chronic lymphocytic leukemia [ASH abstract 31]. Blood. 2019;134(suppl 1).
4. Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL) [ASH abstract 32]. Blood. 2019;134(suppl 1).
5. ClinicalTrials.gov. Study of acalabrutinib (ACP-196) in combination with venetoclax (ABT-199), with and without obinutuzumab (GA101) versus chemoimmunotherapy for previously untreated CLL. https://clinicaltrials.gov/ct2/show/NCT03836261. Identifier: NCT03836261. Accessed January 4, 2020.
Four-Year Analysis of the MURANO Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia
The phase 3 MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia) evaluated venetoclax plus rituximab vs bendamustine plus rituximab in patients with relapsed or refractory CLL.1-3 Patients were stratified based on the presence of del(17p), response to prior therapy, and geographic region, and then randomly assigned to treatment. Patients initially received venetoclax (400 mg daily) plus rituximab (375 mg/m2 on day 1 of cycle 1, then 500 mg/m2 on day 1 of cycles 2-6) or bendamustine (70 mg/m2 on days 1 and 2 of cycles 1-6) plus the same regimen of rituximab. After 6 cycles of combination treatment, patients in the venetoclax arm continued to receive daily venetoclax until a maximum of 2 years from day 1 of cycle 1. The primary endpoint was investigator-assessed PFS.
Baseline characteristics were well balanced between the 2 arms. Among the 389 patients randomly assigned to treatment, the median age was 65.5 years (range, 22-85 years). Two-thirds of patients had a lymphocyte count of at least 25 × 109/L. Forty-two percent had del(17p) or a deleterious mutation in the TP53 gene. Twelve percent of patients in the venetoclax arm and 18% in the bendamustine arm had received 3 or more prior therapies. After a median follow-up of 36 months, treatment with venetoclax plus rituximab was superior to bendamustine plus rituximab, based on median PFS (HR, 0.16; 95% CI, 0.12-0.23; P<.001) and median OS (HR, 0.50; 95% CI, 0.30-0.85; P=.0093). Estimated 3-year PFS was 71.4% with venetoclax plus rituximab vs 15.2% with venetoclax plus bendamustine. The 3-year OS estimates were 87.9% vs 79.5%, respectively.
After a median follow-up of 48 months, 30 patients in the venetoclax combination arm and 63 in the bendamustine combination arm had discontinued treatment.3 Among 194 patients randomly assigned to the venetoclax plus rituximab arm, 174 (90%) completed all 6 cycles of combination therapy, and 130 (67%) completed 2 years of venetoclax monotherapy without progressive disease. Among 195 patients assigned to bendamustine plus rituximab, 154 (79%) completed 6 cycles of treatment. Subsequent treatment after disease progression was reported in 42 patients in the venetoclax arm vs 103 patients in the bendamustine arm.
The 48-month analysis continued to show a benefit with venetoclax plus rituximab vs bendamustine plus rituximab.3 Four-year PFS was 57.3% vs 4.6% (HR, 0.19; 95% CI, 0.14-0.25; P<.0001). In the venetoclax/rituximab arm, 83 patients (64%) had undetectable MRD (<10-4) in the peripheral blood after completing 6 cycles of combination therapy plus 24 months of venetoclax monotherapy. Among the 130 patients who completed 2 years of venetoclax, 35 progression events had occurred at a median of 22 months after cessation of all therapy. Median PFS was longest in patients who had undetectable MRD at the end of treatment (24-month median PFS, 83.9%; 95% CI, 72.9%-94.9%). Among the 14 patients who had an MRD level higher than 10-2, most experienced an initial decrease in the proportion of CLL cells in the peripheral blood, followed by an increase from approximately 8 months until the end of treatment.
The 48-month analysis demonstrated a significant improvement in OS with venetoclax plus rituximab (85.3% vs 66.8%; HR, 0.41; 95% CI, 0.26-0.65; P<.0001; Figure 6), despite the fact that 81 patients (79%) with progressive disease in the bendamustine plus rituximab arm received treatment with a novel targeted agent as their first follow-up therapy after progression. After subsequent therapy, the ORR was 77.3% in the venetoclax arm vs 64.3% in the bendamustine arm. Among 10 patients in the venetoclax plus rituximab arm who subsequently developed progressive disease and received treatment with ibrutinib, 9 achieved a PR and 1 a CR.
No new safety signals emerged during the extended follow-up. There were no reports of new serious AEs that were related to study treatment.
References
1. 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: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019;37(4):269-277.
2. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.
3. Seymour JF, Kipps TJ, Eichhorst BF, et al. Four-year analysis of the MURANO study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [ASH abstract 355]. Blood. 2019;134(suppl 1).
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 1/2 Trial
Zanubrutinib is a next-generation BTK inhibitor designed to maximize binding to BTK while minimizing off-target activity. The multicenter, open-label, phase 1/2 AU-003 trial (Study of the Safety and Pharmacokinetics of BGB-3111 in Subjects With B-Cell Lymphoid Malignancies) investigated the safety, efficacy, and pharmacokinetics of zanubrutinib in patients with B-cell malignancies.1,2 Patients were enrolled into disease-specific expansion cohorts. The doses of zanubrutinib ranged from 40 mg once daily to 160 mg twice daily or 360 mg once daily until unacceptable toxicity or disease progression. No dose-limiting toxicities occurred during dose escalation. BTK occupancy was 89% with the dose of 160 mg twice daily vs 50% with 360 mg once daily (P=.0342). After a median follow-up of 13.7 months, a preliminary analysis showed that zanubrutinib was associated with acceptable toxicity and promising efficacy.2
The AU-003 study included 123 patients with CLL/SLL and no prior exposure to BTK inhibitor therapy.1 Among these patients, 101 had relapsed or refractory disease and 22 were treatment-naive. The patients were a median age of 67 years (range, 24-87 years), and three-fourths were male. Five patients (4.1%) had SLL. Genetic risk factors included unmutated IGHV (68.3%), TP53 mutation (31.0%), del(11q) (23.5%), and del(17p) (16.2%). Bulky disease (>5 cm) was noted in 38.2% of patients. The median duration of follow-up was 29.5 months (range, 3.7-52.0 months), and the median duration of treatment was 25.8 months (range, 1.6-52.0 months). Ninety-eight patients remained on study treatment at the time of the analysis.
Based on investigator assessment, the ORR in the overall study population was 95.9%, including CRs in 15.4% and incomplete CRs in 0.8%. At 12 months, after a median follow-up of 31.2 months (range, 9.4-43.5 months), 97.2% of patients remained in response. Among 16 patients with del(17p), the ORR was 93.8%, including 1 patient (6.3%) with a CR. For PFS, the median follow-up was 32.2 months for treatment-naive patients and 23.1 months for those with relapsed or refractory disease. In the treatment-naive cohort, PFS rates were 95% at both 12 and 24 months. In the relapsed/refractory cohort, PFS rates were 97% at 12 months and 91% at 24 months. The best responses over time for the relapsed/refractory cohort are shown in Figure 7.
AEs of grade 3 or higher were observed in 61.8% of patients. Serious AEs occurred in 47.2% of patients. Five AEs (4.1%) required treatment discontinuation, and 1 AE (0.8%) led to death. The most common AEs of any grade included bruising, diarrhea, and minor bleeding. The most common AEs of grade 3 or higher were neutropenia, pneumonia, and anemia. The rate of grade 3 or higher atrial fibrillation was 1.6%. Most AEs of interest decreased in frequency after the first 12 months of treatment, with the exception of grade 3 or higher infection. The most common reason for treatment discontinuation was progressive disease (12%).
A randomized registration trial is comparing zanubrutinib vs ibrutinib in patients with relapsed or refractory CLL/SLL.3
References
1. 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 (CLL/SLL): updated results from a phase 1/2 trial [ASH abstract 500]. Blood. 2019;134(suppl 1).
2. Tam CS, Trotman J, Opat S, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134(11):851-859.
3. ClinicalTrials.gov. A study of zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia (ALPINE). https://clinicaltrials.gov/ct2/show/NCT03734016. Identifier: NCT03734016. Accessed January 4, 2020.
Rapid Undetectable MRD Responses in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Treated With Lisocabtagene Maraleucel (liso-cel), a CD19-Directed CAR T-Cell Product: Updated Results From TRANSCEND CLL 004, a Phase 1/2 Study Including Patients With High-Risk Disease Previously Treated With Ibrutinib
The phase 1/2 TRANSCEND CLL 004 trial (Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL] or Small Lymphocytic Lymphoma [SLL]) evaluated lisocabtagene maraleucel (JCAR017) in heavily pretreated CLL patients, including those with an inadequate response to both a BTK inhibitor and venetoclax.1 Lisocabtagene maraleucel is a CD19-directed chimeric antigen receptor (CAR) T-cell product that uses a defined composition of CD8- and CD4-positive T cells, with the goal of administering equal doses of both T-cell classes.
The TRANSCEND CLL 004 study included patients with relapsed or refractory CLL/SLL who had an inadequate response to BTK inhibitor therapy or were ineligible for this treatment. Eligibility criteria required that patients with high-risk disease had an inadequate response to at least 2 prior therapies, and patients with standard-risk disease had received at least 3 prior therapies. All patients had an ECOG performance status of 0 or 1. After leukapheresis, the presence of measurable disease was reconfirmed. Bridging therapy was allowed prior to lymphodepletion, which was performed by means of a 3-day regimen of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2). Lisocabtagene maraleucel was administered in 2 dose levels: 50 × 106 CAR T cells (dose level 1) and 100 × 106 CAR T cells (dose level 2).
Among 23 evaluable patients, 9 received lisocabtagene maraleucel at 50 × 106 CAR T cells and 14 received lisocabtagene maraleucel at 100 × 106 CAR T cells. After a median follow-up of 11 months, the ORR was 81.5% (18/22), including a CR/incomplete CR rate of 45.5% (Figure 8). Among the 9 patients previously treated with a BTK inhibitor and venetoclax, the ORR was 89% (8/9), including a CR/incomplete CR rate of 67%. The rate of undetectable MRD (<10-4) was 75% (15/20) in the blood and 65% (13/20) in the bone marrow. In the subgroup of patients who had failed a BTK inhibitor and venetoclax, the rate of undetectable MRD was 87.5% (7/8) in the blood and 75% (6/8) in the bone marrow. Sixty-eight percent (15/22) of patients had a response by day 30. In 27% of patients (6/22), responses deepened over time.
Among 12 patients who had a PR or CR at 6 months, 10 (83%) remained in response at 9 months, and 8 patients were in response for at least 12 months. Eighty percent (12/15) of patients who achieved undetectable MRD in the blood maintained their response, and all cases of progressive disease were associated with Richter transformation.
The most common grade 3/4 treatment-emergent AEs were anemia (78%), thrombocytopenia (70%), and neutropenia (56.5%). Dose-limiting toxicities were observed in 2 patients who received the lisocabtagene maraleucel infusion at 100 × 106 CAR T cells, and both cases resolved. Among the 23 patients, 74% experienced cytokine release syndrome of any grade, including 2 patients (9%) who developed grade 3 cytokine release syndrome. Neurologic events of any grade were reported in 39% of patients, including 5 patients (22%) with neurologic events of grade 3 or higher.
Reference
1. Siddiqi T, Soumerai JD, Dorritie KA, et al. Rapid undetectable MRD (uMRD) responses in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with lisocabtagene maraleucel (liso-cel), a CD19-directed CAR T cell product: updated results from TRANSCEND CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib [ASH abstract 503]. Blood. 2019;134(suppl 1).
Combined Ibrutinib and Venetoclax for Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Two phase 2 studies evaluated ibrutinib plus venetoclax in patients with either treatment-naive or relapsed/refractory CLL/SLL.1,2 In the treatment-naive study, patients had at least 1 high-risk feature: del(17p) or mutated TP53; del(11q); unmutated IGHV; or older age (≥65 years). Patients initially received 3 cycles of ibrutinib at 420 mg daily. Starting with cycle 4, venetoclax was initiated at 20 mg daily, with escalation to 400 mg daily, for a total of 24 cycles of combination treatment. Patients with detectable MRD in the bone marrow after 24 cycles of combination treatment could continue with ibrutinib monotherapy until disease progression. Eighty patients were enrolled. Their median age was 65 years. Five patients left the study during the first 3 cycles of ibrutinib monotherapy, and 75 initiated combination therapy. The median follow-up was 27 months.
The rate of undetectable MRD (<10-4) in the bone marrow was 16% (12/74) after 3 months of combination therapy and increased over time to 75% after 24 months of combination therapy (37/49). High rates of undetectable MRD in the bone marrow were observed across all patient subgroups based on risk factors. Bone marrow MRD continued to improve from 12 months through 24 months.
Five patients left the study during the first 3 cycles of ibrutinib monotherapy, and another 9 patients withdrew while receiving combination therapy. No patient developed CLL progression. Two patients developed Richter transformation, and 3 patients died. Fifty-one percent of patients developed grade 3/4 neutropenia, and 24% required administration of granulocyte colony–stimulating factor. Nineteen percent of patients developed an infection of grade 3 or higher. Four patients (5%) developed neutropenic fever. Dose reductions of ibrutinib or venetoclax were required in 52% and 29% of patients, respectively.
The study of relapsed or refractory patients followed the same treatment protocol. Among 80 patients enrolled, 1 was reclassified with splenic marginal zone lymphoma and excluded from further analyses. Five patients left the study during the first 3 cycles of ibrutinib monotherapy, and 74 patients began combination therapy. Median follow-up was 27 months. Patients were a median age of 61 years. The median number of prior therapies was 1 (range, 1-4), and 85% of patients had unmutated IGHV.
In the intention-to-treat population, the rate of undetectable MRD (<10-4) in the bone marrow was 40% at 9 months of treatment with the combination (Figure 9). After 3 months of combination treatment, the rate of undetectable MRD in the bone marrow was 10% (7/68), which increased over time to 68% (23/34) after 24 months of combination treatment. Undetectable MRD was observed across all patient subgroups. Five patients left the study during the first 3 cycles of ibrutinib monotherapy. An additional 7 patients left during combination therapy, and 4 left after completing all cycles of combination therapy, including 2 who developed CLL progression.
AEs of interest included grade 3/4 neutropenia, reported in 43%, atrial fibrillation in 8%, and grade 3/4 thrombocytopenia in 1%. Dose reductions of ibrutinib or venetoclax were required in 57% and 35% of patients, respectively.
References
1. Jain N, Keating M, Thompson P, et al. Combined ibrutinib and venetoclax for first-line treatment for patients with chronic lymphocytic leukemia [ASH abstract 34]. Blood. 2019;134(suppl 1).
2. Jain N, Keating M, Thompson P, et al. Combined ibrutinib and venetoclax in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [ASH abstract 359]. Blood. 2019;134(suppl 1).
Highlights in Chronic Lymphocytic Leukemia From the 61st American Society of Hematology Annual Meeting and Exposition: Commentary
Farrukh T. Awan, MD
Many presentations at the 61st American Society of Hematology annual meeting provided important insights into the management of patients with chronic lymphocytic leukemia (CLL). Studies provided new data regarding treatments such as acalabrutinib, venetoclax, ibrutinib, and zanubrutinib. In addition, multiple studies evaluating real-world management and outcomes of CLL patients were presented, including an analysis from the US Veterans Heath Administration (VHA) system.
The ELEVATE Study of Acalabrutinib
The ELEVATE trial (Study of Obinutuzumab + Chlorambucil, Acalabrutinib [ACP-196] + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL) compared acalabrutinib alone or with obinutuzumab vs chlorambucil plus obinutuzumab in patients with treatment-naive CLL who were older than 65 years or had comorbidities.1 Obinutuzumab plus chlorambucil is an approved regimen for patients who are not candidates for more intensive chemoimmunotherapy-based regimens. The study population was similar to that enrolled in the phase 3 CLL11 trial, which examined obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.2 Historically, the addition of a CD20 antibody to Bruton tyrosine kinase (BTK) inhibitors has not necessarily improved progression-free survival.3,4 Nevertheless, the ELEVATE study evaluated whether the addition of the CD20 antibody obinutuzumab to acalabrutinib would improve outcomes.
Obinutuzumab is associated with a significant rate of infusion reactions when administered as monotherapy.5 The ELEVATE trial also evaluated whether the rate of infusion reactions would be decreased if the BTK inhibitor acalabrutinib was administered before obinutuzumab, as has been seen in other studies.6 The trial design designated that acalabrutinib was administered first, and then obinutuzumab was added later in the combination arm.
This large trial randomly assigned 535 patients to treatment: 179 to the acalabrutinib-only arm, 179 to the acalabrutinib-plus-obinutuzumab arm, and 177 to the obinutuzumab-plus-chlorambucil arm. Most of the patients were elderly, with a median age of approximately 70 years. At a median follow-up of approximately 28 months, progression-free survival was significantly improved with acalabrutinib plus obinutuzumab vs the control arm of obinutuzumab plus chlorambucil (93% vs 47%; P<.0001). As expected, the risk of infusion reactions was decreased by starting the BTK inhibitor prior to obinutuzumab. The rate of all-grade infusion-related reactions was 13.5% in patients treated with acalabrutinib plus obinutuzumab vs 39.6% in patients treated with obinutuzumab plus chlorambucil.
An important aspect to this study was whether the addition of obinutuzumab to acalabrutinib would improve outcomes as compared with acalabrutinib alone. There was a trend toward slightly better progression-free survival with the addition of obinutuzumab to acalabrutinib (93% vs 87%), without a significant increase in toxicities, although the study was not powered to evaluate this endpoint. Historically, when ibrutinib was combined with the CD20 antibody rituximab, there was no significant difference in progression-free survival vs ibrutinib alone.4 Therefore, this study provided some evidence for an improved outcome when these drug classes were combined.
No significant differences in overall survival were observed between acalabrutinib plus obinutuzumab vs obinutuzumab plus chlorambucil (hazard ratio, 0.47; 95% CI, 0.21-1.06; P=.0577). However, follow-up was short, and it is expected that survival would be better in the BTK inhibitor arm, as shown in previous studies of ibrutinib.7 Longer follow-up is also needed to identify a survival difference between acalabrutinib plus obinutuzumab vs acalabrutinib alone.
Another important observation concerns the risks of bleeding, hypertension, and atrial fibrillation that have been seen with ibrutinib. In this trial, the incidence of all-grade atrial fibrillation was relatively low with acalabrutinib, at 3.4% in the combination arm and 3.9% in the monotherapy arm. These rates were slightly higher, however, than that seen with obinutuzumab plus chlorambucil (0.6%). As expected, bleeding events were also higher in the acalabrutinib arms vs the chlorambucil arm, consistent with results observed with other BTK inhibitors. Rates of all-grade hypertension were 7.3% with acalabrutinib plus obinutuzumab, 4.5% with acalabrutinib monotherapy, and 3.6% with obinutuzumab plus chlorambucil.
In summary, the combination of acalabrutinib plus obinutuzumab was superior to chlorambucil plus obinutuzumab. Early follow-up data show excellent disease control and progression-free survival. There was a trend toward improved outcomes with the combination of acalabrutinib plus obinutuzumab vs acalabrutinib alone.
A VHA Real-World Analysis
Much research has focused on the real-world experience of CLL, including how novel therapies are being used, their outcomes, and how patients tolerate them. The CLOVER study (CLL Outcomes of Veterans in the Real World) evaluated treatment patterns and outcomes among a large cohort of patients treated in the VHA system.8 CLL is among the more common cancers in these patients, and can be associated with Agent Orange, which many veterans were exposed to during the Vietnam and Korean wars.9 This study examined data for patients treated from 2013 to 2018 with novel therapies for CLL. The study identified 1205 patients, but excluded 161 from the final analysis. Ibrutinib was by far the most common treatment, administered to 922 patients. The other novel treatments were idelalisib, received by 45 patients, and venetoclax, received by 77 patients.
Patients ranged in age from 48 to 96 years. Overall, a quarter of the patients required dose reductions, and almost a third discontinued treatment because of adverse events. Among patients who received ibrutinib, the rate of treatment discontinuation for any reason was 33% among treatment-naive patients and 35% among relapsed/refractory patients. Corresponding rates were 21% and 14% in clinical trials.7,10-14 Previous analyses of real-world data have shown that discontinuation rates can reach 40% in some cohorts of patients, particularly the elderly.15 In the CLOVER analysis, rates of discontinuation because of adverse events among patients treated with ibrutinib were 12% in treatment-naive patients and 22% in relapsed/refractory patients. Dose reductions were precipitated by adverse events such as rash, bleeding, infection, and atrial fibrillation. These adverse events are known to be associated with ibrutinib.11,12 The reasons for discontinuation because of adverse events were similar to those seen in previous studies, and included atrial fibrillation, bleeding, infection, and diarrhea.
Another important observation of this analysis is that discontinuation typically occurs early in the treatment course. The median duration to ibrutinib discontinuation was approximately 8 months in treatment-naive patients and 12 months in relapsed/refractory patients. This finding is not unusual; in earlier clinical trials, most patients who discontinued ibrutinib did so in the first 6 to 12 months.11-14
The use of idelalisib has been associated with diarrhea, pneumonitis, transaminitis, and infectious complications.16 This experience was reflected in the VHA population. An interesting observation is that adverse events more frequently led to treatment discontinuation (84%) rather than dose reduction (16%). Clinicians were more likely to stop idelalisib rather than try to manage complications with dose reductions. The median time to discontinuation of idelalisib was approximately 5 months. Confirming earlier observations, a group of patients stopped treatment early, and then another group stopped after 4 to 6 months. Neutropenia was another frequent cause of discontinuation for idelalisib.
With regards to venetoclax, the median time to treatment discontinuation was approximately 5 months. Many of the discontinuations were because of adverse events, which most frequently consisted of anemia, neutropenia, thrombocytopenia, and resulting infections. Dose reduction was required in 28% of patients, and 31% discontinued treatment. These numbers are concerning for the high-risk population in which venetoclax is typically used in a time-limited manner. It appears, however, that a significant number of the patients cannot tolerate this duration, even when clinicians used dose reductions, growth factors, and other strategies to maximize treatment duration.
The VHA analysis raises several important points. The experience with ibrutinib and idelalisib in the real-world setting is inferior to that reported in clinical trials and consistent with earlier reports. Additionally, although clinicians are becoming more comfortable using venetoclax, patients are stopping treatment much earlier than might be expected based on previous studies and even other real-world experiences. These outcomes, however, are probably related to the underlying comorbidities in this patient cohort. The prevalence of coronary artery disease ranged from 18% in relapsed/refractory patients treated with ibrutinib or venetoclax to 33% among relapsed/refractory patients treated with idelalisib.
Acalabrutinib, Venetoclax, and Obinutuzumab
A phase 2 study evaluated acalabrutinib, venetoclax, and obinutuzumab as frontline therapy.17 Acalabrutinib is an exciting alternative BTK inhibitor approved for the treatment of patients with CLL. Early data suggest that acalabrutinib is well tolerated, and possibly better tolerated than ibrutinib.18
This single-arm, phase 2 study combined acalabrutinib with venetoclax and obinutuzumab in a sequential manner. Patients began treatment with acalabrutinib in month 1. They then received obinutuzumab in month 2. After 3 months, venetoclax was initiated. Obinutuzumab was administered for 6 months. Treatment with acalabrutinib and venetoclax continued beyond 6 months, for a total of 24 months of therapy. The trial accrued 37 patients, with a median age of 63 years. The study enrolled patients with low-risk or high-risk disease. Any type of TP53 aberration was seen in 27% of patients. The TP53 mutation and 17p deletion together were present in 21.6%.
The response rate to the triplet therapy was 100%. At an interim staging at cycle 8, 67.8% of patients had undetectable minimal residual disease (MRD) in the peripheral blood. Nearly half of patients had undetectable MRD in the bone marrow, as assessed by an 8-color flow-based assay with a sensitivity of up to 10-4 (1 CLL cell in 10,000 leukocytes). In this study, patients with an undetectable MRD after 24 months of therapy stopped all treatment.
Therapy was fairly well tolerated, with fatigue and headaches being the most frequent adverse events. Bruising was reported in 46% of patients, but most cases were low grade. There were few reports of cardiovascular issues. Thrombocytopenia, neutropenia, and anemia are known side effects of the combination, and they occurred at an expected incidence in this study. Similarly, infusion reactions were infrequent, observed in 19% of patients, with 3% experiencing grade 3 or higher events. With the utilization of debulking therapy for 2 months before the start of venetoclax, tumor lysis was observed in only 2 patients in the study, and both cases occurred prior to initiation of venetoclax. These preliminary results support findings from earlier studies showing that a triplet combination of acalabrutinib, obinutuzumab, and venetoclax is safe and effective. Patients can achieve deep remissions that, in the future, might allow discontinuation of therapy. Moreover, this regimen is also being compared with chemoimmunotherapy in a randomized clinical trial.19 Multiple trials of similar triplet regimens of alternative agents are ongoing.19-21
Measurement of peripheral blood and bone marrow MRD is an established and frequently utilized surrogate survival endpoint that is employed in a multitude of clinical trials of novel therapies. However, there is no standardized approach to the measurement of MRD in the United States, and the availability and use of both flow-based and polymerase chain reaction–based assays are limited. Moreover, there are limited data on long-term outcomes of patients who discontinue treatment based on MRD-negative status. These issues are being actively addressed in ongoing clinical trials.
Zanubrutinib
A phase 1/2 trial examined the selective irreversible BTK inhibitor zanubrutinib in patients with CLL/small lymphocytic leukemia.22 Zanubrutinib is currently approved for relapsed/refractory mantle cell lymphoma.23 The CLL cohort included 122 patients, none of whom had received previous treatment with a BTK inhibitor. Eighteen percent of patients had not received any prior treatment. The median number of prior therapies was 2. The median age was 67 years, and the trial included a mix of younger and older patients. Deletion 17p and TP53 mutations were reported in 10% to 13%, a fairly typical range for the general CLL population. Unmutated immunoglobulin heavy chain variable (IGHV) was present in 68% of patients.
The trial reported a response rate of 100% among patients with treatment-naive disease and 95% among those with relapsed/refractory disease. Interestingly, complete response rates were similar in the treatment-naive and relapsed/refractory cohorts (13.6% vs 14.3%). With a median follow-up of 25 months, the rate of progression-free survival was 95% in the treatment-naive cohort and 88% in the relapsed/refractory cohort.
With regard to safety, almost a third of patients had diarrhea, and a quarter had headaches. Infections and cytopenias were also reported. These adverse events have been seen with the other BTK inhibitors. All-grade minor bleeding was reported in approximately 30%. A major hemorrhage occurred in 2% of patients. Bleeding events consisting of contusion, hematuria, petechia, or purpura occurred in 57%. Atrial fibrillation was reported in 3%, and hypertension was seen in 8%. The rate of secondary malignancies was approximately 20%.
Zanubrutinib may be a potential option for the small cohort of patients who are not candidates for ibrutinib or acalabrutinib. However, additional data and follow-up are required to determine the long-term efficacy in patients with high-risk CLL.24
Ibrutinib Combinations
Updated results were presented from the Eastern Cooperative Oncology Group (ECOG) E1912 study, which compared ibrutinib plus rituximab vs fludarabine, cyclophosphamide, and rituximab (FCR) in young patients with previously untreated CLL.25 Previous data have established clear advantages in overall survival and progression-free survival with the use of ibrutinib plus rituximab as compared with FCR.26 A remaining issue concerns patients with mutated IGHV, in whom ibrutinib plus rituximab does not significantly improve progression-free survival vs FCR. Extended follow-up of these patients in the ECOG E1912 study identified a trend toward improvement in progression-free survival with ibrutinib plus rituximab, but the difference was not statistically significant. This finding will still influence some clinicians to use chemoimmunotherapy in younger patients with mutated IGHV.
Similarly, the Alliance A041202 trial of older patients also showed that ibrutinib combinations were better than chemoimmunotherapy.3 However, there was a higher incidence of sudden death and cardiovascular toxicity among older patients treated with ibrutinib.
Conclusion
Multiple new therapeutic options and combination regimens are now available that are generally well tolerated and extremely effective for the majority of patients with CLL. Moreover, chemoimmunotherapy has an increasingly limited role in the routine management of patients with CLL. The use of MRD assessment as a surrogate for clinical outcomes is also being routinely utilized to guide treatment discontinuation decisions.
Disclosure
Dr Awan has served as a consultant for Gilead, Genentech, Roche, DAVA Oncology, AbbVie, Kite Pharma, Blueprint Medicine, Sunesis, Pharmacyclics, AstraZeneca, Janssen, Celgene, and Karyopharm.
References
1. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients with treatment-naive chronic lymphocytic leukemia [ASH abstract 31]. Blood. 2019;134(suppl 1).
2. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110.
3. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
4. Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011-1019.
5. Freeman CL, Morschhauser F, Sehn L, et al. Cytokine release in patients with CLL treated with obinutuzumab and possible relationship with infusion-related reactions. Blood. 2015;126(24):2646-2649.
6. Lujan JV, Lengerke-Diaz PA, Jacobs C, et al. Ibrutinib reduces obinutuzumab infusion-related reactions in patients with chronic lymphocytic leukemia and is associated with changes in plasma cytokine levels. Haematologica. 2020;105(1):e22-e25.
7. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.
8. Frei CR, Le H, McHugh D, et al. Treatment patterns and outcomes of 1205 patients on novel agents in the US Veterans Health Administration (VHA) system: results from the largest retrospective EMR and chart review study in the real-world setting [ASH abstract 795]. Blood. 2019;134 (suppl 1).
9. Marwick C. Link found between Agent Orange and chronic lymphocytic leukaemia. BMJ. 2003;326(7383):242.
10. Barr P, Robak T, Owen C, et al. Updated efficacy and safety from the phase III RESONATE-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia [ASH abstract 234]. Blood. 2016;128(suppl 22).
11. Barr PM, Robak T, Owen C, et al. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018;103(9):1502-1510.
12. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
13. Byrd JC, Hillmen P, O’Brien SM, et al. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): up to four years follow-up of the RESONATE study [ASH abstract 7510]. J Clin Oncol. 2017;130(suppl 1)
14. Moreno C, Byrd JC, Hillmen P, et al. Ibrutinib in previously treated chronic lymphocytic leukemia: updated efficacy and safety of the RESONATE study with up to four years of follow-up [ESMO abstract S769]. Ann Oncol. 2017;28(suppl 5).
15. Mato AR, Nabhan C, Thompson MC, et al. Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis. Haematologica. 2018;103(5):874-879.
16. Coutré SE, Barrientos JC, Brown JR, et al. Management of adverse events associated with idelalisib treatment: expert panel opinion. Leuk Lymphoma. 2015;56(10):2779-2786.
17. Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL) [ASH abstract 32]. Blood. 2019;134 (suppl 1).
18. Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3(9):1553-1562.
19. ClinicalTrials.gov. Study of acalabrutinib (ACP-196) in combination with venetoclax (ABT-199), with and without obinutuzumab (GA101) versus chemoimmunotherapy for previously untreated CLL. https://clinicaltrials.gov/ct2/show/NCT03836261. Identifier: NCT03836261. Accessed January 8, 2020.
20. ClinicalTrials.gov. Acalabrutinib in combination with anti-CD20 and venetoclax in relapsed/refractory or untreated CLL/SLL/PLL. https://www.clinicaltrials.gov/ct2/show/NCT02296918. Identifier: NCT02296918. Accessed January 8, 2020.
21. ClinicalTrials.gov. Acalabrutinib and venetoclax with or without early obinutuzumab for the treatment of high risk, recurrent, or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. https://clinicaltrials.gov/ct2/show/NCT04169737. Identifier: NCT04169737. Accessed January 8, 2020.
22. 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 (CLL/SLL): updated results from a phase 1/2 trial [ASH abstract 500]. Blood. 2019;134 (suppl 1).
23. FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage. FDA.gov. https://www.fda.gov/news-events/press-announcements/fda-approves-therapy-treat-patients-relapsed-and-refractory-mantle-cell-lymphoma-supported-clinical. Posted November 14, 2019. Accessed January 9, 2020.
24. Strati P, Keating MJ, O’Brien SM, et al. Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion. Haematologica. 2014;99(8):1350-1355.
25. Shanafelt T, Wang XV, 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 [ASH abstract 33]. Blood. 2019;134 (suppl 1).
26. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.