A Review of Selected Presentations From the 2019 ASCO Annual Meeting
• May 31-June 4, 2019 • Chicago, Illinois
Final Analysis From RESONATE: Six-Year Follow-Up in Patients With Previously Treated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma on Ibrutinib
Ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), is approved for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).1 The multicenter, open-label, phase 3 RESONATE trial (A Phase 3 Study of Ibrutinib [PCI-32765] Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia) compared once-daily oral therapy with ibrutinib (420 mg) vs intravenous ofatumumab (300 mg initial dose, followed by 11 doses at 2000 mg administered throughout 24 weeks) in 391 patients with previously treated CLL/SLL. Enrolled patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had measurable disease, and were not candidates for purine analogue therapy. The primary endpoint was progression-free survival (PFS). Patients were a median age of 67 years (range, 30-88 years), 58% had Rai stage III/IV disease, and 46% had received at least 3 prior therapies. After a median follow-up of 9.4 months, the median PFS was not reached with ibrutinib vs 8.1 months with ofatumumab (hazard ratio [HR], 0.22; P<.001).2 Ibrutinib was also associated with superior overall survival (OS; HR, 0.43; P<.001), reducing the risk of death by 57%. The objective response rate (ORR) was 42.6% with ibrutinib vs 4.1% with ofatumumab (P<.001).
Long-term efficacy in the RESONATE study was evaluated after a median follow-up of 65.3 months (range, 0.3+ to 71.6 months) in the ibrutinib arm and 65.6 months (range, 0.1-73.9 months) in the ofatumumab arm.3 The median duration of treatment was 41.0 months with ibrutinib and 5.3 months with ofatumumab. The most common reasons for discontinuation of ibrutinib were disease progression (37%) and adverse events (AEs; 16%). Among the patients in the ofatumumab arm, 68% crossed over to the ibrutinib arm during the study.
In the intention-to-treat population, the median PFS was 44.1 months with ibrutinib vs 8.1 months with ofatumumab (HR, 0.148; 95% CI, 0.113-0.196; Figure 1). The median OS was 67.7 months vs 65.1 months (HR, 0.810; 95% CI, 0.602-1.091).
Several secondary analyses evaluated the outcomes according to the patients’ mutational status. In the subset of patients with the chromosome 17p deletion (del[17p]), chromosome 11q deletion (del[11q]), TP53 mutation, or unmutated immunoglobulin heavy chain variable (IGHV), the median PFS was 44.1 months with ibrutinib vs 8.0 months with ofatumumab (HR, 0.110; 95% CI, 0.080-0.152). Among patients in the ibrutinib arm, the longest median PFS was observed in patients with del(11q), at 60.7 months. The median PFS was 40.6 months in patients with del(17p) and 42.5 months in patients lacking del(11q) or del(17p) (Figure 2). In an exploratory analysis, the median PFS was 40.6 months in patients with del(17p) and/or the TP53 mutation vs 56.9 months in patients with del(11q). The median PFS was not reached in patients who lacked del(17p), del(11q), and the TP53 mutation. The median PFS was 48.4 months in patients with mutated IGHV and 49.7 months for those with unmutated IGHV.
In the ibrutinib arm, infections of grade 3 or higher occurred in 87 patients (45%), with a median time of onset of 7.0 months (range, 0.0-63.0 months). Hypertension of any grade occurred in 41 patients treated with ibrutinib (21%). The median time of onset of hypertension was 13.8 months (range, 1.0-54.0 months).
1. Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics LLC; 2016.
2. 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.
3. Barr PM, Munir T, Brown JR, et al. Final analysis from RESONATE: six-year follow-up in patients (pts) with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) on ibrutinib [ASCO abstract 7510]. J Clin Oncol. 2019;37(18 suppl).
Acalabrutinib With Obinutuzumab in Treatment-Naive and Relapsed/Refractory Chronic Lymphocytic Leukemia: Three-Year Follow-Up
Acalabrutinib is a covalent inhibitor of BTK that has shown minimal off-target binding. In a phase 1/2 study of 61 patients with relapsed CLL, acalabrutinib showed no dose-limiting toxicities and yielded an ORR of 95%.1 Results in treatment-naive patients with CLL have also demonstrated acceptable safety and high response rates.2 Acalabrutinib was evaluated in combination with obinutuzumab in a phase 1/2 study of patients with CLL.3 The trial enrolled 19 treatment-naive CLL/SLL patients ages 65 years or older, as well as younger patients who were ineligible for chemoimmunotherapy. Twenty-six patients with relapsed or refractory disease were also enrolled. Patients had a diagnosis of CLL or SLL with measurable disease.4 They had an ECOG performance status of 0 to 2, and they met the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2008 criteria for treatment. Patients received acalabrutinib at 100 mg twice daily or 200 mg once daily in 28-day cycles. Patients also received obinutuzumab beginning with cycle 2. The cycle 2 loading dose of obinutuzumab was administered at 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15. During cycles 3 to 7, patients received obinutuzumab (1000 mg, day 1). Minimal residual disease (MRD) was measured using multicolor flow cytometry with a 10-4 cutoff.
Among the 45 enrolled patients, the median age was approximately 62 years (range, 42-76 years). Most patients were male, and all patients had an ECOG performance status of 0 or 1. Approximately half of patients had bulky disease. Rai stage III/IV disease was observed in 53% of treatment-naive patients and 27% of previously treated patients. Among the 26 patients with relapsed or refractory disease, the median number of prior therapies was 1 (range, 1-9). Nearly all of the patients had a diagnosis of CLL, with the exception of 1 treatment-naive SLL patient. After a median follow-up of approximately 3.5 years, 78% of patients remained on treatment. Acalabrutinib was discontinued by 11% of treatment-naive patients and 31% of previously treated patients, most commonly owing to an AE. The full course of obinutuzumab was completed by 89% of treatment-naive patients and 100% of previously treated patients.
In the treatment-naive group, the ORR was 95%, including a partial response (PR) rate of 63.2% and a complete response (CR) rate of 31.6%. The median time to a PR or CR was 2.8 months (range, 2.8-2.8 months), and the median time to a CR was 18.4 months (range, 5.6-32.3 months). Among patients with a PR at 22 months’ follow-up, 3 demonstrated a CR at 39 months of follow-up, a finding that is consistent with deepening responses over time. Based on bone marrow analysis, 5 of the 19 treatment-naive patients (26%) had undetectable MRD at the beginning of cycle 12. Among the 26 patients with relapsed or refractory disease at enrollment, 84.6% experienced a PR and 7.7% had a CR, yielding an ORR of 92%. The median time to response was 2.8 months (range, 2.7-21.4 months), and the median time to CR was 12.9 months (range, 10.2-15.7 months). Based on bone marrow analysis, 4 patients with relapsed or refractory disease at baseline (15%) were MRD-negative on day 1 of cycle 12. The median durations of response and PFS were not reached in the subgroups of treatment-naive or previously treated patients. The 39-month PFS rate was 94.4% (95% CI, 66.6%-99.2%) in treatment-naive patients (Figure 3). The 42-month PFS rate was 72.7% (95% CI, 43.8%-88.4%) in previously treated patients. MRD negativity was more common among treatment-naive patients (26% vs 15%). MRD responses in the peripheral blood were generally maintained over time, as observed through cycle 36.
Among the entire cohort, the most common AEs of any grade included upper respiratory tract infection (73%), increased weight (72%), and maculopapular rash (66%). The most common grade 3/4 AEs were decreased neutrophil count (24%) and syncope (11%), followed by decreased platelet count, cellulitis, and increased weight (9% each). The most common serious AE was cellulitis (9%), followed by diarrhea, dyspnea, pneumonia, pyrexia, and syncope (4% each). AEs leading to discontinuation included grade 1 vomiting, grade 3 maculopapular rash, grade 3 diarrhea, grade 3 lung adenocarcinoma, and grade 3 squamous cell carcinoma, each observed in 1 patient. Richter transformation was observed in 1 treatment-naive and 2 previously treated patients. No grade 5 AEs occurred. Bleeding events of any grade occurred in 71%.
One patient with relapsed or refractory disease at baseline had a history of atrial fibrillation, and this patient developed atrial fibrillation prior to the 2-year follow-up.5 No additional atrial fibrillation events were observed as part of the 3.5-year follow-up. Hypertension of any grade occurred in 40% of patients.
1. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332.
2. Byrd JC, Woyach JA, Furman RR, al. Acalabrutinib in treatment-naive (TN) chronic lymphocytic leukemia (CLL): updated results from the phase 1/2 ACE-CL-001 study [ASH abstract 692]. Blood. 2018;132.
3. Woyach JA, Rogers KA, Bhat SA, et al. Acalabrutinib with obinutuzumab (Ob) in treatment-naive (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): three-year follow-up [ASCO abstract 7500]. J Clin Oncol. 2019;37(18 suppl).
4. Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
5. Woyach JA, Awan FT, Jianfar M, et al. Acalabrutinib with obinutuzumab in relapsed/refractory and treatment-naive patients with chronic lymphocytic leukemia: the phase 1b/2 ACE-CL-003 study [ASH abstract 432]. Blood. 2017;130.
Long-Term Follow-Up of Previously Untreated Patients With Chronic Lymphocytic Leukemia Treated With Ofatumumab and Chlorambucil: Final Analysis of the Phase 3 COMPLEMENT 1 Trial
The phase 3 COMPLEMENT 1 trial (Ofatumumab + Chlorambucil vs Chlorambucil Monotherapy in Previously Untreated Patients With Chronic Lymphocytic Leukemia) evaluated chlorambucil with or without ofatumumab in treatment-naive patients with CLL.1 The final analysis of the COMPLEMENT 1 study was based on 5 years of follow-up.2 The study included treatment-naive patients with CLL with active disease and an ECOG performance status of 0 to 2 who were not eligible for fludarabine-based treatment. Prior to randomization, patients were stratified by disease stage, age, and ECOG performance status. The trial randomly assigned 447 patients to receive chlorambucil (10 mg/m2, days 1-7) for 12 cycles of 28 days, either as monotherapy or with the addition of ofatumumab (300 mg, day 1 of cycle 1; 1000 mg, day 8 of cycle 1; then 1000 mg, day 1 of cycles 2-12).
At the time of the 5-year analysis, 183 patients (41%) had died, 245 (55%) had withdrawn from the study, and 19 (4%) had completed 5 years of follow-up. The most common reason for withdrawal was study termination by the sponsor (33%). Patient and disease characteristics were well balanced between the 2 treatment arms. Patients had a median age of 69 years (range, 35-92 years), and 69% were ages 65 years or older. Most patients (63%) were male, and 40% had Rai stage III/IV disease. IGHV sequence homology exceeding 98% was observed in 56% of patients, and the most common chromosomal aberration was deletion 13q, seen in 53%.
The median OS was not estimable with ofatumumab plus chlorambucil vs 84.7 months with chlorambucil monotherapy (HR, 0.88; 95% CI, 0.65-1.17; P=.363; Figure 4). OS was similar among subgroups based on Rai or Binet stage disease at study entry. There were 10 on-treatment deaths (5 in each arm). Median PFS was 23.4 months in the ofatumumab plus chlorambucil arm vs 14.7 months in the chlorambucil monotherapy arm (HR, 0.61; 95% CI, 0.49-0.76; P<.001). After discontinuation of study treatment, a greater proportion of patients in the chlorambucil monotherapy arm received further anticancer therapy (66% vs 56%), and subsequent therapy was initiated sooner among patients in the chlorambucil monotherapy arm (median, 486 vs 743 days).
No new safety concerns were raised with the combination treatment. AEs of any grade were observed in 96% of patients in the ofatumumab plus chlorambucil arm vs 90% in the chlorambucil monotherapy arm. AEs of grade 3 or higher occurred in 64% vs 48%, respectively. The most common AEs of grade 3 or higher were neutropenia (26% in the combination arm vs 15% in the monotherapy arm), thrombocytopenia (5% vs 10%), and pneumonia (9% vs 5%). Serious AEs that were considered drug-related were observed in 15% of the combination arm vs 13% of the monotherapy arm.
1. Hillmen P, Robak T, Janssens A, et al; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385(9980):1873-1883.
2. Offner F, Robak T, Janssens A, et al. Long-term follow-up of previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) treated with ofatumumab (OFA) and chlorambucil (CHL): final analysis of the phase 3 COMPLEMENT 1 trial [ASCO abstract 7528]. J Clin Oncol. 2019;37(18 suppl).
TRANSCEND CLL 004: Minimal Residual Disease Negative Responses After Lisocabtagene Maraleucel (JCAR017), a CD19-Directed CAR T-Cell Product, in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
Lisocabtagene maraleucel, also known as JCAR017, is a chimeric antigen receptor (CAR) T-cell product directed at CD19.1 The lisocabtagene maraleucel product is created by separately expanding the patient’s engineered CD4-positive and CD8-positive cells. The 2 cell types are then administered in precise 1-to-1 doses. Lisocabtagene maraleucel was evaluated in the phase 1 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]) of patients with relapsed or refractory CLL/SLL.2 The study enrolled patients who were ineligible for treatment with a BTK inhibitor or had an inadequate response to this therapy. Patients had an ECOG performance status of 0 or 1. Patients with high-risk cytogenetic factors (eg, the TP53 mutation, unmutated IGHV) had failed at least 2 prior therapies, including a BTK inhibitor. Patients at standard risk had failed at least 3 previous therapies. The study used a modified toxicity probability interval to guide dose escalation. Patients were monitored for dose-limiting toxicities, and responses were assessed based on iwCLL 2008 criteria.3 The primary objectives were to determine the recommended dose of lisocabtagene maraleucel and to evaluate safety. Bridging therapy was allowed after enrollment and leukapheresis. Measurable disease was reconfirmed prior to initiation of study therapy. Lymphodepletion was carried out by daily fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) administered for 3 days. Within 2 to 7 days after lymphodepletion chemotherapy, lisocabtagene maraleucel was administered at 2 dose levels: 50 × 106 CAR T cells and 100 × 106 CAR T cells. MRD was assessed in the blood by flow cytometry, using a cutoff of 10-4, and in the bone marrow by next-generation sequencing, using a cutoff of 10-6.
The trial enrolled 9 patients into the lower dose level cohort and 14 into the higher dose level cohort. The 23 patients had a median age of 66 years (range, 49-79 years), and 48% were male. Bulky disease was observed in 35% of patients, and 65% had Rai stage III/IV disease. Fewer patients in the lower dose level cohort had received bridging therapy (56% vs 86%) or had high-risk genetics (67% vs 93%).
After a median follow-up of 9 months (minimum, 1 month), the best ORR in 22 patients was 81.8%, including a rate of 36.4% for PR/nodular PR and of 45.5% for CR/CR with incomplete blood count recovery (Figure 5). Undetectable MRD was seen in 75% of patients based on blood analysis and in 65% based on bone marrow analysis. An objective response was reported in 68% of patients (15/22), and 60% (12/20) had undetectable MRD in the bone marrow by day 30. Responses deepened over time in 27% of patients (6/22). Durable responses were observed at 6 months after administration of CAR T-cell therapy in most patients. Among 6 patients who experienced a CR at 6 months, this response was still evident at 9 months in 5 patients and beyond 12 months in 3 patients. Pharmacokinetic and pharmacodynamic profiling showed a rapid decrease in CD19-positive cells within 2 to 3 weeks after administration of the study treatment. The higher dose of 100 × 106 CAR T cells was chosen for the phase 2
portion of the study. A separate cohort of patients in the phase 1 portion of the study is receiving lisocabtagene maraleucel in combination with ibrutinib.
Throughout both patient cohorts, the most common treatment-emergent AEs of any grade were anemia (83%), cytokine release syndrome (74%), and thrombocytopenia (74%). The most common AEs of grade 3 or higher included anemia (78%), thrombocytopenia (70%), and neutropenia (57%). High-grade AEs were more common in patients who received the higher dose of CAR T cells. Two dose-limiting toxicities were observed, both in the higher-dose cohort. They consisted of grade 4 hypertension in 1 patient, and a combination of grade 3 encephalopathy, grade 3 muscle weakness, and grade 4 tumor lysis syndrome in the other.
Across the 2 cohorts, the most common serious treatment-emergent AEs of any grade included cytokine release syndrome (26%), pyrexia (17%), encephalopathy (13%), febrile neutropenia (13%), and pneumonia (13%). Six patients died during the study: 4 from disease progression, 1 from respiratory failure that was unrelated to lisocabtagene maraleucel treatment, and 1 from an unknown cause. Across the 2 dose cohorts, cytokine release syndrome of any grade was observed in 74% of patients. Grade 3 cytokine release syndrome occurred in 2 patients receiving the higher dose vs no patients receiving the lower dose. Grade 3/4 tumor lysis syndrome was observed in 1 patient (11%) receiving the lower dose and 3 patients (21%) receiving the higher dose.
1. Chow VA, Shadman M, Gopal AK. Translating anti-CD19 CAR T-cell therapy into clinical practice for relapsed/refractory diffuse large B-cell lymphoma. Blood. 2018;132(8):777-781.
2. Siddiqi T, Dorritie KA, Soumerai JD, et al. TRANSCEND CLL 004: minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (liso-cel; JCAR017), a CD19-directed CAR T-cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) [ASCO abstract 7501]. J Clin Oncol. 2019;37(18 suppl).
3. Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
Phase 1/2 Trial of Cirmtuzumab and Ibrutinib: Planned Analysis of Phase 1 CLL Cohorts
Cirmtuzumab is a humanized antibody that binds with high specificity to the receptor tyrosine kinase–like orphan receptor 1 (ROR1). ROR1 is found on cancer stem cells and is expressed on malignant B cells in the vast majority of patients with CLL.1 In a study of 26 patients with CLL, cirmtuzumab exhibited acceptable safety, without dose-limiting toxicities.2 The antibody had a long plasma half-life and inhibited ROR1 signaling.
The combination of cirmtuzumab plus ibrutinib was evaluated in a phase 1/2 study of patients with CLL/SLL or mantle cell lymphoma.3 In the dose-finding portion of the trial, 3 patients were enrolled per cohort. Cirmtuzumab was administered every 2 weeks for the first 5 doses, followed by monthly administration, for a total duration of 1 year. The cirmtuzumab dose was based on weight, ranging from 2 mg/kg to 16 mg/kg per dose; or was administered in a fixed dose of 300 mg or 600 mg. During the first month, patients received cirmtuzumab monotherapy to allow for assessment of biomarkers. Ibrutinib (420 mg daily) was administered for 48 weeks.4 Patients with prior exposure to a BTK inhibitor were excluded from study enrollment.
The patients’ median age was 69 years (range, 57-86 years), and 3 patients were treatment-naive. Among the 9 patients with relapsed or refractory disease, the median number of prior therapies was 2 (range, 1-5). In the safety cohort of 18 patients, the most common treatment-emergent AEs for the duration of the study were contusions (50%), arthralgia (33%), and fatigue (28%). Two patients discontinued treatment owing to AEs that were unrelated to study treatment.
Results for the 12 patients evaluable for efficacy are shown in Figure 6. The ORR was 91.7%. ROR1 receptor occupancy was superior among patients who received the higher doses of cirmtuzumab. Among 3 patients who completed the 1-year planned treatment course, 1 patient with CLL demonstrated a CR (based on iwCLL criteria).5 Two patients—1 with CLL and 1 with mantle cell lymphoma—had a clinical CR, based on negative imaging and normalization of absolute lymphocyte count, with bone marrow assessment pending. Concurrent administration of cirmtuzumab with ibrutinib appeared to attenuate the lymphocytosis that can be seen with ibrutinib monotherapy. The recommended dose of cirmtuzumab chosen for further study was 600 mg (given with 420 mg daily of ibrutinib), based on safety, efficacy, pharmacokinetics, and pharmacodynamics.
1. Cui B, Ghia EM, Chen L, et al. High-level ROR1 associates with accelerated disease progression in chronic lymphocytic leukemia. Blood. 2016;128(25):2931-2940.
2. Choi MY, Widhopf GF II, Ghia EM, et al. Phase I trial: cirmtuzumab inhibits ROR1 signaling and stemness signatures in patients with chronic lymphocytic leukemia. Cell Stem Cell. 2018;22(6):951-959.e3.
3. Choi MY, Wierda WG, Lee HJ, et al. Phase 1/2 trial of cirmtuzumab and ibrutinib: planned analysis of phase 1 CLL cohorts [ASCO abstract 7527]. J Clin Oncol. 2019;37(18 suppl).
4. Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics LLC; 2016.
5. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
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
CLL and SLL disproportionately affect older patients, and many of these patients have comorbidities that preclude the administration of standard therapeutic regimens. The CLL11 trial (A Study of Obinutuzumab [RO5072759 (GA101)] With Chlorambucil in Patients With Previously Untreated Chronic Lymphocytic Leukemia [Stage 1a]) evaluated chlorambucil therapy, with or without an anti-CD20 antibody, among patients with treatment-naive CLL. The study enrolled patients with a Cumulative Illness Rating Scale (CIRS) score exceeding 6 or an estimated creatinine clearance of 30 mL to 69 mL/min.1,2 At baseline, the 781 patients had a median age of 73 years, a median CIRS score of 8 (range, 0-22), and a median creatinine clearance of 62 mL/min.
The median PFS was 31.1 months with chlorambucil plus obinutuzumab vs 11.1 months with chlorambucil monotherapy (HR, 0.21; 95% CI, 0.16-0.28; P<.0001).2 The median OS was not reached vs 66.7 months (HR, 0.68; 95% CI, 0.49-0.94; P=.0196).
Venetoclax is a BCL2 inhibitor that has shown promise in combination with obinutuzumab as therapy for treatment-naive patients with CLL and coexisting conditions.3 The combination of obinutuzumab plus venetoclax was evaluated in patients with CLL in the international, open-label phase 3 CLL14 trial (A Study to Compare the Efficacy and Safety of Obinutuzumab + Venetoclax [GDC-0199] Versus Obinutuzumab + Chlorambucil in Participants With Chronic Lymphocytic Leukemia).4,5 The study enrolled previously untreated patients with CLL. All patients had comorbidities, as well as a CIRS score exceeding 6 and/or an estimated creatinine clearance of less than 70 mL/min. The study randomly assigned patients to receive 6 cycles of venetoclax plus obinutuzumab followed by 6 cycles of venetoclax monotherapy, or 6 cycles of chlorambucil plus obinutuzumab followed by 6 cycles of chlorambucil monotherapy. All treatment cycles lasted 28 days, so both arms received a maximum of 12 months of treatment for CLL. MRD negativity was defined as less than 10-4 malignant cells. The primary endpoint was PFS.
The study randomly assigned 432 patients into the 2 treatment arms. The patients’ median age was 71 to 72 years, and the median CIRS score was 8 to 9. The median estimated creatinine clearance was 65.2 mL/min in the venetoclax/obinutuzumab arm and 67.5 mL/min in the chlorambucil/obinutuzumab arm. In each arm, 43% of patients had Binet stage C disease. In the venetoclax arm, 61% had unmutated IGHV, 12% had TP53 deletion and/or mutation, 9% had del(17p), and 18% had del(11q). In the control arm, 59% had unmutated IGHV, 12% had the TP53 deletion and/or mutation, 7% had del(17p), and 20% had del(11q).
The ORR was 85% with venetoclax plus obinutuzumab vs 71% with chlorambucil plus obinutuzumab (P<.0001). The median PFS was also longer with venetoclax plus obinutuzumab (HR, 0.35; 95% CI, 0.23-0.53; P<.0001; Figure 7). Two-year PFS was 88% with the venetoclax combination vs 64% with the chlorambucil combination. OS was similar for the 2 arms (P=.52). The addition of venetoclax to obinutuzumab improved the likelihood of achieving MRD negativity. The rate of MRD negativity in the peripheral blood was 76% in the venetoclax/obinutuzumab arm vs 35% in the chlorambucil/obinutuzumab arm (P<.001). The rate of CR with undetectable MRD was 42% vs 14% (P<.001). Similarly, bone marrow MRD was more likely with the venetoclax combination (57% vs 17%), as was the achievement of MRD negativity in CR (34% vs 11%). Low MRD levels persisted for several months after the cessation of venetoclax plus obinutuzumab. Based on next-generation sequencing of peripheral blood at 3 months after completion of treatment, MRD of less than 10-6 was achieved in 42% of patients in the venetoclax/obinutuzumab arm vs 7% in the control arm.
A grade 3/4 hematologic AE occurred in 60% of patients in the venetoclax/obinutuzumab arm and 55% in the chlorambucil/obinutuzumab arm. Neutropenia was the most common of these events, seen in 53% vs 48%. Infusion-related reactions occurred in 9% vs 10% of patients. Infections and infestations were observed in 18% vs 15%. Metabolic and nutritional disorders were observed in 12% vs 6%. Five patients (2%) in the venetoclax/obinutuzumab arm and 4 patients (2%) in the control arm died during the active treatment phase of the study. In addition, 11 patients (5%) in the venetoclax arm and 4 (2%) in the chlorambucil arm died after completion of study treatment.
1. 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.
2. Goede V, Fischer K, Dyer MJ, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. Abstract presented at: the 23rd Congress of the European Hematology Association; June 14-17, 2018; Stockholm, Sweden. Abstract S151.
3. Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129(19):2702-2705.
4. Fischer K, Al-Sawaf O, Bahlo J, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD–) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities [ASCO abstract 7502]. J Clin Oncol. 2019;37(18 suppl).
5. 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.
Effect of Dose Modifications on Response to Duvelisib in Patients With Relapsed/Refractory CLL/SLL in the DUO Trial
The open-label phase 3 DUO trial (A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory CLL/SLL) evaluated duvelisib vs ofatumumab in patients with relapsed or refractory CLL/SLL.1 The median PFS was superior with duvelisib (13.3 vs 9.9 months; HR, 0.52; P<.0001), as was ORR (74% vs 45%; P<.0001). The standard dose of duvelisib was 25 mg twice daily, administered continuously. To manage treatment-emergent AEs, the dose could be interrupted or reduced to 15 mg, 10 mg, or 5 mg administered twice daily.
A retrospective analysis of data from the DUO trial assessed the rate of duvelisib dose modifications and their impact on response.2 The 158 patients in the duvelisib arm had a median exposure to duvelisib of 11.6 months (range, 0.2-36.8 months). The median dose intensity was 97.7 (range, 34.7-100) out of a maximum score of 100. Dose interruptions were more common than dose reductions (80% vs 27%). The most common AEs of special interest that led to dose interruptions were diarrhea/colitis (28%), infection (27%), and cutaneous reactions (13%), whereas those that led to dose reductions were diarrhea/colitis (8%), cutaneous reactions (4%), and neutropenia (4%).
Among the 118 responders in the duvelisib arm, the median time to first response was 1.9 months, and the estimated median duration of response was 11.1 months. In 50 patients, the dose interruption lasted longer than 1 week. Treatment then resumed for at least 3 weeks. Among these patients, 84% maintained or improved their response. A similar observation was made in the cohort of patients who had a dose interruption lasting longer than 2 weeks. The median PFS was 17.8 months for the subset of patients with a dose interruption lasting at least 1 week vs 16.3 months for those who did not. The same durations of median PFS, 17.8 months and 16.3 months, were shown for patients who did or did not have a dose interruption lasting at least 2 weeks (Figure 8). Among patients with a dose reduction during the first 3 months of treatment, the median PFS was 22.1 months, vs 15.1 months among those without a dose reduction. Similarly, median PFS was longer in patients who had a dose reduction during the first 6 months of study treatment vs those who did not (22.1 vs 17.4 months). The study authors suggested that duvelisib dose interruptions and dose reductions can be used to manage treatment-emergent AEs in patients with relapsed or refractory CLL/SLL.
1. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018;132(23):2446-2455.
2. Flinn IW, Montillo M, Illés Á, et al. Effect of dose modifications on response to duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial [ASCO abstract 7523]. J Clin Oncol. 2019;37(18 suppl).
Phase 2 Study of Acalabrutinib in Ibrutinib-Intolerant Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia
Acalabrutinib monotherapy was evaluated in a multicenter, international, open-label phase 2 trial of patients with CLL who had developed intolerance to ibrutinib during prior treatment.1 The ACE-CL-208 trial (A Study of ACP-196 [Acalabrutinib] in Subjects With Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy) enrolled patients with CLL who had received at least 1 prior systemic treatment, with ibrutinib as the most recent prior therapy. Intolerance was defined as persistent grade 3 or 4 AEs that led to discontinuation of ibrutinib, or grade 2 AEs related to ibrutinib that persisted for at least 2 weeks or recurred at least twice, despite dose reduction or discontinuation. Patients developed disease progression after discontinuation of ibrutinib. Enrolled patients were not candidates for treatment with a purine analogue–based regimen. Acalabrutinib (100 mg) was administered twice daily in 28-day cycles until disease progression or unacceptable toxicity. AE severity was graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.
The 60 patients in the study were a median age of 70 years (range, 43-88 years), and 63% were male. Thirty-two percent had bulky lymph nodes, and 52% had Rai stage III/IV disease. Genetic risk factors included unmutated IGHV in 79%, del(17p) in 28%, and del(11q) in 23%. Mutations in phospholipase C gamma 2 (PLCG2) or BTK were each observed in 4% of patients. Among 55 patients tested, 52% had wild-type BTK and PLCG2 genes. The 60 patients had received a median of 2 prior therapies (range, 1-10). The median duration of prior ibrutinib therapy was 6 months (range, 1-56 months).
After a median follow-up of 23 months, 48 patients (80%) remained on the study. The investigator-assessed ORR was 72%, including a CR rate of 5%. The inclusion of PR with lymphocytosis increased the investigator-assessed ORR to 77% (Figure 9). Among 17 patients with del(17p), the ORR was 71% (95% CI, 44%-90%). The median duration of response, the median PFS, and the median OS were not reached.
Most AEs were grade 1 or 2. The most common AEs of grade 3 or higher were pneumonia (10%), neutropenia (8%), reduced neutrophil count (7%), decreased lymphocyte count (7%), and lymphocytosis (7%). Serious AEs of any grade were observed in 35% of patients and included pneumonia (10%) and syncope (3%). AEs led to treatment discontinuation in 12% of patients; these events consisted of pneumonia in 2 patients, as well as diarrhea, headache, endometrial cancer, arthralgia, and subdural hematoma, each observed in 1 patient. Grade 5 AEs included pneumonia (n=2), bronchopulmonary aspergillosis (n=1), and ventricular fibrillation (n=1), but none of these events were considered related to acalabrutinib treatment. Events of clinical interest included bleeding (62%), cardiac events (15%), hypertension (12%), and grade 3/4 infections (17%).
1. Rogers KA, Thompson PA, Allan JN, et al. Phase 2 study of acalabrutinib in ibrutinib (IBR)-intolerant patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [ASCO abstract 7530]. J Clin Oncol. 2019;37(18 suppl).
Outcomes in Chronic Lymphocytic Leukemia Patients With NOTCH1 Signaling Pathway Mutations
Dysregulation of the NOTCH1 pathway plays a key role in CLL pathogenesis, affecting cell growth, division, and apoptosis.1,2 Activating mutations in NOTCH1 are common in leukemic cells and associated with a poor prognosis. Less is known regarding how genes that regulate NOTCH1 contribute to the development and progression of CLL.
A retrospective study conducted at a single center assessed the relationship between mutations in genes that regulate NOTCH1 and outcomes in patients with CLL.3 The study included patients with a diagnosis of CLL who had data for next-generation sequencing, based on a lymphoid-specific gene panel. Genes of interest included mediator complex subunit 12 (MED12), F-box and WD repeat domain containing 7 (FBXW7), and spen family transcriptional repressor (SPEN). Mutations in these genes can lead to increased activity of NOTCH1. Outcomes in patients with mutations in MED12, FBXW7, and SPEN were pooled and then compared with outcomes in patients with the wild-type genes, as well as wild-type NOTCH1.
The study analyzed data from 557 patients who underwent next-generation sequencing. It found that 33 (5.9%) had a mutation in MED12, FBXW7, or SPEN; 63 (11.3%) had a mutation in NOTCH1; and 465 (83.5%) had wild-type copies of these genes. Ten patients (1.8%) had MED12 mutations, 17 (3.1%) had FBXW7 mutations, and 9 (1.6%) had mutations in the SPEN gene. More than half of the patients had Rai stage 0 or 1 disease.
Compared with the wild-type cohort, patients with mutations in NOTCH1 or the regulatory genes of interest were more likely to have CD38-positive disease, trisomy 12, and unmutated IGHV. The time to first treatment was significantly reduced among patients who had a mutation in MED12, FBXW7, or SPEN compared with patients who lacked mutations in these genes and in NOTCH1 (P=.039; Figure 10). Based on a univariate analysis, the time to first treatment was decreased among patients with CD38-positive disease, unmutated IGHV, Zap-70 expression, del(11p), del(17p), the TP53 mutation, or a mutation in any of the NOTCH1 regulatory genes of interest (MED12, FBXW7, or SPEN). However, multivariate analysis showed that only unmutated IGHV remained as an independent predictor of reduced time to first treatment (P<.001).
1. Di Ianni M, Baldoni S, Rosati E, et al. A new genetic lesion in B-CLL: a NOTCH1 PEST domain mutation. Br J Haematol. 2009;146(6):689-691.
2. Rosati E, Baldoni S, De Falco F, et al. NOTCH1 aberrations in chronic lymphocytic leukemia. Front Oncol. 2018;8:229.
3. Helbig DR, Zeinah GF, Bhavsar EB, et al. Outcomes in chronic lymphocytic leukemia (CLL) patients with NOTCH1 signaling pathway mutations [ASCO abstract 7524]. J Clin Oncol. 2019;37(18 suppl).
Highlights in Chronic Lymphocytic Leukemia From the 2019 American Society of Clinical Oncology Annual Meeting: Commentary
Susan M. O’Brien, MD
At the 2019 American Society of Clinical Oncology Annual Meeting, several presentations in chronic lymphocytic leukemia (CLL) explored new treatment options, such as lisocabtagene maraleucel, venetoclax plus obinutuzumab, and acalabrutinib. Long-term follow-up data were presented for ibrutinib.
CAR T-Cell Therapy
Dr Tanya Siddiqi presented results from the phase 1 component of the TRANSCEND CLL 004 trial, which evaluated lisocabtagene maraleucel, a chimeric antigen receptor (CAR) T-cell therapy, in patients with CLL.1 There are CAR T-cell therapies approved by the US Food and Drug Administration (FDA) for pediatric acute lymphoblastic leukemia and adult lymphoma, but none for CLL.2 A unique characteristic of this product, also known as liso-cel, is that it uses equal amounts of CD4 and CD8 T cells. With most of the other CAR T-cell therapies, this ratio is not fixed. Researchers performing preclinical work on liso-cel suggested that efficacy and toxicity might be better with a product that uses a 1-to-1 ratio of CD4 to CD8.3 The phase 1 cohort included 23 patients with CLL, so it was not a large number. The patients were heavily pretreated, with a median of 5 prior therapies. All patients had received prior ibrutinib, and more than half had received prior venetoclax. This study continues the theme of using CAR T-cell therapy in the most advanced patients who have few other options.
Two dose-limiting toxicities were reported: a case of grade 4 hypertension and a case of grade 3 encephalopathy, grade 3 muscle weakness, and grade 4 tumor lysis syndrome. Cytokine-release syndrome occurred in 73.9% of patients, but only 2 cases were grade 3 or higher. That low incidence of severity is promising. The main toxicity concerns with CAR T-cell therapy are grade 3 to 4 cytokine release syndrome and neurotoxicity. Grade 3/4 neurologic events occurred in 21.7% of patients.
Liso-cel was associated with a high response rate of 81.9%, with a complete response (CR) rate of 45.5%. Many patients had undetectable minimal residual disease (MRD) at day 30.
Data from this phase 1 trial are encouraging. The study investigators selected the higher dose for evaluation in the phase 2 portion of the trial. The efficacy and toxicity were similar between the 2 doses. However, early data showed that the CAR T cells persisted longer with the higher dose, which could be important for efficacy in the long-term.
Venetoclax and Obinutuzumab
CLL-14 evaluated the effect of fixed-duration venetoclax plus the anti-CD20 agent obinutuzumab in patients with previously untreated CLL.4 Approximately a year ago, results of the MURANO trial were presented.5 The MURANO trial compared venetoclax plus the anti-CD20 therapy rituximab vs bendamustine plus rituximab in relapsed CLL. A hallmark of the MURANO trial was that it tested a time-limited small-molecule therapy. Patients in the bendamustine plus rituximab arm received the standard 6-cycle regimen. Patients in the venetoclax plus rituximab arm received 6 cycles of the antibody and then single-agent venetoclax for 2 years total. This strategy was novel because the small molecules, including venetoclax, are administered as continuous therapy until the patient becomes intolerant to treatment or develops progressive disease. The MURANO trial showed high response rates with the novel strategy. Results presented at the 2018 American Society of Hematology meeting showed that after a year of follow-up among all patients off-therapy, most of the remissions persisted.6
The CLL-14 study also evaluated a time-limited strategy. The antibody was changed to obinutuzumab, which the investigators thought might be more potent. The trial enrolled more than 400 patients, with a median age older than 70. The eligibility criteria did not specify older patients, but it required a high comorbidity score and/or reduced renal function. These eligibility criteria are used in all of this group’s trials that are directed at older, less-fit patients. The patients were randomly assigned to treatment with venetoclax or chlorambucil, both in combination with obinutuzumab for 6 cycles, followed by single-agent venetoclax or chlorambucil alone for 6 cycles. In contrast to the MURANO trial, single-agent venetoclax was given for only 1 year. The idea was that in this population of previously untreated patients, those likely to achieve undetectable MRD would do so in a shorter period compared with patients who have relapsed disease.
The study’s primary endpoint of progression-free survival (PFS) was significantly better with venetoclax plus obinutuzumab. The median PFS was not reached. The MRD undetectable rate in the peripheral blood was 76% with venetoclax plus obinutuzumab vs only 35% with chlorambucil plus obinutuzumab. This rate is high for chlorambucil, and likely reflects the addition of obinutuzumab. Bone marrow MRD was undetectable in 57% of patients receiving venetoclax plus obinutuzumab vs only 17% in those receiving the chlorambucil-based regimen. These high rates of MRD negativity were exciting to see in patients who stopped therapy after 1 year. The median time off treatment was approximately 19 months, and most of the remissions achieved with venetoclax plus obinutuzumab were still persisting at that time. It will be interesting to see how durable these remissions are. It is an important advantage to be able to administer small molecules in a time-limited fashion.
The combination regimen of venetoclax plus obinutuzumab was well tolerated. The most frequent adverse event (AE) was neutropenia, which developed in 53% of the venetoclax arm and 48% of the chlorambucil arm. Chlorambucil is a weak chemotherapy, so myelosuppression is minimal. With venetoclax, neutropenia can sometimes prevent use of the full dose of 400 mg.
Dr Kerry Rogers presented results of a trial evaluating acalabrutinib in patients with CLL who were intolerant to ibrutinib.7 Ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor approved by the FDA, and it is the only one currently approved for CLL. Acalabrutinib is approved for mantle cell lymphoma,8 but not CLL. Another BTK inhibitor, zanubrutinib, is undergoing evaluation in clinical trials.9,10 A putative advantage of next-generation BTK inhibitors is that they may be more potent against BTK than ibrutinib; confirmation remains to be seen. In addition, it is known that they have higher half maximal inhibitory concentration (IC50) values for some of the other kinases targeted by ibrutinib. A possible advantage to the higher IC50 values concerns the drugs’ toxicity profiles. It is thought that some of the AEs associated with ibrutinib, such as atrial fibrillation and bleeding problems from platelet dysfunction, are not related to inhibition of BTK, but rather to inhibition of other kinases, such as Tec or the epidermal growth factor receptor. Boys with X-linked agammaglobulinemia are born with mutations in their BTK, but they do not have any bleeding disorders or platelet dysfunction. This suggests that some of the toxicities associated with ibrutinib may be off-target, and are not related to the inhibition of BTK.
An ongoing, randomized head-to-head trial is comparing acalabrutinib vs ibrutinib in relapsed patients with high-risk CLL (defined as having the 17p or 11q deletions).11 Zanubrutinib is also being studied in a head-to-head comparison with ibrutinib.9 Data from direct comparison trials of ibrutinib vs the next-generation BTK inhibitors are therefore forthcoming. Currently, it is known that the toxicity profiles differ. Phase 1/2 presentations have shown that a common AE with acalabrutinib is headache, which tends to be minor.12 Headaches become less common over time, as is seen with diarrhea among patients treated with ibrutinib. The study presented by Dr Rogers evaluated acalabrutinib in patients who could not tolerate ibrutinib owing to either persistent grade 3 or 4 AEs, or grade 2 AEs that persisted or recurred even after the dose was reduced or discontinued. Grade 3 to 4 AEs are uncommon with ibrutinib. It is more common to see persistent or recurrent grade 2 AEs. Most patients can tolerate grade 2 toxicity for a limited period. Since ibrutinib is given indefinitely, however, even these grade 2 AEs can become intolerable over time. All patients in the trial developed progressive disease after discontinuing ibrutinib.
Acalabrutinib was administered at 100 mg twice daily. Unlike ibrutinib, which is administered once daily, both acalabrutinib and zanubrutinib are administered twice daily. The primary endpoint of the study was overall response. Tolerability was a key secondary endpoint. The trial enrolled 60 patients, who had received a median of 2 prior therapies. The median duration of prior ibrutinib therapy was approximately 6 months, but the duration was much longer for some patients. Not surprisingly, atrial fibrillation was the most frequent AE that led to discontinuation of ibrutinib; others included diarrhea, arthralgia, and rash, which are also known to be associated with ibrutinib.
After a median follow-up of approximately a year and a half, two-thirds of the patients were still receiving acalabrutinib, which shows that they were tolerating treatment well. Approximately half the cases of treatment discontinuation were related to disease progression, and only 10% were due to AEs. The response rate of 77% was not higher than that typically seen with ibrutinib, but it is similar. It is comforting to know that in patients who discontinue ibrutinib because of toxicity, another BTK inhibitor can have very good efficacy. The main AE of interest was atrial fibrillation, which occurred in 3 patients. All episodes were grade 1 to 2. Major bleeding occurred in 2 patients.
The use of acalabrutinib will be an attractive strategy once it is approved by the FDA, certainly for patients who cannot tolerate ibrutinib. Without data from randomized trials, it is difficult to say whether acalabrutinib should be used before ibrutinib. Ibrutinib is a very active drug that is well tolerated in most patients. The current trial data do not provide an incentive to start treatment with acalabrutinib rather than ibrutinib. One possible exception might be in patients with prior or current atrial fibrillation. It is possible that physicians may elect to use acalabrutinib before ibrutinib in patients who have a history of atrial fibrillation but no recent episodes. There is a chance that atrial fibrillation will be less likely to recur with acalabrutinib vs ibrutinib. However, in patients with atrial fibrillation that is well controlled, treatment with ibrutinib will not necessarily exacerbate the condition.
Hypertension is another AE seen with ibrutinib. The reported frequencies vary, but it appears that hypertension becomes more common with longer durations of treatment. Ibrutinib is administered indefinitely, and hypertension does not always arise early in the treatment course. It stands to reason that the longer patients receive ibrutinib, the more likely they are to develop hypertension. In contrast, there is a decrease in the incidence of the more common AEs, such as diarrhea or rash. To determine the long-term impact of ibrutinib on blood pressure, researchers at the MD Anderson Cancer Center performed a retrospective study of 150 patients treated in clinical trials.13 The study assessed how many patients developed new-onset hypertension, which was defined as a systolic rate greater than 130 mm Hg and/or a diastolic rate greater than 80 mm Hg on 2 separate visits with no prior history of hypertension or antihypertensive therapy. Preexisting hypertension was seen in 44%, as would be expected in an older population with comorbidities. Forty percent of the patients were receiving antihypertensive therapy before they started ibrutinib. Among patients without a prior diagnosis of hypertension, nearly two-thirds met the study criteria for diagnosis. Only approximately half of these patients were then started on therapy, which could mean 1 of 2 things. It may be that physicians are undertreating hypertension or failing to recognize it. A more probable explanation is that some of these patients met the criteria based on a rare-time reading. Elevations in blood pressure can be related to stress or other circumstances.
Nearly one third of the patients required initiation of antihypertensive therapy during treatment with ibru-tinib. This finding is reasonable and consistent with other studies. The retrospective study also eval-uated possible predictors for new hypertension. New onset was not associated with cigarette or tobacco use, obesity, kidney disease, or sleep apnea. Therefore, it was not easy to predict which patients would develop hypertension.
This study highlights the need for clinicians to pay attention to their patients’ blood pressure during treatment with ibrutinib. This should be feasible because when patients visit the clinic, they always have their vital signs monitored. In my own practice, I sometimes ask patients receiving long-term ibrutinib to keep a log of blood pressure readings. For example, if I notice that a patient has an elevated blood pressure reading during a visit, and if their next appointment is some time away, I ask him or her to maintain a log of readings to review next time. An isolated abnormality should not be used to initiate treatment, but it is important to recognize hypertension that does require management.
Another important abstract was the final analysis of the RESONATE trial.14 This trial compared ibrutinib vs the anti-CD20 antibody ofatumumab in patients with relapsed/refractory CLL or small lymphocytic lymphoma, and it led to the full FDA approval of ibrutinib in this setting.15 Originally, ibrutinib received an accelerated approval based on phase 2 data.16,17 RESONATE was a confirmatory randomized trial of nearly 400 patients. The data showed that ibrutinib was dramatically better than ofatumumab, producing much longer durations of PFS. In many of the prior analyses, the median PFS had not been reached for ibrutinib.
The current analysis provided data for 6 years of follow-up; the median follow-up was 65.3 months.14 The RESONATE trial allowed treatment crossover, and two-thirds of the patients in the ofatumumab arm subsequently received ibrutinib. A sustained PFS benefit was observed with ibrutinib, with the median PFS now at 44 months vs 8 months with ofatumumab. This finding is particularly impressive given that two-thirds of patients in the ofatumumab arm crossed over to the ibrutinib arm. Ibrutinib was associated with very durable remissions, with a median of almost 4 years, in a very heavily pretreated population. The median number of prior regimens was between 3 and 4.
This randomized trial confirmed the phase 2 data, showing that even in a heavily pretreated population, the remissions were durable.14,17 The ORR was 88% with ibrutinib, a very high rate. CRs are not common with ibrutinib, particularly in the relapsed setting. The rate of CR/CR with incomplete bone marrow recovery was 11%, which is similar to the 10% reported in the phase 2 trial. An interesting finding is that even if the responses are not complete, they are still durable. In some cases, patients are not categorized as a CR based on very minimal disease, for example, a lymph node that measures between 1.5 cm and 2 cm on a computed tomography scan. Therefore, even the partial responses are very deep, with reductions in the lymph node bulk of 90% or 95%. These large reductions in tumor bulk might explain why the responses are so durable.
All-grade hypertension occurred in 21% of patients; it was grade 3 in 9%. As I discussed earlier, in the MD Anderson experience, 32% of patients began treatment for new-onset hypertension. The incidence of hypertension will rise slowly, not dramatically. Atrial fibrillation was seen in 12% of patients, which mirrors the typical range of 10% to 12% seen in other studies. Major hemorrhage was not common, occurring in only 10% of patients. The main reason for treatment discontinuation was disease progression; 37% of patients discontinued treatment for this reason. AEs led to treatment discontinuation in 16%. Another important aspect of these long-term follow-up trials is that they provide insight into how many patients discontinue ibrutinib over time because of toxicity. In most trials, this incidence ranges from 10% to 20%. This low long-term rate might reflect the fact that patients who do not tolerate treatment will have discontinued it before they would be eligible for long-term follow-up. However, it is encouraging to see that no unexpected toxicity arises in long-term studies. In fact, the discontinuation rates for AEs are highest in the first year, at 6%, and range from 3% to 6% each year thereafter. The 6-year analysis therefore shows that ibrutinib has no late unexpected toxicities, good long-term benefits, and very good long-term tolerability.
Dr O’Brien is a consultant for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc, Vaniam Group LLC, AbbVie, and Alexion. She has received research support from Kite, Regeneron, and Acerta. She is a consultant and/or has received research support from Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis.
1. Siddiqi T, Dorritie KA, Soumerai JD, et al. TRANSCEND CLL 004: minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (liso-cel; JCAR017), a CD19-directed CAR T-cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) [ASCO abstract 7501]. J Clin Oncol. 2019;37(18 suppl).
2. Pehlivan KC, Duncan BB, Lee DW. CAR-T cell therapy for acute lymphoblastic leukemia: transforming the treatment of relapsed and refractory disease. Curr Hematol Malig Rep. 2018;13(5):396-406.
3. Sommermeyer D, Hudecek M, Kosasih PL, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30(2):492-500.
4. Fischer K, Al-Sawaf O, Bahlo J, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD–) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities [ASCO abstract 7502]. J Clin Oncol. 2019;37(18 suppl).
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.
6. Seymour JF, Kipps TJ, Eichhorst B, et al. MURANO trial establishes feasibility of time-limited venetoclax-rituximab (VenR) combination therapy in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [ASH abstract 184]. Blood. 2018;132(suppl 1).
7. Rogers KA, Thompson PA, Allan JN, et al. Phase 2 study of acalabrutinib in ibrutinib (IBR)-intolerant patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [ASCO abstract 7530]. J Clin Oncol. 2019;37(18 suppl).
8. Witzig TE, Inwards D. Acalabrutinib for mantle cell lymphoma. Blood. 2019;133(24):2570-2574.
9. ClinicalTrials.gov. A study of zanubrutinib (BGB-3111) versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. https://clinicaltrials.gov/ct2/show/NCT03734016. Identifier: NCT03734016. Accessed June 27, 2019.
10. ClinicalTrials.gov. Study of zanubrutinib, obinutuzumab, and venetoclax in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). https://clinicaltrials.gov/ct2/show/NCT03824483. Identifier: NCT03824483. Accessed June 27, 2019.
11. ClinicalTrials.gov. Study of acalabrutinib (ACP-196) versus ibrutinib in previously treated subjects with high risk CLL. https://clinicaltrials.gov/ct2/show/NCT02477696. Identifier: NCT02477696. Accessed June 27, 2019.
12. Byrd JC, Owen R, O’Brien SM, et al. Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in hematologic malignancies [ASH abstract 4326]. Blood. 2017;130(suppl 1).
13. Jones J, George B, Peterson CB, et al. Long-term effects of ibrutinib on blood pressure in patients with chronic lymphocytic leukemia (CLL) [ASCO abstract e19009]. J Clin Oncol. 2019;37(18 suppl).
14. Barr PM, Munir T, Brown JR, et al. Final analysis from RESONATE: six-year follow-up in patients (pts) with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) on ibrutinib [ASCO abstract 7510]. J Clin Oncol. 2019;37(18 suppl).
15. 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.
16. de Claro RA, McGinn KM, Verdun N, et al. FDA approval: ibrutinib for patients with previously treated mantle cell lymphoma and previously treated chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3586-3590.
17. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58.