A Review of Selected Presentations From the XVIII iwCLL • September 20-23, 2019
• Edinburgh, Scotland
Ibrutinib Versus Placebo in Patients With Asymptomatic, Treatment-Naive Early-Stage Chronic Lymphocytic Leukemia: Primary Endpoint Results of the Phase 3 Double-Blind Randomized CLL12 Trial
A 1998 study of chlorambucil in patients with Binet stage A chronic lymphocytic leukemia (CLL) suggested that treatment of indolent disease was not beneficial.1 Since that time, novel drugs with improved efficacy and less toxicity have been incorporated into the management of several subgroups of patients with CLL. The double-blind, randomized phase 3 CLL12 trial (Ibrutinib in Previously Untreated Binet Stage A Chronic Lymphocytic Leukemia With Risk of Disease Progression) evaluated the efficacy and safety of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib as first-line treatment of patients with asymptomatic, Binet stage A CLL.2 Among the 515 patients enrolled in the trial, 152 had low-risk disease and were assigned to the watch-and-wait arm. The remaining 363 patients were randomly assigned to receive ibrutinib (420 mg daily) or placebo. Risk of progression was intermediate in 273 patients, high in 82 patients, and very high in 8 patients. The primary endpoint was event-free survival from the time of randomization until symptomatic disease progression, initiation of new treatment, or death. Secondary endpoints evaluated survival, response, and safety.
The baseline characteristics were well balanced between the 2 arms. Among the 363 patients, the median age was 64 years (range, 36-85 years).Approximately 29% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. The median score on the Cumulative Illness Rating Scale (CIRS) was 2 (range, 0-14). The 17p deletion was reported in 3.3% of the ibrutinib arm and 3.9% of the placebo arm. The 11q deletion was observed in 11.5% vs 10.5%, respectively. The immunoglobulin heavy chain variable region gene (IGHV) was unmutated in 38.7% of the patients in each group. TP53 was mutated in 7.7% of the ibrutinib arm and 7.2% of the placebo arm. The level of β2 microglobulin exceeded 3.5 mg/dL in 7.7% of patients in each arm, and more than three-fourths of patients in each arm had a thymidine kinase level higher than 10 U/L.
The median observation time was 31.0 months for both arms. The median treatment duration was 21 months (range, 1-57 months) in the ibrutinib arm vs 18 months (range, 1-57 months) in the placebo arm. Ten patients in each arm had not yet started study treatment. An additional 17 patients in the ibrutinib arm and 13 in the placebo arm had received no treatment at all. The study treatment was discontinued by 65 patients (34.1%) in the ibrutinib arm and 83 (45.9%) in the placebo arm. In the ibrutinib arm, the primary reason for treatment discontinuation was adverse events (AEs; 53 patients vs 26 patients). Most patients in the placebo arm discontinued treated owing to progressive disease (45 patients vs 2 patients). In the ibrutinib arm, 54.9% of patients remained on study treatment, vs 47% in the placebo arm.
Primary endpoint analysis showed a median event-free survival of not reached in the ibrutinib arm vs 47.8 months in the placebo arm (hazard ratio [HR], 0.248; P<.0001; Figure 1). The median progression-free survival (PFS) was not reached in the ibrutinib arm vs 14.8 months in the placebo arm (HR, 0.176; P<.0001; Figure 2). The median time to next treatment was also significantly prolonged in the ibrutinib arm (HR, 0.205; P<.0001).
Approximately 95% of patients in each arm developed an AE of any grade. AEs of grade 3 or higher were observed in 50.6% of patients in the ibrutinib arm and 43.2% of patients in the placebo arm. AEs required interruption of ibrutinib in 41.6% of patients and interruption of placebo in 21.3% of patients. The AEs that led to treatment interruption included arrhythmias (in 18 patients treated with ibrutinib vs 0 with placebo), bleeding (8 vs 1), diarrhea (4 vs 3), neoplasia (4 vs 3), infection (3 vs 4), and myocardial infarction (1 vs 3). In the ibrutinib vs the placebo arm, the most common serious AEs included infections (12% each), neoplasms (7% vs 12%), and cardiac disorders (10% vs 6%). Any-grade AEs of special clinical interest that occurred at a higher rate in the ibrutinib arm included bleeding (32.3% vs 10.3%; P=.000), atrial fibrillation (20.9% vs 7.7%; P=.001), and hypertensive disorders (11.4% vs 4.5%; P=.04). Fatal AEs occurred in 2.5% of the ibrutinib arm vs 3.2% of the placebo arm, but none of the events were related to treatment.
Until data from the full survival analysis are available, the study authors recommend a watch-and-wait strategy for early-stage patients who have an increased risk of progression.
References
1. Dighiero G, Maloum K, Desablens B, et al; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998;338(21):1506-1514.
2. Langerbeins P, Bahlo J, Rhein C, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment-naïve early stage chronic lymphocytic leukemia (CLL): primary endpoint results of the phase 3 double-blind randomized CLL12 trial. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 1938.
Obinutuzumab and Ibrutinib Treatment Induction Followed by a Minimal Residual Disease–Driven Strategy in Chronic Lymphocytic Leukemia: Long-Term Results in the ICLL-07 FILO Trial
For many years, chemoimmuno-therapy consisting of fludarabine, cyclophosphamide, and rituximab (FCR) has been the treatment of choice for medically fit patients with CLL who have wild-type TP53.1 In the CLL8 trial (Fludarabine and Cyclophosphamide With or Without Rituximab in Patients With Previously Untreated Chronic B-Cell Lymphocytic Leukemia), reported in 2012, longer PFS and overall survival (OS) were seen among patients with a clinical complete response (CR) plus a level of minimal residual disease (MRD) below 0.01% (as measured in the bone marrow).2 The phase 2 ICLL-07 trial (Obinutuzumab and Ibrutinib Induction Therapy Followed by a Minimal Residual Disease-Driven Strategy in Patients With Chronic Lymphocytic Leukaemia) evaluated a treatment strategy in which the second course of therapy was determined by the patient’s response and MRD status following initial therapy.3 This multicenter, open-label trial enrolled treatment-naive, medically fit patients without the 17p deletion. Patients had a CIRS score of 6 or lower.
During part 1 of the study, patients received 8 doses of obinutuzumab (1000 mg) over 6 cycles of 4 weeks each, plus daily ibrutinib (420 mg) for 9 months. During part 2 of the study, patients received different treatments based on an assessment performed on day 1 of month 9. Patients with a CR and a bone marrow MRD of less than 0.01% continued treatment with ibrutinib monotherapy (420 mg daily) for 6 additional months. All other patients received 4 cycles of FC plus obinutuzumab (1000 mg), administered every 4 weeks for 4 cycles, plus daily ibrutinib (420 mg) for 6 months. The assessment of CR was based on criteria from the International Workshop on CLL (iwCLL).4 The primary objective was to demonstrate an increase of at least 30% in the rate of CR plus MRD below 0.01% by month 16, based on an intention-to-treat analysis.
The trial enrolled 135 patients, and 130 were randomly assigned to treatment. The patients’ median age was 65 years (range, 35-80 years), and two-thirds were male. Seven percent of patients had active stage A disease, 67% had active stage B disease, and 26% had stage C disease. Fifty-six percent had unmutated IGHV, 26% had the 11q deletion, and 15% had a complex karyotype. The median rate of creatinine clearance was 82 mL/min (range, 42-173.5 mL/min). Based on the evaluation on day 1 of month 9, 10 patients had a CR plus an MRD level of less than 0.01%. These patients continued treatment with daily ibrutinib monotherapy in part 2 of the study. The remaining 120 had a partial response (PR) or a CR, plus a bone marrow MRD level of 0.01% or higher. Among these patients, 115 received daily ibrutinib as well as FC plus obinutuzumab in part 2.
In the intention-to-treat analysis, at month 16, 73% of patients had a CR and 79% had a bone marrow MRD level of less than 0.01%. Both of these outcomes combined were seen in 62% of patients. An MRD level of less than 0.01% was more common among patients with the IGHV mutation vs without the mutation (Figure 3). After a median follow-up of 26.3 months, 2-year PFS was 97.0% and 2-year OS was 97.5%.
In part 1 of the study, the most common grade 3/4 hematologic AEs included thrombocytopenia (31%), neutropenia (24%), and anemia (5%). The most common nonhematologic AEs were infusion-related reactions (8%), gastrointestinal disorders (3%), and cardiac events (2.2%). In part 2, the most common grade 3/4 AEs among all patients included neutropenia (24%), thrombocytopenia (15%), and gastrointestinal disorders (10%).
References
1. Hallek M, Fischer K, Fingerle-Rowson G, et al; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174.
2. Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980-988.
3. Michallet AS, Dilhuydy MS, Subtil F, et al. Obinutuzumab and ibrutinib treatment induction followed by a minimal residual disease-driven strategy in chronic lymphocytic leukaemia: long-term results in the ICLL-07 FILO trial. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 1962.
4. 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.
Ibrutinib for First-Line Treatment of Chronic Lymphocytic Leukemia in Patients Aged ≥65 Years: Results With 5 Years of Follow-Up for the RESONATE-2 Study
The international, open-label phase 3 RESONATE-2 trial (Open-Label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil Patients 65 Years or Older With Treatment-Naive CLL or SLL) randomly assigned older patients with CLL to receive first-line treatment with ibrutinib or chlorambucil.1 The trial enrolled patients ages 70 years or older, or patients ages 65 years to 69 years with comorbidities. Patients had CLL or small lymphocytic lymphoma (SLL) requiring therapy. Patients with the 17p deletion were excluded from the trial. Patients were stratified by ECOG performance status and Rai disease stage before treatment. The trial randomly assigned 136 patients to ibrutinib (420 mg daily) and 133 patients to 12 cycles of chlorambucil (0.5 mg/kg to a maximum of 0.8 mg/kg, administered on days 1 and 15 in 28-day cycles). The primary endpoint was PFS assessed by independent review. Secondary endpoints included OS, the objective response rate (ORR), sustained hematologic improvement, and safety.
The baseline characteristics were generally well balanced between the 2 arms. The 269 patients were a median age of 73 years (range, 65-90 years). Approximately 63% of patients were male, and 43% had an ECOG performance status of 0. Forty-five percent of patients had Rai stage III/IV disease, 32% had a CIRS score higher than 6, and 35% had bulky disease. Twenty-two percent of patients had the 11q deletion, and 58% had unmutated IGHV. The TP53 mutation was reported in 10% of patients (12/124) in the ibrutinib arm vs 3% (3/94) in the chlorambucil arm. A high prognostic risk was reported in 53% of patients overall. After a median follow-up of 18.4 months, the median PFS was not reached with ibrutinib vs 18.9 months with chlorambucil (HR, 0.16; P<.001). The 2-year OS was 98% with ibrutinib vs 85% with placebo (HR, 0.16; P=.001).
After a median follow-up of 5 years (range, 0.1-66 months), 79 patients (58%) in the ibrutinib arm continued to receive the BTK inhibitor as part of the study.2 The median duration of ibrutinib treatment was 57.1 months (range, 0.7-66.0 months), and 27% of patients had received ibrutinib for longer than 5 years. Twenty-nine patients discontinued ibrutinib owing to an AE.
Long-term follow-up underscored the benefits of ibrutinib compared with chlorambucil. The median PFS was not evaluable with ibrutinib vs 15.0 months with chlorambucil (HR, 0.146; 95% CI, 0.098-0.218; Figure 4). The estimated 5-year OS was 83% with ibrutinib vs 68% with chlorambucil (HR, 0.450; 95% CI, 0.266-0.761). Ibrutinib maintained a PFS improvement vs chlorambucil regardless of whether patients had the 11q deletion or IGHV mutations. The HRs for median PFS were 0.034 (95% CI, 0.010-0.108) in patients with the 11q deletion, 0.205 (95% CI, 0.132-0.318) in patients without the 11q deletion, 0.105 in those with unmutated IGHV (95% CI, 0.058-0.190), and 0.153 (95% CI, 0.067-0.349) in those with mutated IGHV. Among patients treated with ibrutinib, the ORR was 92%. The rate of CR/incomplete CR increased from 11% after 18 months of follow-up to 30% with long-term follow-up.1,2
In the ibrutinib arm, AEs of any grade and grade 3/4 occurred most frequently during the first year of treatment. The most common grade 3/4 AEs in the ibrutinib arm were neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), hyponatremia (6%), atrial fibrillation (5%), and cataracts (5%). Among the 27 patients who developed AEs that led to a dose reduction of ibrutinib, these events improved or resolved in 25 (93%). During the 5 years of the study, an AE was the primary cause of treatment discontinuation in 29 patients. Ibrutinib administration was interrupted for 7 or more consecutive days in 70 patients.
References
1. 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.
2. Tedeschi A, Burger J, Barr PM, et al. Ibrutinib for first-line treatment of chronic lymphocytic leukemia in patients aged ≥65 year of age: results with 5 years of follow-up for the RESONATE-2 study. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 1956.
Obinutuzumab as Consolidation After Chemo-Immunotherapy Is Highly Effective in Achieving MRD Clearance From Bone Marrow and Peripheral Blood Resulting in Improved Progression-Free Survival: Results of UK NCRI Phase II/III GALACTIC Trial
MRD negativity is an independent predictor of survival among patients with CLL, regardless of treatment.1 The GALACTIC trial (GA101 [Obinutuzumab] Monoclonal Antibody as Consolidation Therapy in CLL) was a seamless phase 2/3 study that evaluated the ability of obinutuzumab to eradicate MRD when administered as consolidation therapy after immunochemotherapy in patients with B-cell CLL.2 The multicenter, parallel-group, open-label trial enrolled adults who had received between 1 and 3 prior lines of therapy and whose most recent outcome was a PR or better. Prior therapy had ended between 3 and 24 months before study enrollment. The study excluded patients with a lymph node larger than 1.5 cm. The primary endpoint of the trial was undetectable MRD (<0.01%) at 6 months after randomization.
The planned enrollment of 188 patients was not met. The trial was terminated in January 2017 after enrollment of 48 patients. The 29 patients with positive MRD (>0.01%) were randomly assigned to consolidation therapy with obinutuzumab (n=14) or no consolidation therapy (n=15). Among patients in the consolidation cohort, their most recent prior treatment led to a CR in 7 and a PR in 7. Fifty-five percent of the patients randomly assigned to obinutuzumab had an MRD level higher than 0.3% at study entry. Twelve of these patients (86%) received all planned obinutuzumab infusions, and 2 patients missed a planned dose after developing hematologic dose-limiting toxicity.
At 6 months after randomization, 10 of the 14 patients (71.4%) who received obinutuzumab consolidation achieved undetectable MRD in the bone marrow. MRD was also undetectable in all 13 blood samples that were available for analysis. The median OS was similar for the consolidation and control arms (P=.2491). The median PFS, however, was not reached in the obinutuzumab consolidation arm vs 17.6 months in the control arm (P=.001; Figure 5). Similar rates of PFS and OS were observed in patients who achieved MRD negativity after chemoimmunotherapy (n=19) or after consolidation with obinutuzumab (n=10). The most common AEs in the obinutuzumab consolidation arm included thrombocytopenia (22%), infection (9%), and cough (8%).
References
1. Del Giudice I, Raponi S, Della Starza I, et al. Minimal residual disease in chronic lymphocytic leukemia: a new goal? Front Oncol. 2019;9:689.
2. Munir T, Hockaday A, Oughton J, et al. Obinutuzumab as consolidation after chemo-immunotherapy is highly effective in achieving MRD clearance from bone marrow and peripheral blood resulting in improved progression-free survival: results of UK NCRI phase II/III GALACTIC trial. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 2121.
Final 5-Year Updated Results From a Phase 3 Study (HELIOS) of Ibrutinib Plus Bendamustine and Rituximab in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
The double-blind, phase 3 HELIOS study (A Study of Ibrutinib in Combination With Bendamustine and Rituximab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma) compared the 3-drug combination of ibrutinib plus bendamustine/rituximab vs placebo plus bendamustine/rituximab in patients with relapsed or refractory CLL/SLL.1,2 Conducted at 133 sites in 21 countries, the study enrolled 578 patients with previously treated CLL/SLL without the 17p deletion. Patients were randomly assigned to treatment in the ibrutinib or placebo arm. Patients first received up to 6 cycles of bendamustine and rituximab, plus either ibrutinib or placebo. Treatment then continued with either ibrutinib or placebo alone until the patient developed progressive disease or unacceptable toxicity. Patients in the placebo arm who developed progressive disease were permitted to cross over to the ibrutinib group.
After an initial median follow-up of 17 months, the addition of ibrutinib to bendamustine/rituximab significantly improved median PFS (HR, 0.203; 95% CI, 0.150-0.276; P<.0001).1 After a median follow-up of 34.8 months, ibrutinib plus bendamustine/rituximab continued to show a PFS benefit vs placebo plus bendamustine/rituximab (HR, 0.206; 95% CI, 0.159-0.265; P<.0001).2
The final analysis of the HELIOS study was conducted after a median follow-up of 63.7 months.3 Patients received ibrutinib monotherapy for a median of 55.7 months (range, 0.2-72.9 months). In the ibrutinib arm, the most common reason for discontinuation of study treatment was a decision by the investigator or sponsor (reported in 47.1% of cases), which was most often made because the patient reached the end of the study period. Other common reasons that patients stopped ibrutinib included AEs (in 20.1%) and progressive disease or relapse (in 19.0%). In the placebo arm, the most common reason for discontinuation was progressive disease or relapse (in 51.2%). The next most common reason was investigator or sponsor decision (in 29.1%), mostly occurring after unblinding at the primary analysis.
Median PFS was 65.1 months among patients in the ibrutinib plus bendamustine/rituximab arm vs 14.3 months among those in the comparator arm (HR, 0.229; 95% CI, 0.183-0.286; P<.0001; Figure 6). Despite the fact that 183 patients in the placebo arm had crossed over to the ibrutinib arm, the 5-year analysis showed an OS advantage with the addition of ibrutinib to bendamustine/rituximab (HR, 0.611; 95% CI, 0.455-0.822; P=.0010). The median OS was not reached for either arm. The 5-year rate of OS was 75.7% with ibrutinib plus bendamustine/rituximab vs 61.2% with bendamustine/rituximab alone. The ibrutinib regimen also yielded a superior ORR, at 87.2% vs 66.1%, respectively (P<.0001). The responses deepened over time.
The rates of treatment-emergent AEs in the ibrutinib arm were consistent with previous reports. Grade 5 treatment-emergent AEs of interest included infections and infestations (3.8%) and bleeding (1.0%).
References
1. Chanan-Khan A, Cramer P, Demirkan F, et al; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016;17(2):200-211.
2. Fraser G, Cramer P, Demirkan F, et al. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019;33(4):969-980.
3. Fraser G, Chanan-Khan A, Demirkan F, et al. Final 5-year updated results from a phase 3 study (HELIOS) of ibrutinib plus bendamustine and rituximab (BR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 2021.
Venetoclax Combined With Ibrutinib Based on a Minimal Residual Disease–Guided Approach in Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of the IMPROVE Study
The combination of ibrutinib plus venetoclax is generally well tolerated among patients with relapsed or refractory CLL. This treatment elicits a high response rate, including high proportions of CRs and low or undetectable levels of MRD.1,2 Venetoclax monotherapy can also result in undetectable MRD in some patients.3
The IMPROVE study was a single-arm, phase 2 trial that evaluated initial treatment with venetoclax, followed by the addition of ibrutinib based on MRD status, in patients with previously treated CLL.4 The study enrolled patients with relapsed or refractory CLL who had no prior exposure to BTK or Bcl-2 inhibitors. Patients initially received venetoclax (starting at 20 mg daily, and increased to 400 mg daily) for up to 12 cycles. On day 1 of cycle 12, patients were evaluated for MRD in the peripheral blood and bone marrow. Patients with undetectable MRD (defined as <10-4) in both the blood and bone marrow continued venetoclax monotherapy through the end of cycle 12 and then were monitored periodically for MRD. Patients with detectable MRD on day 1 of cycle 12 continued treatment with venetoclax, and also received ibrutinib (420 mg daily) starting on day 1 of cycle 13. Combination treatment was continued through a maximum of 24 cycles of 28 days each, at which point responding patients with detectable MRD continued on ibrutinib monotherapy. The primary endpoint was undetectable MRD (<10-4) in both the peripheral blood and bone marrow.
Among the 38 patients, the median age was 64 years (range, 47-81 years). Sixty-one percent had bulky disease exceeding 5 cm, and 90% had Binet stage B/C disease. Most patients had genetic risk factors, and 55% were at high risk for tumor lysis syndrome. After 12 treatment cycles, the ORR was 92%, including a CR rate of 18% (Figure 7). MRD levels of less than 10-4 were observed in 45% of patients. After a median follow-up of 14 months (range, 6-22 months), the proportion of patients with undetectable MRD had increased during 12 cycles of venetoclax monotherapy and with the MRD-based addition of ibrutinib.
No clinical or laboratory tumor lysis syndrome occurred. Two serious AEs were observed, both of which were considered unrelated to study treatment. Among the 12 cases of grade 3/4 AEs, the most common was neutropenia (9 events).
References
1. Ghia P, Tam C, Siddiqi T, et al. Ibrutinib lead-in followed by venetoclax in patients with chronic lymphocytic leukemia: phase 2 CAPTIVATE early safety and efficacy results. Abstract presented at: the 23rd European Hematology Association; June 14-17, 2018; Stockholm, Sweden. Abstract S806.
2. Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. J Clin Oncol. 2019;37(30):2722-2729.
3. Roberts AW, Ma S, Kipps TJ, et al. Efficacy of venetoclax in relapsed chronic lymphocytic leukemia is influenced by disease and response variables. Blood. 2019;134(2):111-122.
4. Scarfo L, Heltai S, Farina L, et al. Venetoclax combined with ibrutinib based on a minimal residual disease–guided approach in relapsed/refractory chronic lymphocytic leukemia: results of the IMPROVE study. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 2068.
Ibrutinib Plus Venetoclax in Relapsed/Refractory CLL: The CLARITY Study
The phase 2 CLARITY trial (Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia) investigated ibrutinib plus venetoclax in patients with relapsed or refractory CLL.1,2 Enrolled patients required therapy based on iwCLL criteria. They had either relapsed within 3 years of prior immunochemotherapy or had the 17p deletion after at least 1 prior regimen. After 8 weeks of single-agent ibrutinib (420 mg daily), patients then received additional venetoclax, starting at a dose of 10 mg or 20 mg daily and escalating to a final dose of 400 mg daily. Peripheral blood and bone marrow samples were assessed at months 8, 14, and 26, with additional peripheral blood samples taken at various time points. The primary endpoint was undetectable MRD in the bone marrow, defined as less than 0.01% CLL cells and assessed by 6- or 8-color flow cytometry, after 12 months of combination treatment.
The presentation provided data for 50 patients. Their median age was 64 years (range, 31-83 years). Seventy-two percent had Binet stage B/C disease, and 8% had bulky lymph nodes. Seventy-four percent had unmutated IGHV, 20% had the 17p deletion, and 25% had the 11q deletion. The median number of prior therapies was 1 (range, 1-6).
After 12 months of ibrutinib plus venetoclax, 29 of 50 patients (58%) had undetectable MRD in the peripheral blood, and 20 of 50 (40%) had undetectable MRD in the bone marrow. Among patients who had relapsed within 3 years of prior FCR or bendamustine/rituximab, the rates of MRD negativity were 70% (14/20) in the peripheral blood and 45% (9/20) in the bone marrow. Peripheral blood and bone marrow analysis showed a continuous increase in MRD negativity from screening (n=50) through week 26 (n=46; Figure 8). Among 17 patients who achieved undetectable MRD at month 8 or month 14, 16 (94%) reached month 26 and remained MRD-negative. Among 46 patients who were evaluable at month 26, MRD negativity of less than 0.01% was reported in 32 (70%) with peripheral blood assays and in 23 (50%) with bone marrow assays. MRD negativity of less than 10-5 was detected in the peripheral blood of 21 patients (46%) and in the bone marrow of 13 patients (28%). Among all 50 patients, the ORR assessed at month 14 was 96%, including a rate of CR plus incomplete CR of 56%. One case of tumor lysis syndrome was successfully managed by delaying venetoclax escalation. One patient achieved an MRD-positive CR during the CLARITY study, but later developed disease progression with Richter transformation and died.
An in-depth analysis of paired peripheral blood and bone marrow samples demonstrated a high correlation in MRD levels. Based on 142 paired samples taken at month 8 or later, bone marrow levels of CLL cells were a median of 0.48 logs higher than in the peripheral blood. After 6 months of study treatment, 16 of 48 evaluable patients (34%) had achieved less than 0.01% CLL cells in the peripheral blood, and all of these patients achieved less than 10-4 bone marrow MRD after 12 months of study treatment. In contrast, among 26 patients whose peripheral blood showed greater than 0.01% CLL cells, only 3 patients (12%) subsequently achieved bone marrow MRD of less than 0.01% after 12 months of study treatment. Exposure to ibrutinib and venetoclax resulted in changes in the expression of Bcl-2 and Bax.
References
1. Munir T, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory CLL: the CLARITY study. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 2143.
2. Rawstron AC, Webster M, Dalal S, et al. Biological responses to ibrutinib plus venetoclax in the Bloodwise TAP CLARITY study. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 2163.
ASCEND Phase 3 Study of Acalabrutinib vs Investigator’s Choice of Rituximab Plus Idelalisib or Bendamustine in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia
Rituximab given in combination with either bendamustine or idelalisib is a standard therapy for patients with relapsed or refractory CLL.1 Acalabrutinib is a BTK inhibitor that has demonstrated less off-target kinase inhibition in vitro compared with ibrutinib.2 The global, open-label, phase 3 ASCEND trial (A Study of Acalabrutinib vs Investigator’s Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL) evaluated acalabrutinib monotherapy vs idelalisib/rituximab or bendamustine/rituximab in patients with relapsed or refractory CLL.3 Prior to random assignment to therapy, patients were stratified based on 17p deletion status, ECOG performance status, and number of prior therapies. Acalabrutinib was administered at a dose of 100 mg twice daily. In the combination arms, patients were treated with rituximab (initially administered at 375 mg/m2, with subsequent doses of 500 mg/m2) plus either idelalisib (150 mg, twice daily) or bendamustine (70 mg/m2, on days 1 and 2 of each cycle), based on the choice of their physician. Crossover into the acalabrutinib arm was allowed after confirmed disease progression. The primary endpoint was independently assessed PFS.
The trial randomly assigned 310 patients into the 2 arms. The patients’ median age was 67.5 years (range, 32-90 years). Nearly half of patients (48.5%) had bulky disease, and 41.5% had Rai stage III/IV disease. In the acalabrutinib arm, patients had received a median of 1 prior therapy (range, 1-8). Genetic status in this arm included unmutated IGHV in 77%, complex karyotype in 32%, the 11q deletion in 25%, and the 17p deletion in 18%. In the control arms, patients had received a median of 2 prior therapies (range, 1-10). Genetic status included unmutated IGHV in 82%, complex karyotype in 30%, the 11q deletion in 29%, and the 17p deletion in 14%.
Based on independent review, the median PFS was not reached with acalabrutinib vs 16.5 months with the rituximab combinations (HR, 0.31; 95% CI, 0.20-0.49; P<.0001; Figure 9). Among patients with high-risk cytogenetics, the median PFS was not reached vs 16.2 months, respectively (HR, 0.27; 95% CI, 0.17-0.44; P<.0001). The PFS benefit seen with acalabrutinib was maintained across most patient subgroups, including those stratified by age, sex, Rai stage at screening, extent of bulky disease, and mutational status. PFS was better with the rituximab combinations among patients with an ECOG performance status of 2 at baseline and those who had received 4 or more therapies before study enrollment. Acalabrutinib demonstrated a superior response duration (HR, 0.33; 95% CI, 0.19-0.59; P<.0001). When PR with lymphocytosis was included in the analysis, the ORR was 88% with acalabrutinib vs 77% with the control regimens (P=.01). After excluding PR with lymphocytosis, the ORR did not differ significantly between the arms (P=.22).
The most common grade 3 or higher AEs associated with acalabrutinib included neutropenia (16%) and anemia (12%). Infections of any grade occurred in 56.5% of the acalabrutinib arm, vs 65.3 of the idelalisib/rituximab arm and 48.6% of the bendamustine/rituximab arm. Any-grade bleeding occurred in 26.0%, 8.0%, and 6.0%, respectively.
References
1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2020. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Updated October 8, 2019. Accessed October 18, 2019.
2. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240-252.
3. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IdR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 2158.
Treatment of CLL From 2019 Onwards
Presentations at the XVIII iwCLL included several updates of trial data. The phase 3 E1912 trial compared ibrutinib plus rituximab, followed by maintenance ibrutinib, vs FCR in 529 patients ages 70 years and older with previously untreated CLL.1,2 At a median follow-up of 48 months, 73% of patients remained on treatment. Among patients who stopped treatment with ibrutinib, median PFS was 22.5 months after discontinuation. PFS continued to show a benefit from treatment with ibrutinib plus rituximab compared with FCR (HR, 0.39; 95% CI, 0.26-0.57; P<.0001; Figure 10), with 3-year PFS rates of 89% vs 71%. PFS rates were similar with either treatment for patients with mutated IGHV (HR, 0.42; 95% CI, 0.16-1.16; P=.086). However, patients with unmutated IGHV benefited from treatment with ibrutinib plus rituximab compared with FCR (HR, 0.28; 95% CI, 0.17-0.48; P<.0001). OS was also superior with the ibrutinib combination (HR, 0.34; 95% CI, 0.15-0.79; P=.009).
The randomized phase 3 ALLIANCE (A041202) trial (Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia) compared 3 treatment regimens: bendamustine plus rituximab, ibrutinib plus rituximab, and ibrutinib monotherapy. The trial enrolled 547 patients ages 65 years or older with previously untreated CLL.3,4 The estimated rate of 2-year PFS was 88% with ibrutinib plus rituximab, 87% with ibrutinib, and 74% with bendamustine plus rituximab. At 52 months, the primary endpoint analysis showed superior PFS with both ibrutinib monotherapy (HR, 0.39; 95% CI, 0.26-0.58; P<.001) and ibrutinib plus rituximab (HR, 0.38; 95% CI, 0.25-0.59; P<.001) compared with bendamustine plus rituximab. There was no significant difference in PFS with ibrutinib monotherapy vs ibrutinib plus rituximab (P=.49). The trial included several subgroup analyses. Among the patients with a complex karyotype, the estimated 24-month PFS was 91% with ibrutinib, 87% with ibrutinib/rituximab, and 59% with bendamustine plus rituximab. Patients with the 17p deletion and unmutated IGHV also benefited from ibrutinib alone or ibrutinib plus rituximab vs bendamustine/rituximab. Two-year OS was similar for all 3 treatment cohorts, at 95% with bendamustine plus rituximab, 94% with ibrutinib plus rituximab, and 90% with ibrutinib (P≥.65). At a median follow-up of 38 months, the rates of grade 3/4 hematologic AEs were higher with bendamustine plus rituximab (61%) vs ibrutinib monotherapy (41%) or ibrutinib plus rituximab (39%; P<.001). Rates of grade 3/4 nonhematologic AEs were higher in the 2 ibrutinib arms (74%) compared with bendamustine/rituximab (63%; P=.04).
The phase 3 ILLUMINATE trial (A Multi-Center Study of Ibrutinib in Combination With Obinutuzumab Versus Chlorambucil in Combination With Obinutuzumab in Patients With Treatment Naïve CLL or SLL) compared ibrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab in 229 patients with treatment-naive CLL/SLL.5,6 At a median follow-up of 31.3 months (range, 0.2-36.9 months), the median PFS was not reached with the ibrutinib combination vs 19.0 months with the chlorambucil combination (HR, 0.231; 95% CI, 0.145-0.367; P<.0001). Among the patients with high-risk genetic features, median PFS was not reached with ibrutinib plus obinutuzumab vs 14.7% with chlorambucil plus obinutuzumab (HR, 0.154; 95% CI, 0.087-0.270; P<.0001). Nearly all subgroups benefited from treatment with ibrutinib vs chlorambucil. ORR was 88% with ibrutinib plus obinutuzumab vs 73% with chlorambucil plus obinutuzumab. The rates of CR/incomplete CR were 19% vs 8%, respectively. Patients in the ibrutinib arm also had higher rates of undetectable MRD. The safety profile of ibrutinib plus obinutuzumab was consistent with the known AE profiles of the individual agents.
The phase 3 CLL14 trial randomly assigned 432 patients with CLL and coexisting medical conditions to receive fixed-duration venetoclax plus obinutuzumab or chlorambucil plus obinutuzumab as first-line therapy.7,8 Treatment consisted of 6 cycles of combination therapy followed by 6 cycles of venetoclax or chlorambucil monotherapy. After a median of 38 months of follow-up, the median PFS was significantly prolonged with the venetoclax combination (HR, 0.35; 95% CI, 0.23-0.53; P<.0001). The proportion of patients with negative (<10-4) MRD status was higher with venetoclax plus obinutuzumab compared with chlorambucil plus obinutuzumab, reaching 76% vs 35% (P<.001) with peripheral blood testing and 57% vs 17% (P<.001) with bone marrow testing.
References
1. Shanafelt TD. Treatment of CLL from 2019 onwards: E1912 trial. Presentation at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland.
2. 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.
3. Woyach JA, Ruppert AS, Heerema NA, et al. Treatment of CLL from 2019 onwards: ALLIANCE trial. Presentation at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland.
4. 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.
5. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: up to 4 years of extended follow-up from phase 3 iLLUMINATE. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 2069.
6. Tedeschi A, Moreno C, Greil R, et al. Treatment of CLL from 2019 onwards: iLLUMINATE trial. Presentation at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland.
7. Fischer K. Treatment of CLL from 2019 onwards: CLL14 trial. Presentation at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland.
8. 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.
Highlights From the XVIII International Workshop on Chronic Lymphocytic Leukemia: Commentary
Susan M. O’Brien, MD
Associate Director for Clinical Sciences, Chao Family Comprehensive Cancer Center
Medical Director, Sue and Ralph Stern Center for Clinical Trials & Research
Professor of Medicine, Division of Hematology/Oncology, Department of Medicine
University of California, Irvine
Orange, California
Study presentations at the XVIII International Workshop on Chronic Lymphocytic Leukemia (iwCLL) provided interesting new data. In addition, there were long-term follow-up analyses for several important clinical trials. Studies evaluated treatments such as ibrutinib, acalabrutinib, and venetoclax plus rituximab.
Ibrutinib
Dr Petra Langerbeins and colleagues presented preliminary results of the randomized, phase 3 German CLL12 trial (Ibrutinib in Previously Untreated Binet Stage A Chronic Lymphocytic Leukemia With Risk of Disease Progression), which compared ibrutinib vs placebo among patients with asymptomatic, treatment-naive, early-stage CLL.1 This trial examined the important question of whether early treatment of CLL can be beneficial. This question is not yet answered by these preliminary results.
Approximately 80% of patients with CLL have asymptomatic, early-stage disease. Although the standard approach to these patients is watch and wait, the value of this strategy is unknown. In general, the paradigm in cancer is that the best chance of curing a disease is to catch it early and administer treatment. With the watch-and-wait approach, the disease might progress and develop more molecular abnormalities. When treatment is initiated, it then leads to a small cure fraction limited to young, fit patients who can tolerate treatment with fludarabine, cyclophosphamide, and rituximab (FCR).2
In the 1980s, several randomized trials in patients with early-stage, asymptomatic CLL compared watch and wait vs immediate treatment with chlorambucil.3 These trials consistently showed no benefit to early treatment with chlorambucil. Currently, however, there are far more effective therapies than chlorambucil, such as ibrutinib.4 However, it is known that approximately one-third of patients with CLL will never need treatment. Therefore, a more effective clinical trial design would limit enrollment to high-risk patients with disease that will ultimately progress and require treatment. The CLL12 trial enrolled patients with Binet stage A, which is equivalent to Rai stage 0 to 1.1 The standard approach for these asymptomatic, treatment-naive patients is watch and wait. The CLL12 trial stratified patients according to a previously published German criteria that identified low, intermediate, high, or very high risk.5 The 152 patients with low-risk disease were assigned to the watch-and-wait arm. The remaining 363 patients—those at intermediate, high, or very high risk—were randomly assigned to treatment with ibrutinib (n=182) or placebo (n=181). The study combined these risk levels into one group based on relatively small numbers of patients with high-risk (n=82) or very high-risk (8) disease. Ideally, it would have been preferable to enroll only patients at high or very high risk, but a population of 90 would have been challenging for a randomized trial. A limitation to the CLL12 trial is the heterogeneous enrollment. However, the ibrutinib arm and the placebo arm were well matched in terms of age, performance status, and comorbidity scores, as assessed by the Cumulative Illness Rating Scale (CIRS).
The rates of any-grade adverse events (AEs) were 94.9% in the ibrutinib arm and 95.5% in the placebo arm. The rate of AEs in the placebo arm highlights the fact that many AEs reported in a clinical trial are not, in fact, related to treatment, but rather to the underlying disease. Grade 3 or higher AEs were reported in 50.6% of the ibrutinib arm and 43.2% of the placebo arm. A difference between the arms is seen among AEs leading to interruption. For example, 18 patients in the ibrutinib arm discontinued treatment owing to arrhythmias, whereas none did so in the placebo arm. Bleeding led to treatment discontinuation among 8 patients in the ibrutinib arm vs 1 in the placebo arm. Infections required 3 patients to stop ibrutinib and 4 patients to stop placebo. Therefore, the biggest difference in AEs was arrhythmias leading to discontinuation in the ibrutinib arm. It is known that ibrutinib can cause atrial fibrillation and, occasionally, ventricular arrhythmias, as well as bleeding. There were no treatment-related fatal adverse events in either arm.
The study also provided data on AEs of clinical interest.1 Rates of grade 3 or higher diarrhea were 1.3% with ibrutinib and 3.2% with placebo. These rates show that throughout a follow-up duration of 18 months, some patients will develop diarrhea that has nothing to do with treatment. It is known that bleeding can be related to ibrutinib. Grade 3 or higher bleeding was reported in 3.8% of the ibrutinib arm vs 1.2% of the placebo arm. All-grade atrial fibrillation occurred in 20.9% of the ibrutinib arm vs 7.7% of the placebo arm. Grade 3 or higher events occurred in 7.6% vs 1.3%, respectively. All-grade hypertension, another known side effect of ibrutinib, occurred in 11.4% vs 4.5%. Grade 3 or higher hypertension was reported in 1.9% of patients in both groups. Therefore, severe toxicities in the ibrutinib arm consisted of a small proportion of AEs overall.
The presentation by Dr Langerbeins provided data for the time to symptomatic progression.1 Among patients treated with ibrutinib, the median time to symptomatic progression was not reached. Not surprisingly, patients in the placebo arm developed slowly progressive disease, with a median time to symptomatic progression of approximately 4 years. (It should be mentioned that progression does not always signal a need for therapy.) This finding shows that these patients as a group were not at very high risk.
The more important endpoint is survival. An analysis of progression-free survival (PFS) showed that events occurred in 30 patients treated with ibrutinib vs 101 patients treated with placebo. The median PFS was 14.8 months with placebo vs not reached with ibrutinib (hazard ratio, 0.176; P<.0001). However, thus far there is no difference in overall survival. Therefore, the results at this point will probably not change clinical practice. The important issue is whether earlier treatment will improve survival, and it is too early to know based on this report. As just discussed, even with a very effective therapy like ibrutinib, there are side effects. For example, arrhythmias are a significant side effect that can occur with ibrutinib. It will be important to confirm the benefits of early treatment before this strategy enters clinical practice.
Dr Alessandra Tedeschi and colleagues presented long-term follow-up data from the RESONATE-2 trial (Open-Label Phase 3 BTK Inhibitor Ibrutinib vs Chlorambucil in Patients 65 Years or Older With Treatment-Naive CLL or SLL).6 RESONATE-2 was the first randomized trial of ibrutinib in the frontline setting. The trial randomly assigned older patients who required therapy to ibrutinib or chlorambucil.4 Most patients were older than 69 years; patients ages 65 to 69 years could be enrolled if they had a comorbidity that precluded FCR. The patients’ median age was approximately 73 years, which reflects the trial’s aim of selecting an older cohort with significant comorbidities, which is reasonable because the control arm consisted of chlorambucil, a mild chemotherapy. Approximately one-third of the patients had a comorbidity score higher than 6. The trial did not enroll patients with the 17p deletion, who do not benefit from chemotherapy. The primary endpoint was PFS.
Dr Tedeschi presented results from the 5-year analysis, which represents the longest follow-up data for a randomized clinical trial of ibrutinib in the frontline setting.6 The rate of complete response was 30% among patients treated with ibrutinib, increasing from 11% at the primary analysis. Impressively, the median PFS was still not reached in the ibrutinib arm. As previously reported, the median PFS for chlorambucil was 15 months. At 5 years, the estimated rates of PFS were 70% in the ibrutinib arm vs 12% in the chlorambucil arm. The estimated rates of overall survival at 5 years were 83% with ibrutinib vs 68% with chlorambucil. The improvement in overall survival is particularly impressive given that patients who developed progressive disease during treatment with chlorambucil were allowed to cross over to the ibrutinib arm when they met iwCLL criteria for further therapy. These data show that frontline remissions are durable with continued ibrutinib.
The study found an interesting outcome for patients with the 11q deletion. It is known that this mutation is associated with a lower PFS in response to any type of chemotherapy, and results in the chlorambucil arm of RESONATE-2 confirmed this earlier observation.4 In the ibrutinib arm, however, the presence of the 11q deletion did not worsen PFS. In fact, there was a benefit to PFS, albeit that lacked statistical significance, among patients with the mutation receiving ibrutinib. Similarly, it is known that patients with the immunoglobulin heavy chain gene (IGHV) mutation have a shorter PFS in response to chemotherapy. In RESONATE-2, patients with this mutation had a worse response to chlorambucil, but not to ibrutinib. No difference in PFS was observed based on IGHV status in the ibrutinib arm.
Acalabrutinib
Dr Wojciech Jurczak and coworkers presented results of the ASCEND trial (A Study of Acalabrutinib vs Investigator’s Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL), which will likely lead to the FDA approval of acalabrutinib for patients with CLL.7 Acalabrutinib is already approved for mantle cell lymphoma, but not yet for any other disease. Compared with ibrutinib, acalabrutinib is a more-selective BTK inhibitor and has less off-target kinase inhibition.8 Acalabrutinib has a higher half maximal inhibitory concentration (IC50) for some of the kinases that lead to the side effects seen with ibrutinib (eg, atrial fibrillation). ASCEND was a global, multicenter, randomized phase 3 trial that enrolled 310 patients with relapsed CLL. The trial consisted of 3 arms: acalabrutinib, idelalisib plus rituximab, and bendamustine plus rituximab. The dose of acalabrutinib was 100 mg twice daily. (In contrast, ibrutinib is administered once daily.) The other treatments were administered at the standard doses. The selection of the control arm was made by the investigator. The primary endpoint was PFS.
The patient characteristics were well matched between the treatment and control arms. The population was not heavily pretreated. Patients in the acalabrutinib arm had received a median of 1 prior therapy, and those in the control arms had received a median of 2.
Median PFS was not reached in the acal-abrutinib arm vs 16.5 months for patients treated with idelalisib/rituximab or bendamustine/rituximab combined.7 Rates of 1-year PFS were 88% with acalabrutinib vs 68% among patients in the control arms. Outcomes were similar between the 2 control arms. This trial had an independent review committee, which verified the findings. The overall response rate was high in all of the arms, at 81% with acalabrutinib and 76% in the control arms. There were only 2 complete responses, both reported in the control arms. At a median follow-up of 16 months, the survival curves were overlapping.
Acalabrutinib was generally well tolerated. Some differences were noted regarding toxicities. There was more neutropenia with either idelalisib/rituximab (45%) or bendamustine/rituximab (34%) than with acalabrutinib (19%). Diarrhea was significantly more common with idelalisib/rituximab (47%) vs bendamustine/rituximab (14%) or acalabrutinib (18%). The incidence of atrial fibrillation was 5% in the acalabrutinib arm vs 3% in the control arms. Hypertension occurred in 3% of the acalabrutinib arm, 3% of the idelalisib/rituximab arm, and 0% of the bendamustine/rituximab arm. Bleeding occurred in 26%, 8%, and 6%, respectively, and most events were minor. Rates of grade 3 or higher bleeding were similar among the arms.
Venetoclax Plus Rituximab
The randomized, open-label 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 [CLL]) led to the FDA approval of venetoclax and rituximab for patients with relapsed CLL. Results from this trial were published by Dr John Seymour and colleagues in the New England Journal of Medicine,9 and updated with 3-year follow-up at the 60th American Society of Hematology (ASH) annual meeting.10 A report at the iwCLL meeting provided 4-year follow-up.11 The MURANO trial compared venetoclax/rituximab vs bendamustine/rituximab. Importantly, this trial is among the first to evaluate a time-limited regimen of a small molecule therapy. When venetoclax was approved as a single agent, the indication encompassed an indefinite, continuous administration regimen, as is used for ibrutinib. In the MURANO trial, the investigational regimen consisted of venetoclax and rituximab given for the first 6 months, followed by venetoclax alone for the next 18 months.
With a median follow-up of approximately 4 years, the median time off therapy was approximately 2 years. The estimated rates of 4-year PFS were 57% with venetoclax/rituximab vs 4.6% with bendamustine/rituximab. The median PFS was not yet reached with venetoclax/rituximab vs approximately 16 months with bendamustine/rituximab.10
The MURANO trial included several subanalyses of patients based on genetic mutations and molecular abnormalities. Among patients treated with venetoclax/rituximab, the 3-year PFS was 76% in those without the 17p deletion vs 64% in those with the deletion.10 Presence of the TP53 mutation did not impact 3-year PFS among patients treated with venetoclax/rituximab. In the bendamustine/rituximab arm, PFS was shorter among patients with a TP53 mutation. Data verify that patients with a 17p deletion or TP53 mutation generally should not be treated with chemotherapy.12-14 Mutations in the ataxia telangiectasia mutated (ATM) gene or the neurogenic locus notch homolog protein 1 (NOTCH1) gene did not appear to greatly impact outcome in either arm. The study defined high-genomic complexity as more than 5 aberrations on cytogenetic analysis. In this group of patients, PFS was shorter in both treatment arms. The 4-year analysis showed a continued improvement in survival with venetoclax/rituximab, although this trial did not allow crossover.
The study assessed minimal residual disease (MRD) and categorized results as undetectable, low-positive, or high-positive. Relapse appeared to closely correlate with positive MRD status at the end of therapy. At the end of 2 years of treatment with venetoclax/rituximab, 83 patients were undetectable for MRD. Only 11 of these patients had developed progressive disease by the 4-year follow-up analysis. Among the 23 patients who were low MRD positive at the end of therapy, 9 progressed (39%). Among the 14 patients who were high MRD positive, 13 progressed (93%). It is known that patients with high MRD positive values are more likely to have the 17p deletion or TP53 mutation. Although these patients had better outcomes with venetoclax/rituximab vs chemotherapy, their outcomes were still inferior to those without the 17p deletion or TP53 mutation.
At the 60th ASH meeting, the question was raised regarding whether extending therapy beyond 2 years might have allowed patients who were high MRD positive to become MRD negative. Interestingly, Dr Seymour did not think so.10 During the trial, MRD was assessed at several time points before the 2-year mark. Dr Seymour noted that for most of those patients, levels of MRD had already reached a plateau or were actually increasing. He expressed doubts that the refractory group would have become MRD negative with continued therapy. A further question is whether continued therapy might lead to prolonged remission among patients who remained MRD positive.
Disclosure
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.
References
1. Langerbeins P, Bahlo J, Rhein C, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment-naïve early stage chronic lymphocytic leukemia (CLL): primary endpoint results of the phase 3 double-blind randomized CLL12 trial. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 1938.
2. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016;127(2):208-215.
3. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists’ Collaborative Group. J Natl Cancer Inst. 1999;91(10):861-868.
4. 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.
5. Pflug N, Bahlo J, Shanafelt TD, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124(1):49-62.
6. Tedeschi A, Burger J, Barr PM, et al. Ibrutinib for first-line treatment of chronic lymphocytic leukemia in patients aged ≥65 year of age: results with 5 years of follow-up for the RESONATE-2 study. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 1956.
7. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IdR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 2158.
8. Patel V, Balakrishnan K, Bibikova E, et al. Comparison of acalabrutinib, a selective Bruton tyrosine kinase inhibitor, with ibrutinib in chronic lymphocytic leukemia cells. Clin Cancer Res. 2017;23(14):3734-3743.
9. 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.
10. 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).
11. Seymour JF, Kipps TJ, Eichhorst B, et al. Time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): first presentation of 4-year data from the MURANO study. Abstract presented at: the XVIII International Workshop on CLL; September 20-23, 2019; Edinburgh, Scotland. Abstract 2266.
12. Hallek M, Fischer K, Fingerle-Rowson G, et al; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164-1174.
13. Tam CS, O’Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975-980.
14. Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German chronic lymphocytic leukemia study group. J Clin Oncol. 2012;30(26):3209-3216.