Efficacy and Safety of Bruton Tyrosine Kinase Inhibitor Monotherapy Compared with Combination Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Systematic Review and Meta-Analysis
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Registration and Protocol
2.2. Data Sources and Search Strategies
2.3. Study Selection
2.4. Data Extraction Process and Risk of Bias Assessment
2.5. Study Outcome Evaluation
2.6. Statistical Analysis
3. Results
3.1. Literature Search and Study Selection
3.2. Study Features
3.3. Description of Patients
3.4. BTK Inhibitor Monotherapy versus Combination Therapy
3.5. Risk of Bias
3.6. Primary Outcomes of Interest
3.7. Secondary Outcomes of Interest
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Alliance Woyach JA et al. 2018 [25] | Ascend Ghia P et al. 2020 [42] | Elevate-TN Sharman JP et al. 2020 [30] | Sequoia Tam CS et al. 2022 [45] | |
---|---|---|---|---|
Study design | Phase III, MC, OL | Phase III, MC, OL | Phase III, MC, OL | Phase III, MC, OL |
Enrolled period | December 2013–May 2016 | February 2017–January 2018 | September 2015–February 2017 | October 2017–July 2019 |
ClinicalTrials.gov ID | NCT01886872 | NCT02970318 | NCT02475681 | NCT03336333 |
Method of analysis | ITT | ITT | ITT | ITT |
Response definition | iwCLL 2008 criteria | iwCLL 2008 criteria | iwCLL 2008 criteria | iwCLL 2008 criteria (CLL) or Lugano classification (SLL) |
Safety assessment | NR | CTCAE v4.03 | CTCAE v4.03 | CTCAE v4.03 |
Inclusion criteria | Treatment-naive patients | Relapsed or refractory patients | Treatment-naive patients | Treatment-naive patients |
Randomization | 1:1 | 1:1 | 1:1 | 1:1 |
Masking | No | No | No | No |
Randomization stratification | Risk factors for CLL | Presence or absence of del[17p] status, ECOG PS score, and lines of prior therapy received | Presence or absence of del[17p], ECOG PS score, and geographic region | Based on age, Binet stage, IGHV mutational status, and geographical region |
Primary outcome | PFS | PFS | PFS | PFS |
Secondary outcome | OS, ORR, CR, safety, etc | ORR, OS, DOR, safety, etc | ORR, OS, CR, safety, etc | ORR, OS, safety, etc |
Definition PFS | The interval time from randomization until disease progression or death from any cause | The time from randomization until disease progression or death | The time from randomization until disease progression or death | The time from randomization until disease progression or death |
Intervention arm | Ibrutinib 420 mg/day | Acalabrutinib 200 mg/day | Acalabrutinib 200 mg/day | Zanubrutinib 320 mg/day |
Standard of care arm | Bendamustine 90 mg/m2 + Rituximab (375 mg/m2) | Bendamustine 70 mg/m2 or Idelalisib 300 mg/day + Rituximab (500 mg/m2) | Chlorambucil (0.5 mg/kg on day 1 and day 15) + Obinutuzumab (1000 mg) | Bendamustine 90 mg/m2 + Rituximab (500 mg/m2) |
Sample size | 365 | 310 | 356 | 479 |
Time of initial response assessment | NR | NR | Week 12 | Week 12 |
Crossover design | Yes | Yes | Yes | Yes |
Study (First Author, Year) | BTK Inhibitor Group/Investigator’s Choice of Combination Therapy Group | Patient, n | Patient ≥ 65 years old | Patient age, median (range) | Sex, male, n (%) | ECOG PS (0–1), n (%) | ECOG PS (2), n (%) | High-Risk Disease (Rai/Binet Stage), n (%) | Treatment-Naïve Patients, n (%) | Relapsed or Refractory Patients, n (%) | Unmutated IGHV, n (%) | Del(17p), n (%) | Del(11q), n (%) | TP53 Mutation, n (%) | Complex Karyotype, n (%) | Follow-Up, Month, Median (Range) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Woyach JA et al. 2018 [25] | Ibrutinib Bendamustine + Rituximab | 182 183 | 182 183 | 71 (65–89) 70 (65–86) | 123 (68) 119 (65) | 177 (97) 173 (95) | 5 (3) 10 (5) | 99 (54) 99 (54) | 182 (100) 183 (100) | 0 (0) 0 (0) | 77/122 (63) 71/123 (58) | 9/181 (5) 14/181 (8) | 35/181 (19) 33/181 (18) | 15/168 (9) 16/174 (9) | 39/165 (24) 44/166 (27) | 38 38 |
Ghia P et al. 2020 [42] | Acalabrutinib Bendamustine/Idelalisib +Rituximab | 155 155 | 97 98 | 68 (32–89) 67 (34–90) | 108 (70) 100 (65) | 136 (88) 134 (86) | 19 (12) 21 (14) | 65 (42) 64 (41) | 0 (0) 0 (0) | 155 (100) 155 (100) | 118/154 (77) 125/153 (82) | 28/155 (18) 21/154 (14) | 39/155 (25) 44/155 (29) | 39/152 (26) 34/153 (22) | 50/154 (32) 46/153 (30) | 46.5 45.7 |
Sharman JP et al. 2020 [30] | Acalabrutinib Chlorambucil + Obinutuzumab | 179 177 | 151 153 | 70 (66–75) 71 (67–76) | 111 (62) 106 (59.9) | 165 (92.2) 167 (94.4) | 14 (7.8) 10 (5.6) | 87 (48.6) 78 (44.1) | 179 (100) 177 (100) | 0 (0) 0 (0) | 119 (66.5) 116 (65.5) | 16 (8.9) 16 (9.0) | 31 (17.3) 33 (18.6) | 19 (10.6) 21 (11.9) | 31 (17.3) 32 (18.1) | 46.9 46.9 |
Tam CS et al. 2022 [45] | Zanubrutinib Bendamustine + Rituximab | 241 238 | 196 192 | 70 (66–75) 70 (66–74) | 154 (64) 144 (61) | 226 (96) 218 (92) | 15 (6) 20 (8) | 70 (29) 70 (29) | 241 (100) 238 (100) | 0 (0) 0 (0) | 125/234 (53) 121/231 (52) | 2 (1) 0 (0) | 43 (18) 46 (19) | 15/232 (6) 13/223 (6) | NR | 26.2 26.2 |
Study | Bias arising from the Randomization Process | Bias due to Deviations from Intended Interventions | Bias due to Missing Outcome Data | Bias in the Measurement of the Outcome | Bias in the Selection of the Reported Result | The Overall Risk of Bias |
---|---|---|---|---|---|---|
Woyach JA et al. 2018 [25] | ||||||
Ghia P et al. 2020 [42] | ||||||
Sharman JP et al. 2020 [30] | ||||||
Tam CS et al. 2022 [45] |
Adverse Events | BTK Inhibitor | Combination Therapy | Risk Ratio | 95% Confident Interval | I2 (%) | p -Value | ||
---|---|---|---|---|---|---|---|---|
Events | Total | Event | Total | |||||
AE any grade | 543 | 573 | 530 | 549 | 0.98 | 0.91–1.06 | 51 | 0.13 |
AE of grade 3 or higher | 452 | 753 | 535 | 725 | 0.82 | 0.55–1.23 | 92 | <0.01 |
AE of grade 3 or higher subgroup | 319 | 573 | 424 | 549 | 0.73 | 0.54–0.98 | 64 | 0.06 |
Anemia | 54 | 753 | 49 | 725 | 1.06 | 0.45–2.49 | 30 | 0.23 |
Arthralgia | 7 | 753 | 3 | 725 | 1.79 | 0.58–5.57 | 0 | 0.81 |
Diarrhea | 11 | 753 | 42 | 725 | 1.58 | 0.22–11.56 | 43 | 0.15 |
Fatigue | 16 | 753 | 12 | 725 | 1.29 | 0.92–1.82 | 0 | 0.97 |
Hemorrhage | 21 | 753 | 8 | 752 | 2.01 | 0.54–7.44 | 0 | 0.40 |
Infection | 150 | 753 | 127 | 725 | 1.18 | 0.68–2.03 | 52 | 0.10 |
Neutropenia | 103 | 753 | 315 | 725 | 0.32 | 0.18–0.58 | 70 | 0.02 |
Neutropenia subgroup | 74 | 599 | 257 | 572 | 0.28 | 0.14–0.55 | 44 | 0.17 |
Pneumonia | 23 | 573 | 26 | 549 | 0.85 | 0.18–4.05 | 30 | 0.24 |
Sepsis | 14 | 753 | 25 | 725 | 0.55 | 0.32–0.93 | 0 | 0.86 |
SPM | 45 | 753 | 20 | 725 | 2.09 | 1.01–4.36 | 0 | 0.53 |
Thrombocytopenia | 27 | 753 | 73 | 725 | 0.37 | 0.20–0.70 | 0 | 0.48 |
URTI | 17 | 753 | 22 | 725 | 0.77 | 0.51–1.16 | 0 | 0.91 |
UTI | 14 | 753 | 13 | 725 | 1.03 | 0.21–4.95 | 22 | 0.28 |
Cardiac adverse events | 35 | 573 | 23 | 549 | 1.50 | 0.17–13.49 | 62 | 0.07 |
Atrial fibrillation | 22 | 753 | 10 | 725 | 1.74 | 0.30–9.96 | 32 | 0.22 |
Ventricular tachycardia | 2 | 753 | 0 | 725 | - | - | - | - |
Sudden death | 7 | 420 | 2 | 403 | - | - | - | - |
Hypertension | 80 | 753 | 43 | 725 | 1.64 | 0.60–4.51 | 36 | 0.19 |
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Nguyen, T.T.; Nhu, N.T.; Tran, V.K.; Nguyen, T.T.H.; Lin, C.-F. Efficacy and Safety of Bruton Tyrosine Kinase Inhibitor Monotherapy Compared with Combination Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Systematic Review and Meta-Analysis. Cancers 2023, 15, 1996. https://doi.org/10.3390/cancers15071996
Nguyen TT, Nhu NT, Tran VK, Nguyen TTH, Lin C-F. Efficacy and Safety of Bruton Tyrosine Kinase Inhibitor Monotherapy Compared with Combination Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Systematic Review and Meta-Analysis. Cancers. 2023; 15(7):1996. https://doi.org/10.3390/cancers15071996
Chicago/Turabian StyleNguyen, Thi Thuy, Nguyen Thanh Nhu, Van Khoi Tran, Tran Thuc Huan Nguyen, and Chiou-Feng Lin. 2023. "Efficacy and Safety of Bruton Tyrosine Kinase Inhibitor Monotherapy Compared with Combination Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: A Systematic Review and Meta-Analysis" Cancers 15, no. 7: 1996. https://doi.org/10.3390/cancers15071996