Ibrutinib Associated with Rituximab-Platinum Salt-Based Immunochemotherapy in B-Cell Lymphomas: Results of a Phase 1b-II Study of the LYSA Group
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design and Patients
2.2. Procedures
2.3. Endpoints
2.4. Statistical Analyses
3. Results
3.1. Safety and Tolerability
3.1.1. Ibrutinib in Combination with R-DHAP
3.1.2. Ibrutinib in Combination with R-DHAOx
3.2. Patient Outcomes
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Type of Immunochemotherapy | R-DHAP | R-DHAOx | ||
---|---|---|---|---|
Administration of Ibrutinib | Concomitant | Intermittent | Concomitant | Intermittent |
D1–21 | D5–18 | D1–21 | D5–18 | |
Group | A | A’ | B | B’ |
Patients enrolled | 13 | 13 | 12 | 37 |
Patients evaluable for DLT | 13 | 10 | 12 | 12 |
Patients evaluable for safety | 13 | 12 £ | 12 | 36 ££ |
Median age * | 63 (40–68) | 60 (49–69) | 58 (42–66) | 62 (25–70) |
≤60 years | 5 (38%) | 9 (75%) | 8 (67%) | 16 (44%) |
>60 years | 8 (62%) | 3 (25%) | 4 (33%) | 20 (56%) |
Sex | ||||
Male | 9 (69%) | 8 (67%) | 8 (67%) | 23 (64%) |
Female | 4 (31%) | 4 (33%) | 4 (33%) | 13 (36%) |
Stage at inclusion | ||||
I | 2 (15%) | 4 (33%) | 3 (25%) | 3 (8%) |
II | 3 (23%) | 1 (8%) | 0 | 3 (8%) |
III | 2 (15%) | 3 (25%) | 2 (17%) | 6 (17%) |
IV | 6 (45%) | 4 (33%) | 7 (58%) | 24 (67%) |
ECOG at inclusion | ||||
0 | 8 (63%) | 9 (75%) | 8 (67%) | 25 (69%) |
1 | 3 (23%) | 3 (25%) | 3 (25%) | 9 (25%) |
2 | 2 (15%) | 0 | 1 (8%) | 2 (6%) |
LDH > upper normal limit | ||||
No | 6 (69%) | 7 (64%) | 3 (75%) | 18 (50%) |
Yes | 7 (31%) | 4 (36%) | 9 (25%) | 18 (50%) |
Bone marrow | ||||
Performed | 11 (85%) | 9 (75%) | 11 (92%) | 34 (94%) |
Involved | 2 (18%) | 0 | 2 (18%) | 6 (79%) |
Non-involved | 9 (82%) | 9 (100%) | 8 (73%) | 28 (82%) |
Unspecified | 0 | 0 | 1 (9%) | 0 |
Histology at inclusion | ||||
DLBCL | 4 (31%) | 4 (33%) | 7 (58%) | 15 (46%) |
Other large B-cell lymphoma † | 0 | 2 (16%) | 1 (8%) | 2 (6%) |
Follicular lymphoma Grade 1, 2, or 3a | 2 (15%) | 4 (33%) | 2 (16%) | 11 (33%) |
Nodal marginal zone lymphoma | 1 (8%) | 0 | 1 (8%) | 1 (3%) |
Mantle cell lymphoma | 2 (15%) | 0 | 1 (8%) | 0 |
Transformed indolent lymphoma ‡ | 4 (32%) | 1 (8%) | 0 | 3 (9%) |
Missing | 0 | 2 (17%) | 0 | 4 (13%) |
Disease status | ||||
Refractory | 3 (23%) | 6 (50%) | 3 (25%) | 13 (36%) |
Relapsed/progressive | 10 (77%) | 6 (50%) | 9 (75%) | 23 (64%) |
Number of previous treatment lines | ||||
1 | 12 (92%) | 12 (100%) | 10 (83%) | 31 (86%) |
2 | 1 (8%) | 0 | 2 (17%) | 5 (14%) |
Previous treatments | ||||
Rituximab | 13 (100%) | 11 (92%) | 10 (83%) | 36 (100%) |
Anthracycline-based chemotherapy | 13 (100%) | 11 (92%) | 12 (100%) | 35 (97%) |
Radiotherapy | 1 (8%) | 0 | 3 (25%) | 1 (3%) |
Autologous stem cell transplantation | 2 (15%) | 0 | 0 | 1 (3%) |
Allogenic stem cell transplantation | 0 | 0 | 1 (8%) | 0 |
Chemotherapy | R-DHAP | R-DHAOx | ||||||
---|---|---|---|---|---|---|---|---|
Enrolled set | 26 | 49 | ||||||
Safety set | 25 | 48 | ||||||
Ibrutinib administration | Concomitant | Intermittent | Concomitant | Intermittent | ||||
Group | A | A’ | B | B’ | ||||
Enrolled set | 13 | 13 | 12 | 37 | ||||
Safety set | 13 | 12 | 12 | 36 | ||||
Grade >2 AEs in >10% of patients and AESIs | Patients (%) | AE | Patients (%) | AE | Patients (%) | AE | Patients (%) | AE |
13 (100%) | 127 | 12 (100%) | 98 | 12 (100%) | 81 | 33 (92%) | 171 | |
Blood and lymphatic disorders | 13 (100%) | 87 | 12 (100%) | 56 | 12 (100)% | 59 | 30 (83%) | 111 |
Thrombocytopenia | 13 (100%) | 31 | 9 (75%) | 18 | 12 (100%) | 26 | 30 (83%) | 65 |
Neutropenia | 11 (85%) | 18 | 6 (50%) | 9 | 5 (42%) | 8 | 12 (33%) | 17 |
Febrile neutropenia | 6 (47%) | 8 | 3 (25%) | 3 | 3 (25%) | 3 | 3 (8%) | 4 |
Anemia | 8 (62%) | 11 | 3 (25%) | 9 | 2 (17%) | 4 | 8 (22%) | 9 |
Infections | 4 (31%) | 4 | 3 (25%) | 5 | 4 (33%) | 4 | 8 (22%) | 12 |
Bacterial sepsis | 2 (15%) | 2 | ||||||
Bronchitis | 2 (17%) | 3 | ||||||
Hemorrhagic manifestations | 2 (15%) | 2 | 1 (3%) | 1 | ||||
General disorders and administration site conditions | 2 (15%) | 3 | 2 (17%) | 2 | 3 (8%) | 3 | ||
Cardiac disorders | 2 (15%) | 4 | 3 (25%) | 3 | 4 (11%) | 5 | ||
Atrial fibrillation | 2 (15%) | 2 | 2 (17%) | 2 | 3 (8%) | 3 | ||
Vascular disorders | 1 (8%) | 1 | 1 (8%) | 1 | ||||
Metabolism and nutrition disorders | 6 (46%) | 9 | 1 (8%) | 1 | 2 (17%) | 2 | 6 (17%) | 11 |
Hypocalcemia | 3 (23%) | 3 | ||||||
Hypokalemia | 2 (15%) | 2 | 1 (8%) | 1 | 2 (6%) | 3 | ||
Renal and urinary disorders | 7 (54%) | 7 | 8 (67%) | 8 | ||||
Renal failure | 7 (54%) | 7 | 8 (67%) | 8 | ||||
Gastrointestinal disorders | 4 (31%) | 5 | 2 (17%) | 3 | 6 (17%) | 7 | ||
Diarrhea | 4 (11%) | 4 | ||||||
Hepatobiliary disorders | 2 (17%) | 2 | 5 (14%) | 7 | ||||
Congenital, familial, and genetic disorders | 2 (17%) | 2 | ||||||
Aplasia | 2 (17%) | 2 | ||||||
Nervous system disorders | 3 (25%) | 3 | 8 (22%) | 10 | ||||
Peripheral neuropathy | 1 (8%) | 1 | 7 (19%) | 7 | ||||
Skin and subcutaneous disorders | 2 (15%) | 2 | 2 (17%) | 2 | ||||
Second primary neoplasias | 2 (17%) | 2 | ||||||
Patients with at least one SAE | Patients (%) | SAE | Patients (%) | SAE | Patients (%) | SAE | Patients (%) | SAE |
10 (77) | 27 | 10 (77%) | 34 | 6 (50%) | 17 | 17 (47%) | 30 | |
Infection | 3 (23%) | 4 | 2 (17%) | 2 | 5 (42%) | 6 | 6 (27%) | 10 |
Renal failure | 4 (31%) | 4 | 8 (67%) | 8 | ||||
Atrial fibrillation | 1 (8%) | 1 | 1 (8%) | 1 | 2 (6%) | 2 | ||
Cutaneous eruption | 1 (8%) | 1 | 2 (17%) | 2 | ||||
Hemorrhagic complication | 2 (17%) | 2 | 2 (6%) | 2 | ||||
Veno-occlusive disease | 3 (8%) | 3 | ||||||
DLT evaluable patients (n) | 13 | 10 | 12 | 12 | ||||
Patients with DLT | 5 | 3 | 4 | 1 | ||||
Number of DLTs | 7 | 6 | 6 | 1 | ||||
Patients who discontinued treatment | 4 | 7 | 5 | 3 | ||||
Treatment discontinuation due to toxicity | 4 | 2 | 2 | |||||
Treatment discontinuation due to progression | 3 | 1 | 3 | |||||
Treatment discontinuation due to consent withdrawal | 1 | 2 | ||||||
Treatment discontinuation due to concurrent illness | 1 |
R-I-DHAP | R-I-DHAOx | ||
---|---|---|---|
Group A: Concomitant Administration: 13 Patients | Group B: Concomitant Administration: 12 Patients | ||
Ibrutinib 420 mg/day: 6 Patients | Ibrutinib 420 mg/day: 6 Patients | ||
Patient 1 | Grade 4 cutaneous eruption lasting 5 days | Patient 1 | Grade 3 prostate infection lasting 11 days |
Patient 2 | Grade 4 sepsis lasting 10 days | Grade 3 cutaneous eruption lasting 10 days | |
Patient 3 | Grade 4 thrombocytopenia lasting 7 days £ | Patient 2 | Grade 3 cutaneous infection lasting 10 days |
Grade 3 febrile neutropenia lasting 1 day | |||
Patient 3 | Grade 4 thrombocytopenia lasting 14 days | ||
Ibrutinib 280 mg/day: 7 patients | Ibrutinib 280 mg/day: 6 patients | ||
Patient 4 | Grade 4 neutropenia lasting 12 days | Patient 4 | Grade 3 epigastric pain lasting 11 days |
Patient 5 | Grade 4 gastric hemorrhage lasting 13 days | ||
Grade 4 thrombocytopenia lasting 13 days | |||
Grade 3 atrial fibrillation lasting 2 days | |||
Group A’: Intermittent administration: 10 patients * | Group B’: Intermittent administration: 12 patients | ||
Ibrutinib 420 mg/day: 4 patients | Ibrutinib 420 mg/day: 6 patients | ||
No DLT | Patient 1 | Grade 3 hepatitis lasting 141 days | |
Ibrutinib 560 mg/day: 6 patients | Ibrutinib 560 mg/day: 6 patients | ||
Patient 1 | Grade 3 acute renal insufficiency lasting 2 days | No DLT | |
Patient 2 | Grade 3 hyponatremia lasting 1 day | ||
Grade 3 nausea lasting 19 days | |||
Grade 3 hypophosphatemia lasting 1 day. | |||
Patient 3 | Grade 3 acute renal insufficiency lasting 5 days | ||
Grade 3 vomiting lasting 17 days |
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Bonnet, C.; Dupuis, J.; Tilly, H.; Lamy, T.; Fruchart, C.; le Gouill, S.; Thieblemont, C.; Morschhauser, F.; Casasnovas, O.; Bouabdallah, K.; et al. Ibrutinib Associated with Rituximab-Platinum Salt-Based Immunochemotherapy in B-Cell Lymphomas: Results of a Phase 1b-II Study of the LYSA Group. Cancers 2022, 14, 1761. https://doi.org/10.3390/cancers14071761
Bonnet C, Dupuis J, Tilly H, Lamy T, Fruchart C, le Gouill S, Thieblemont C, Morschhauser F, Casasnovas O, Bouabdallah K, et al. Ibrutinib Associated with Rituximab-Platinum Salt-Based Immunochemotherapy in B-Cell Lymphomas: Results of a Phase 1b-II Study of the LYSA Group. Cancers. 2022; 14(7):1761. https://doi.org/10.3390/cancers14071761
Chicago/Turabian StyleBonnet, Christophe, Jehan Dupuis, Hervé Tilly, Thierry Lamy, Christophe Fruchart, Steven le Gouill, Catherine Thieblemont, Franck Morschhauser, Olivier Casasnovas, Krimo Bouabdallah, and et al. 2022. "Ibrutinib Associated with Rituximab-Platinum Salt-Based Immunochemotherapy in B-Cell Lymphomas: Results of a Phase 1b-II Study of the LYSA Group" Cancers 14, no. 7: 1761. https://doi.org/10.3390/cancers14071761