Druggable Molecular Pathways in Chronic Lymphocytic Leukemia
Abstract
:1. Introduction
2. Targeting the BCR in CLL
2.1. BTK Inhibitors
2.1.1. Ibrutinib
2.1.2. Acalabrutinib
2.1.3. Zanubrutinib
2.1.4. Pirtobrutinib
2.2. PI3K Inhibitors
2.2.1. Idelalisib
2.2.2. Duvelisib
3. Targeting the BCL2 Pathway in CLL
BCL2 Inhibitors
4. Targeting Notch Signaling in CLL
5. Targeting the NF-κB Signaling Pathway in CLL
6. Targeting Molecular Pathways in High-Risk CLL with TP53 Disruption
7. Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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The Biological Pathways | Mutated Genes |
---|---|
NOTCH1 Signaling | NOTCH1, FBXW7 |
BCR and Toll-like receptor signaling | EGR2, BCOR, MYD88, TLR2, IKZF3 |
MAPK-ERK pathway | KRAS, NRAS, BRAF, MAP2K1 |
RNA Splicing and metabolism | SF3B1, U1, XPO1, DDX3X, RPS15 |
NF-κB Signaling | BIRC3, NFKBIE, TRAF2, TRAF3 |
DNA damage response | ATM, TP53, POT1 |
Apoptosis | miR15/16, BCL2 |
Trial | Phase | Setting | Interventions | N. of Patients | PFS | OS |
---|---|---|---|---|---|---|
Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia [34] | 3 | Untreated patients with CLL or SLL subtype of CLL | Ibrutinib-Rituximab | 354 | 3 years: 89.4% | 3 years: 98.8% |
Chemoimmunotherapy (FCR) | 175 | 3 years: 72.9% | 3 years: 91.5% | |||
Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions [38] | 3 | Untreated patients with CLL | Venetoclax + Obinutuzumab | 216 | 24 months: 88.2% | 24 months: 91.8% |
Chlorambucil + Obinutuzumab | 216 | 24 months: 64.1% | 24 months: 93.3% | |||
Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL [36] | 3 | Untreated patients with CLL aged ≥65 | Bendamustine + Rituximab | 183 | 24 months: 74% | 24 months: 95% |
Ibrutinib | 182 | 24 months: 87% | 24 months: 90% | |||
Ibrutinib + Rituximab | 182 | 24 months: 88% | 24 months: 94% | |||
Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial [39] | 3 | Untreated patients with CLL or SLL either aged 65 years or older or younger than 65 years with coexisting conditions | Ibrutinib + Obinutuzumab | 113 | Median PFS: not reached (Estimated) 30 months: 79% | Median OS: not reached (Estimated) 30 months: 86% |
Chlorambucil + Obinutuzumab | 116 | Median PFS: 19 months (Estimated) 30 months: 31% | Median OS: not reached at (Estimated) 30 months: 85% | |||
Long-term follow-up of the RESONATE phase 3 trial of Ibrutinib vs. Ofatumumab [37] | 3 | Previously treated patients with CLL or SLL requiring a new therapy and not eligible for purine analog-based therapy | Ibrutinib | 195 | Median PFS: not reached 3 years: 59% | Median OS: not reached 3 years: 74% |
Ofatumumab [Note: 68% of patients in this arm crossing over to ibrutinib] | 196 | Median PFS: 8.1 months 3 years: 3% | Median OS: not reached 3 years: 65% | |||
Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia [40] | 3 | Patients aged 18 years or older with relapsed or refractory CLL | Venetoclax + Rituximab | 194 | 2 years overall: 84.9% | 2 years overall: 91.9% |
Bendamustine + Rituximab | 195 | 2 years overall: 36.3% | 2 years overall: 86.6% | |||
Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial [41] | 3 | Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) | Ibrutinib | 265 | Median PFS: 34.8 months | Median OS: not reached 3 years: >60% |
Acalabrutinib | 268 | Median PFS: 34.8 months | Median OS: not reached 3 years: >60% | |||
Acalabrutinib with or without obinutuzumab versus chlorambucil and Obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial [42] | 3 | Untreated patients with CLL ged 65 years or older, or older than 18 years and younger than 65 years with creatinine clearance of 30–69 mL/min or Cumulative Illness Rating Scale for Geriatrics score greater than 6. | Acalabrutinib | 179 | Median PFS not reached | Median OS: not reached 3 years: >80% |
Acalabrutinib + Obinutuzumab | 179 | Median PFS not reached | Median OS: not reached 3 years: >80% | |||
Chlorambucil + Obinutuzumab | 177 | Median PFS: 22.6 months | Median OS: not reached 3 years: >80% | |||
The phase 3 DUO trial: duvelisib vs. ofatumumab in relapsed and refractory CLL/SLL | 3 | Relapsed or refractory CLL/SLL [43] | Duvelisib | 160 | Median PFS: 13.3 months | Median OS: not reached 3 years: >50% |
Ofatumumab | 159 | Median PFS: 9.9 months | Median OS: not reached 3 years: >50% |
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Almasri, M.; Amer, M.; Ghanej, J.; Mahmoud, A.M.; Gaidano, G.; Moia, R. Druggable Molecular Pathways in Chronic Lymphocytic Leukemia. Life 2022, 12, 283. https://doi.org/10.3390/life12020283
Almasri M, Amer M, Ghanej J, Mahmoud AM, Gaidano G, Moia R. Druggable Molecular Pathways in Chronic Lymphocytic Leukemia. Life. 2022; 12(2):283. https://doi.org/10.3390/life12020283
Chicago/Turabian StyleAlmasri, Mohammad, Marah Amer, Joseph Ghanej, Abdurraouf Mokhtar Mahmoud, Gianluca Gaidano, and Riccardo Moia. 2022. "Druggable Molecular Pathways in Chronic Lymphocytic Leukemia" Life 12, no. 2: 283. https://doi.org/10.3390/life12020283