Targeted Therapy for Chronic Lymphocytic Leukemia: Current Status and Future Directions

Drugs ◽  
2015 ◽  
Vol 75 (2) ◽  
pp. 143-155 ◽  
Author(s):  
Jon E. Arnason ◽  
Jennifer R. Brown
Keyword(s):  
Targeted Therapy ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Current Status ◽  
Future Directions

scholarly journals Modeling tumor–host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy

Leukemia ◽  
2013 ◽  
Vol 27 (12) ◽  
pp. 2311-2321 ◽  
Author(s):  
S E M Herman ◽  
X Sun ◽  
E M McAuley ◽  
M M Hsieh ◽  
S Pittaluga ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Chronic Lymphocytic Leukemia ◽  
Tumor Biology ◽  
Lymphocytic Leukemia ◽  
Host Interactions

scholarly journals The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

2021 ◽  
Author(s):  
Tadeusz Robak ◽  
Magda Witkowska ◽  
Piotr Smolewski
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Effects ◽  
Kinase Inhibitors ◽  
Clinical History ◽  
Lymphocytic Leukemia ◽  
Current Status ◽  
Covalent Inhibitors ◽  
History Of ◽  
Reduced Toxicity ◽  
Btk Inhibitors

The use of the Bruton’s tyrosine kinase (BTK) inhibitors has changed the management and clinical history of patients with chronic lymphocytic leukemia (CLL). BTK is a critical molecule that interconnects B-cell antigen receptor (BCR) signaling. BTKIs are classified into two categories: irreversible (covalent) inhibitors and reversible (non-covalent) inhibitors. Ibrutinib is the first irreversible BTK inhibitor approved by the U.S. Food and Drug Administration in 2013 as a breakthrough therapy in CLL patients. Subsequently, several studies evaluated the efficacy and safety of new agents with reduced toxicity when compared with ibrutinib. Two other irreversible, second-generation BTK inhibitors, acalabrutinib and zanubrutinib, were developed to reduce ibrutinib-mediated adverse effects. Additionally, new reversible BTK inhibitors are currently under development in an early phase studies to improve their activity and to diminish adverse effects. This review summarizes the pharmacology, clinical efficacy, safety, dosing, drug-drug interactions associated with the treatment of CLL with BTK inhibitors, and examines its further implications.

scholarly journals An Updated Perspective on Current Prognostic and Predictive Biomarkers in Chronic Lymphocytic Leukemia in the Context of Chemoimmunotherapy and Novel Targeted Therapy

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 894 ◽  
Author(s):  
Jared A. Cohen ◽  
Riccardo Bomben ◽  
Federico Pozzo ◽  
Erika Tissino ◽  
Andrea Härzschel ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Predictive Biomarkers ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Region Gene ◽  
Novel Biomarkers

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.

Targeted therapy for chronic lymphocytic leukemia

2009 ◽  
Vol 4 (1) ◽  
pp. 11-21 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Susan O’Brien
Keyword(s):  
Targeted Therapy ◽  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia

Factors Predictive for Graft Failure Following Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia in a Population-Based Provincial Transplant Cohort

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4132-4132 ◽  
Author(s):  
Chinmay B. Dalal ◽  
Chandrakala Shanmukhaiah ◽  
Thomas J. Nevill ◽  
Michael J. Barnett ◽  
Stephen H. Nantel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Current Status ◽  
Lower Probability ◽  
Hematopoietic Stem ◽  
Age Range

Abstract Abstract 4132 Allogeneic stem cell transplantation (allo HSCT) is the only modality that may produce long-term disease-free survival/cure for chronic lymphocytic leukemia (CLL). Successful transplant is hindered by relapse (REL), infections (INF), graft versus host disease (GVHD) and rejection of graft (GF). GF may manifest as either lack of initial donor (dn) cell engraftment (primary, P) or loss of donor cells after initial engraftment (secondary, S). To ascertain factors predictive for GF and outcomes thereafter including complete remission (CR), clearance of FISH abnormality (abn), non-relapse mortality (NRM), REL and survival, consecutive patients (pts) proceeding to allo HSCT at the Leukemia/BMT Program of BC with CLL (1991–2011) (n=81 total, 11 GF, 4P, 7S) were studied using prospective databases. HSCT Comorbidity index (Sorror) (CoI) was calculated for all pts, FISH performed pre and post SCT in 67 and 55 pts (10 GF), and chimerism for pts not receiving myeloablative (MA) conditioning (CON). P-values show relationship between non-GF and GF pts. Median (med) pt age (range) at diagnosis (dx) was 49 years (yrs) (26–65) whole cohort; younger at 47 (30–57) yrs in GF pts (p = 0.047). Gender was F in 24 (3 GF): M in 57 (8 GF) pts; 23 F (1 GF): 58 M (10 GF) dn (p = 0.3). Max stage was Rai advanced (III/IV) in 48 pts (59%) (8 GF) (p = 0.3); 17 (6 GF) had B-symptoms prior to HSCT (p = 0.005). Of 77 pts (95%) (11 GF) who received prior fludarabine (flu) (p = 0.4), 47 were refractory (REF) (7 GF) (p = 0.8); 35 (43%) (2 GF) were REF to last therapy (tx) pre-HSCT (p = 0.07). Med number of prior tx was 4 for both groups (range 1–14 whole cohort, 3–7 GF) (p = 0.5). CoI was 0 in 46 (57%) (6 GF), 1–2 in 26 (32%) (5 GF), and 3 or > in 9 pts (11%) (p = 0.3). Med pt age (range) at HSCT, whole cohort vs GF was similar at 57 (32–68) vs 58 (37–63) yrs (p = 0.4); and 45 (19–76) vs 42 (21–58) yrs for dn (p = 0.5). Dn was unrelated (UD) in 38 (47%) (9 GF) (p = 0.01), and HLA-mismatched (MM) in 17 (21%) (4 GF) (p = 0.2); 9 had HLA-C MM (2 GF) (p = 0.9). CON was MA (Cy/TBI) in 23 (28%) (2 GF) (p = 0.4), reduced intensity (RIC) in 41 (51%); flu/bu in 22 (27%), flu/bu + alemtuzumab (A) in 19 (23%) pts, (7 total RIC with GF, 6 post A CON) (p = 0.4), and non-myeloablative (NMA) (flu/cy) in 17 pts (21%) (2 GF) (p = 0.8). Peripheral blood (PB) was used for most pts (69, 85%) (10 GF) (p = 0.6). Cell dose, med (range) was 9.6 (0.4–25.8) TNC x108/kg pt wt (9.9, 2.7–18.4 for GF pts) (p = 0.4). CD34 count was 6.3 (2.4–578.9) x106/kg pt wt (5.9, 3.0–9.5 for GF pts) (p = 0.4). GVHD prophylaxis was CSP/MTX for the majority (79, 98%) (p = 0.1); 2 pts (1 GF) had T-Cell depletion. Pre-HSCT FISH abnormalities (abn) (61, 75% of pts) (10 GF) (p = 0.3) included: del 13q (37, 46%) (10 GF) (p = 0.09); +12 (11, 14%) (2 GF) (p = 0.9); del 11q (24, 30%) (6 GF) (p = 0.09) and del 17p (19, 23%) (3 GF) (p = 0.9). CR was achieved in 48 pts (2 GF) (p = 0.004), a med of 132.5d (28d to 3.5yrs) post HSCT (93d for GF pts, range -30–216 d) (p = 0.2). 42 pts with CR did not REL (2 GF), 6 did; 12 pts without CR have progressive CLL (4 GF), and 21 pts have no CR but no progression (5 GF) (p=0.02). 27 pts cleared FISH abn post HSCT a med of 98d (28d to 2.1yrs) (2 GF) (p = 0.09). AGVHD occurred in 45 pts (2 GF) (p = 0.09) and CGVHD in 55 pts (1 GF) (p = 0.001). KM estimate of OS (whole group vs GF) is similar at 66% vs 71% at 2yr, 57% vs 71% at 5yr and beyond (p = 0.8) At med post-HSCT follow-up (FU) of 3yrs (0.4–17yrs), 48 of 81 pts (60%) survive (7 GF, 64%). 33 are deceased at a med of 1.2yr (39d to 7.1yrs), 10 with NRM (1 GF) and 21 with REL (3 GF). Of the 11 GF pts, 7 required 2nd HSCT (64%, 3 with prior dn, all with different CON; 4 flu+treosulfan+ATG, 1 flu/cy, 1 Cy+ATG and 1 Cy+ATG+TBI); 2 pts (20%) 3rd HSCT. Current status is 7/11 GF pts alive (64%, 4 with CLL, 3 in CR) and 4 deceased (1 NRM, 2 INF, 1 CLL). Factors predictive for GF include (p-value, Odds-Ratio (if applicable)): younger age at dx (0.047), B-symptoms pre-HSCT (0.005, 6.3) (Fig 1), UD (0.01, 5) (Fig 2), alemtuzumab CON (0.008, 5.3) (Fig 3), clonal evolution (CE) by FISH (development of new FISH abn) (0.03, 5.8), and major ABO MM (0.04). GF pts had lower probability of CGVHD (0.001, 0.02), and post HSCT CR (0.004, 0.1), but similar OS to non-GF pts (p= 0.8 log rank). Strategies to decrease GF post allo HSCT for CLL include avoidance of major ABO MM and alemtuzumab in CON. Higher vigilance is required for GF in pts with pre-HSCT B symptoms, CE by FISH, and with use of UD. Of interest, survival for CLL pts with GF is not decreased due to effective rescue tx, but resource utilization is high with extra HSCT procedures required. Disclosures: No relevant conflicts of interest to declare.

Current Status in Management of Patients with Chronic Lymphocytic Leukemia (CLL) in Republic of Macedonia

2016 ◽  
Vol 70 (1) ◽  
pp. 30-34
Author(s):  
Marica Pavkovic ◽  
Sonja Genadieva-Stavric ◽  
Gazmend Amzai ◽  
Tatjana Sotirova ◽  
Lidija Cevreska ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Western Europe ◽  
Progression Free Survival ◽  
Staging System ◽  
Lymphocytic Leukemia ◽  
Current Status ◽  
Female Ratio ◽  
Republic Of Macedonia ◽  
The Republic ◽  
The Moment

Abstract Chronic lymphocytic leukemia (CLL) is the most commonly diagnosed type of leukemia in Western Europe and North America, and represents about 30% of all leukemias in adults. CLL is a disease of elderly, who often have multiple comorbidities. These factors affect further treatment decisions, despite the great progress in the therapy of CLL in the last two decades. The aim of this study was to evaluate the current status in the management of patients with CLL in the Republic of Macedonia and to compare it with CLL patients in other western countries. We analyzed 102 patients with CLL referred to our Institution for control and/or treatment in the period from January 2015 to October 2015. Median age of our group of patients at the time of diagnosis was 62.7 years with almost 40% of patients older than 64 years. Male to female ratio was 1.3:1 and 54% of patients were diagnosed in stage “0” according to Rai staging system. Watch and wait was the most common treatment approach (58.8%) at the time of diagnosis, but at the moment of analysis only 33% of patients were still with-out treatment. The most common treatment in this group of CLL patients was FCR protocol with 39.5% of patients treated with an average of 5 cycles of this immunochemotherapeutic regimen. The average time of progression free survival (PFS) in all treated patients was 32.8 months with range between 2-72 months. In summary, clinical characteristics of CLL patient in our clinical settings and the most common therapeutic approach at our Institution do not differ significantly from the characteristics of the average CLL patient in other studies.

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