scholarly journals Idelalisib for the Treatment of Chronic Lymphocytic Leukemia

ISRN Oncology ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Maliha Khan ◽  
Areeba Saif ◽  
Steven Sandler ◽  
Aibek E. Mirrakhimov
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitor ◽  
Alkylating Agents ◽  
Treatment Strategies ◽  
The United States ◽  
Lymphocytic Leukemia ◽  
Durable Response ◽  
Significant Toxicity ◽  
Treatment Naïve ◽  
Chemotherapeutic Treatment

Chronic lymphocytic leukemia is the most common leukemia in the United States. It is a slowly progressive disease, with an 82% five-year survival rate. The treatment strategies are highly individualized with patients in the early and stable stages typically not requiring treatment. However, those with progressive or clinically advanced disease will require treatment. Cytotoxic drugs, such as the alkylating agents, purine nucleoside antagonists, and immunotherapeutic agents, have been the mainstay of chemotherapeutic treatment in CLL. However, given the lack of therapeutic specificity, these medications (especially older ones) have limited tolerability due to side effects. In this paper, we will discuss the data on the use of phosphatidylinositol 3 kinase inhibitor Idelalisib in the management of patients with chronic lymphocytic leukemia. The preclinical and clinical data thus far demonstrate that Idelalisib produces a dramatic and durable response in patients with chronic lymphocytic leukemia and without causing significant toxicity. Moving forward, the ongoing clinical trials will help address the various questions currently being raised regarding the long-term application and safety of Idelalisib. With greater clinical experience following more widespread use of Idelalisib, we will be able to determine the optimal combination therapies in treatment-naïve and relapsed/refractory patients, resulting in more individualized therapeutic strategies for patients with chronic lymphocytic leukemia.

ROS-Mediated Upregulation of Noxa Overcomes Drug-Resistance Due to P53-Dysfunction in Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2382-2382
Author(s):  
Sanne H. Tonino ◽  
Jacoline M van Laar ◽  
Marinus H. J. van Oers ◽  
Jean Y.J. Wang ◽  
Eric Eldering ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Combination Treatment ◽  
Conflicts Of Interest ◽  
Alkylating Agents ◽  
Single Agent ◽  
Treatment Strategies ◽  
Cd40 Ligand ◽  
Lymphocytic Leukemia

Abstract Abstract 2382 Poster Board II-359 Although recent advances in treatment-strategies for chronic lymphocytic leukemia (CLL) have resulted in increased remission rates and response duration, the disease eventually relapses, which necessitates repeated cycles of therapy. Eventually most patients develop chemo-resistant disease which infers a very poor prognosis. The activity of purine-analogs and alkylating agents, the backbone of current treatment regimens, depends on functional p53 and chemo-resistance is highly associated with a dysfunctional p53-response. P53-independent sensitization of CLL cells to these compounds could represent a novel strategy to overcome chemo-resistance. Platinum-based compounds have been successfully applied in relapsed lymphoma and recently also in high-risk CLL. In various cancer-types, the activity of such compounds has been found to be p53-independent and in part mediated by p73. In this study we investigated the efficacy and mechanism of action of platinum-based compounds in chemo-refractory CLL. Neither cisplatinum nor oxaliplatin as a single agent induced cell death in clinically relevant doses. However, independent of p53-functional status, platinum-based compounds acted synergistically with fludarabine, which was found to be caspase-dependent. Combination-treatment resulted in strong upregulation of the pro-apoptotic BH3-only protein Noxa. We did not find evidence for a role of p73; however, the observed synergy was found to involve generation of reactive oxygen species (ROS). Co-treatment with ROS-scavengers completely abrogated Noxa-upregulation and cell-death upon combination treatment in p53-dysfunctional CLL. Noxa RNA-interference markedly decreased sensitivity to combination treatment, supporting a key role for Noxa as mediator between ROS signaling and apoptosis induction. In addition to these findings, we tested the effects of platinum-based compounds and fludarabine on drug-resistance resulting from CD40-ligand stimulation of CLL cells, which represents a model for CLL cells in the protective micro-environment of the secondary lymph node-tissue (Hallaert et al Blood 2008 112(13):5141). Combination treatment could overcome CD40-ligand induced chemo-resistance and was, at least in part, mediated by the generation of ROS and marked induction of expression of Noxa. Our data indicate that interference with the cellular redox-balance represents an interesting target to overcome drug resistance due to both p53-dysfunction as well as micro-environmental protective stimuli in CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Novel ex vivo analysis of nonclassical, pleiotropic drug resistance and collateral sensitivity induced by therapy provides a rationale for treatment strategies in chronic lymphocytic leukemia

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1962-1971 ◽  
Author(s):  
AG Bosanquet ◽  
PB Bell
Keyword(s):  
Drug Resistance ◽  
Chronic Lymphocytic Leukemia ◽  
Ex Vivo ◽  
Alkylating Agents ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Agents ◽  
Differential Staining ◽  
Pleiotropic Drug Resistance ◽  
Previously Treated

Abstract Extensive research into mechanisms of cytotoxic drug resistance and subsequent clinical trials of drug resistance modifiers have produced few encouraging results. In this report, we analyze 4,400+ ex vivo Differential Staining Cytotoxicity (DiSC) assay drug response results from patients with chronic lymphocytic leukemia (CLL) to investigate the development of drug resistance during treatment. Patients were untreated (n = 216) or previously treated with various cytotoxic agents (n = 188). Data was processed to identify ex vivo resistance (or sensitivity) induced by treating patients with prednisolone, chlorambucil, cyclophosphamide, anthracycline, or fludarabine. Induced resistance was apparently not associated with any one known mechanism. Treatment with chlorambucil induced a 10-fold sensitivity to steroids; cyclophosphamide induced greater resistance to anthracyclines than alkylating agents; anthracyclines induced greatest resistance to chlorambucil, cisplatin, carboplatin, and cladribine. Patients previously treated with at least two regimens were only 2.16-fold more resistant to CLL drugs than untreated patients, but had significantly reduced survival (median survival, 7.9 months compared with 61.1 months for untreated patients). These results suggest that chlorambucil and/or an antimetabolite should be administered before cyclophosphamide or anthracyclines to delay the onset of extensive pleiotropic drug resistance. Because individual differences in drug sensitivity are considerable, specific guidance could be obtained from ex vivo assay results. Furthermore, as a model for investigating drug resistance mechanisms, fresh CLL lymphocytes represent a useful alternative to drug-resistant cell lines.

scholarly journals What Influences the Choice of Ibrutinib–Rituximab vs Classic Chemoimmunotherapy for Chronic Lymphocytic Leukemia?

2020 ◽  
Vol 29 ◽  
pp. 096368972095020
Author(s):  
Sara Bravaccini ◽  
Giovanni Martinelli ◽  
Claudio Cerchione
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Lymphocytic Leukemia ◽  
Western World ◽  
Phosphatidylinositol 3 Kinase ◽  
Fda Approval ◽  
Bruton Tyrosine Kinase ◽  
Treatment Naïve

Chronic lymphocytic leukemia (CLL), with an incidence rate between 4 and 6 cases per 100,000 persons per year, is considered the most prevalent leukemia in the western world. Chemoimmunotherapy (such as fludarabine, cyclophosphamide, and rituximab), bendamustine plus rituximab, and, more recently, novel agents such as ibrutinib (Bruton tyrosine kinase inhibitor), idelalisib (phosphatidylinositol-3-kinase δ inhibitor), and venetoclax (BCL-2 inhibitor) have changed the management of CLL. Shanafelt and colleagues compared the efficacy of ibrutinib–rituximab with that of standard chemoimmunotherapy in patients with treatment-naïve CLL. They did not, however, mention that the therapy varies on the basis of where patients live and, given that local guidelines not immediately reflect US Food and Drug Administration (FDA) updates, discrepancies in treatment occur. Important CLL goals are the availability of rapidly reproducible tests, standardization of national and international guidelines, and FDA approval-based treatment reimbursement.

scholarly journals Detection of Emerging Ibrutinib Resistance by Flow Cytometry in Patients with Chronic Lymphocytic Leukemia

2021 ◽  
Author(s):  
Ferenc Takács ◽  
Lili Kotmayer ◽  
Ágnes Czeti ◽  
Gábor Szalóki ◽  
László Tamás ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitor ◽  
Resistance Mutation ◽  
Lymphocytic Leukemia ◽  
Flow Cytometric ◽  
Clinical Resistance ◽  
Treatment Naïve ◽  
Droplet Pcr ◽  
Ibrutinib Resistance

Abstract Purpose: Bruton’s tyrosine kinase inhibitor ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). Although ibrutinib is a highly effective drug, during the treatment acquired ibrutinib resistance may occur and its early detection is an important issue. Our aim was to investigate several phenotypic markers on CLL cells to reveal changes in their expression during ibrutinib treatment.Methods: In our study 28 (treatment naive, ibrutinib sensitive, clinically ibrutinib resistant) peripheral blood (PB), and 6 paired PB and bone marrow (BM) samples were examined. The expression of several surface markers (CD69, CD184, CD86, CD185, CD27) was assessed by flow cytometry in each sample. Furthermore, the presence of the BTKC481S resistance mutation was tested using digital droplet PCR. In addition, we investigated the changes of the phenotype of CLL cells during ibrutinib treatment in one patient with acquired ibrutinib resistance.Results: The expression of CD27 decreased during ibrutinib therapy but increased again at the onset of clinical resistance. Expressions of CD69 and CD86 were also elevated at the onset of clinical ibrutinib resistance. The expression of CD86 showed correlation between PB and BM samples. Relapsed cases with high CD86 expression were positive for BTKC481S mutation. Our prospective study showed that the increases in the expression of CD27, CD69 and CD86 were detectable up to several months before the onset of clinical resistance.Conclusion: Our research suggests that the flow cytometric measurements of certain markers, especially CD86, may predict development of ibrutinib resistance, however, confirmatory experiments are still required.

Novel ex vivo analysis of nonclassical, pleiotropic drug resistance and collateral sensitivity induced by therapy provides a rationale for treatment strategies in chronic lymphocytic leukemia

Blood ◽  
1996 ◽  
Vol 87 (5) ◽  
pp. 1962-1971 ◽  
Author(s):  
AG Bosanquet ◽  
PB Bell
Keyword(s):  
Drug Resistance ◽  
Chronic Lymphocytic Leukemia ◽  
Ex Vivo ◽  
Alkylating Agents ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Agents ◽  
Differential Staining ◽  
Pleiotropic Drug Resistance ◽  
Previously Treated

Extensive research into mechanisms of cytotoxic drug resistance and subsequent clinical trials of drug resistance modifiers have produced few encouraging results. In this report, we analyze 4,400+ ex vivo Differential Staining Cytotoxicity (DiSC) assay drug response results from patients with chronic lymphocytic leukemia (CLL) to investigate the development of drug resistance during treatment. Patients were untreated (n = 216) or previously treated with various cytotoxic agents (n = 188). Data was processed to identify ex vivo resistance (or sensitivity) induced by treating patients with prednisolone, chlorambucil, cyclophosphamide, anthracycline, or fludarabine. Induced resistance was apparently not associated with any one known mechanism. Treatment with chlorambucil induced a 10-fold sensitivity to steroids; cyclophosphamide induced greater resistance to anthracyclines than alkylating agents; anthracyclines induced greatest resistance to chlorambucil, cisplatin, carboplatin, and cladribine. Patients previously treated with at least two regimens were only 2.16-fold more resistant to CLL drugs than untreated patients, but had significantly reduced survival (median survival, 7.9 months compared with 61.1 months for untreated patients). These results suggest that chlorambucil and/or an antimetabolite should be administered before cyclophosphamide or anthracyclines to delay the onset of extensive pleiotropic drug resistance. Because individual differences in drug sensitivity are considerable, specific guidance could be obtained from ex vivo assay results. Furthermore, as a model for investigating drug resistance mechanisms, fresh CLL lymphocytes represent a useful alternative to drug-resistant cell lines.

scholarly journals Patterns of resistance to B cell–receptor pathway antagonists in chronic lymphocytic leukemia and strategies for management

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 355-360 ◽  
Author(s):  
Jennifer A. Woyach
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Treatment Strategies ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Mechanisms Of Resistance ◽  
Number Of Patients ◽  
Active Investigation

Abstract Small-molecule kinase inhibitors, especially the two Food and Drug Administration–approved agents idelalisib and ibrutinib, have changed the treatment landscape for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). However, with these positive changes comes the new challenge of managing patients who relapse after these agents. The number of patients who have relapsed after taking idelalisib and ibrutinib is low, but as the drugs gain wider use and patients are treated for longer, this number is likely to grow. Because these patients can be challenging to manage effectively, coordinated efforts now to determine how and why patients relapse along with optimal treatment strategies are required to better serve our patients in the future. As well, identification of mechanisms of resistance is crucial to develop rational strategies for management. Current work has identified mechanisms of resistance to ibrutinib, and resistance to idelalisib is also under active investigation. In this review, we will discuss these mechanisms of resistance, as well as current and potential strategies for the management of kinase inhibitor-resistant CLL.

scholarly journals Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion

Haematologica ◽  
2020 ◽  
pp. 0-0
Author(s):  
Constantine S. Tam ◽  
Tadeusz Robak ◽  
Paolo Ghia ◽  
Brad S. Kahl ◽  
Patricia Walker ◽  
...  
Keyword(s):  
Adverse Event ◽  
Survival Rate ◽  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Upper Respiratory Tract ◽  
Small Lymphocytic Lymphoma ◽  
Treatment Naïve

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 – 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

scholarly journals New Insights into the Pathogenesis of Systemic Mastocytosis

2021 ◽  
Vol 22 (9) ◽  
pp. 4900
Author(s):  
Zhixiong Li
Keyword(s):  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Systemic Mastocytosis ◽  
Treatment Strategies ◽  
The United States ◽  
European Medicines Agency ◽  
Myeloid Neoplasm ◽  
Organ Systems ◽  
United States Food ◽  
Kit D816v

Mastocytosis is a type of myeloid neoplasm characterized by the clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells that infiltrate one or more organ systems. Systemic mastocytosis (SM) is a more aggressive variant of mastocytosis with extracutaneous involvement, which might be associated with multi-organ dysfunction or failure and shortened survival. Over 80% of patients with SM carry the KIT D816V mutation. However, the KIT D816V mutation serves as a weak oncogene and appears to be a late event in the pathogenesis of mastocytosis. The management of SM is highly individualized and was largely palliative for patients without a targeted form of therapy in past decades. Targeted therapy with midostaurin, a multiple kinase inhibitor that inhibits KIT, has demonstrated efficacy in patients with advanced SM. This led to the recent approval of midostaurin by the United States Food and Drug Administration and European Medicines Agency. However, the overall survival of patients treated with midostaurin remains unsatisfactory. The identification of genetic and epigenetic alterations and understanding their interactions and the molecular mechanisms involved in mastocytosis is necessary to develop rationally targeted therapeutic strategies. This review briefly summarizes recent developments in the understanding of SM pathogenesis and potential treatment strategies for patients with SM.

scholarly journals Chronic Lymphocytic Leukemia: A Rare Cause of Pathological Fracture of the Femur

2017 ◽  
Vol 5 (4) ◽  
pp. 232470961773513 ◽  
Author(s):  
Parita Soni ◽  
Nidhi Aggarwal ◽  
Anand Rai ◽  
Vivek Kumar ◽  
Kamholz Stephan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Endotracheal Intubation ◽  
Pathological Fracture ◽  
The United States ◽  
Left Knee ◽  
Lymphocytic Leukemia ◽  
Initial Presentation ◽  
Richter’S Transformation ◽  
Richter's Transformation

The incidence rate of chronic lymphocytic leukemia (CLL) in the United States is approximately 0.005%; men are at slightly higher risk than women. Bony involvement or pathological fracture rarely occurs in CLL, and it may be the initial presentation. An 85-year-old woman presented with acute respiratory failure secondary to pneumonia. Symptomatology included dyspnea. She was found to have pathological fracture of the femur caused by CLL. The diagnosis of CLL had been made 6 years previously, but the patient had refused therapy. On admission, the patient required endotracheal intubation, mechanical ventilation, and admission to the medical intensive care unit. Endotracheal intubation extubation was successful after 48 hours. The patient then complained of severe left knee pain. Bone radiograph and femoral computed tomography scan revealed acute pathological fracture of the left distal femur. There was no history of trauma. The fracture was stabilized with extension lock splint. Pathological fracture in patients with CLL is associated with hypercalcemia, Richter’s transformation, or multiple myeloma. This patient exemplifies the fact that pathological fracture can be caused by CLL in the absence of hypercalcemia, Richter’s transformation, or multiple myeloma and can be the initial presentation of CLL.

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