scholarly journals Treatment Options for Elderly/Unfit Patients with Chronic Lymphocytic Leukemia in the Era of Targeted Drugs: A Comprehensive Review

2021 ◽  
Vol 10 (21) ◽  
pp. 5104
Author(s):  
Alberto Fresa ◽  
Francesco Autore ◽  
Eugenio Galli ◽  
Annamaria Tomasso ◽  
Luca Stirparo ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
Geriatric Syndromes ◽  
Safety Issues ◽  
Unfit Patients ◽  
Individualize Treatment ◽  
Anti Cd20

Chronic lymphocytic leukemia (CLL) incidence increases with age reaching 37.9/100,000 in patients over 85 years. Although there is no standardized geriatric tool specifically validated for CLL, a correct framing of the fitness status is of critical importance to individualize treatment strategies. Based on the evidence available to date, frontline chemoimmunotherapy has an increasingly narrowing application, being eligible for candidacy only in elderly fit patients without or with minimal geriatric syndromes. On the other hand, treatment with BCR inhibitors, monotherapy, or in combination with anti-CD20 antibodies (e.g., obinutuzumab), must be preferred both for frontline and relapsed CLL not only in unfit patients, but also in fit patients with unmutated IGHV or harboring del(17p) and/or TP53 mutations/deletions. Second-generation inhibitors (e.g., acalabrutinib, zanubrutinib, pirtobrutinib) are novel compounds that, due to their better safety profile and different specificity, will help physicians overcome some of the safety issues and treatment resistances. In the era of targeted therapies, treatment decisions in elderly and/or unfit patients with CLL must be a balance between efficacy and safety, carefully evaluating comorbidities and geriatric syndromes to ensure the best approach to improve both quality of life and life expectancy.

scholarly journals Managing Patients With TP53-Deficient Chronic Lymphocytic Leukemia

2017 ◽  
Vol 13 (6) ◽  
pp. 371-377 ◽  
Author(s):  
Jennifer Edelmann ◽  
John G. Gribben
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Investigation ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Clinical Trial Data ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Chromosome 17

Patients with chronic lymphocytic leukemia (CLL) having a chromosomal loss on the short arm of chromosome 17 including the TP53 gene locus (17p deletion) and/or having mutations in TP53 have a short overall survival and, until recently, limited treatment options. The recent introduction of two novel substance classes, B-cell receptor inhibitors and BH3 mimetics, into CLL treatment has provided enormous clinical progress in this previously difficult-to-treat patient subgroup characterized by high risk for treatment failure with standard chemoimmunotherapy and rapid disease progression. Compounds now approved for the treatment of TP53-deficient CLL are the two B-cell receptor inhibitors ibrutinib and idelalisib and the BH3 mimetic venetoclax. All three compounds were approved on the basis of favorable response rates that, importantly, revealed no differences between TP53-competent and TP53-deficient CLL cases. Using these compounds, longer-lasting remissions in patients with TP53-deficient CLL could be demonstrated for the first time. Whether TP53 alterations will maintain their significance as adverse prognostic factors in treatment strategies involving novel compounds needs to be assessed. This review provides an overview of current treatment options for 17p-deleted/ TP53-mutated CLL, including those compounds that are already approved by the US Food and Drug Administration or are under advanced clinical investigation. Available clinical trial data are discussed, as is the use of novel targeted treatment options in the context of transplant strategies, and an algorithm for off-study treatment of 17p-deficient CLL is suggested.

Expanding the armamentarium for chronic lymphocytic leukemia: A review of novel agents in the management of chronic lymphocytic leukemia

2016 ◽  
Vol 23 (7) ◽  
pp. 502-517 ◽  
Author(s):  
Bernard L Marini ◽  
Lisa Samanas ◽  
Anthony J Perissinotti
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Treatment Options ◽  
Cell Receptor ◽  
The United States ◽  
Lymphocytic Leukemia ◽  
Novel Agents ◽  
Great Promise ◽  
Therapeutic Landscape ◽  
Excellent Activity ◽  
Anti Cd20

Treatment options for chronic lymphocytic leukemia, the most common leukemia in the United States, have expanded rapidly in recent years. While traditional chemoimmunotherapy still remains a mainstay for young, fit patients, a number of novel targeted therapies have emerged that have changed the therapeutic landscape. Two innovative anti-CD20 monoclonal antibodies, obinutuzumab and ofatumomamab, have demonstrated activity in chronic lymphocytic leukemia and represent well-tolerated options in upfront management of elderly patients or in those with significant comorbidities. Agents targeting the B-cell receptor pathway, ibrutinib and idelalisib, have excellent activity in chronic lymphocytic leukemia, particularly in those patients with 17p deletions, in which responses to chemoimmunotherapy are traditionally dismal. Venetoclax (ABT-199), the recently FDA-approved BCL2 inhibitor, as well as several other agents and therapy combinations in the pipeline offer great promise for patients with chronic lymphocytic leukemia, particularly in the relapsed/refractory setting. This article comprehensively reviews the data for novel agents in chronic lymphocytic leukemia, including the pharmacology of therapies, unique toxicities, and other practical management considerations for clinicians.

scholarly journals Current and future treatment strategies in chronic lymphocytic leukemia

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Krish Patel ◽  
John M. Pagel
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Unmet Need ◽  
Treatment Strategies ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Free Survival ◽  
Emerging Therapies ◽  
B Cell Leukemia ◽  
Anti Cd20 ◽  
Insight Into

AbstractTreatment decisions for patients with chronic lymphocytic leukemia (CLL) are dependent on symptoms and classification into high-, medium-, or low-risk categories. The prognosis for CLL hinges, in part, on the presence or absence of less-favorable genetic aberrations, including del(17p), del(11q), TP53 dysfunction, and IGHV mutations, as these markers are associated with worse treatment response. Promising results from multiple clinical trials show emerging therapies targeting Burton tyrosine kinase, B-cell leukemia/lymphoma 2, and phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta result in better outcomes and prolonged progression-free survival for patients both with and without certain high-risk aberrations. Favorable outcomes using these novel oral targeted therapies, either alone or in combination with other treatments such as anti-CD20 antibodies, has led to their use almost entirely supplanting chemoimmunotherapy in the treatment of CLL. In this narrative review, we summarize the current clinical evidence for the use of targeted mono- and combination therapies for CLL, discuss new and next-generation treatment approaches currently in development, and provide insight into areas of unmet need for the treatment of patients with CLL.

scholarly journals New Insights into Biology, Prognostic Factors, and Current Therapeutic Strategies in Chronic Lymphocytic Leukemia

ISRN Oncology ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Piotr Smolewski ◽  
Magdalena Witkowska ◽  
Anna Korycka-Wołowiec
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Treatment Strategies ◽  
Lymphocytic Leukemia ◽  
Biologically Relevant ◽  
Clonal Proliferation ◽  
Apoptosis Inhibition ◽  
Risk Patients ◽  
New Treatment ◽  
Anti Cd20

Chronic lymphocytic leukemia (CLL) is characterized by the clonal proliferation and accumulation of mature B lymphocytes. CLL cells show an antiapoptotic profile, suggesting the important role of apoptosis inhibition in the disease development. However, there is some population of proliferating CLL cells, which may also play a role in progression of the disease. There are several newer, biological prognostic factors in CLL. Currently, cytogenetic abnormalities with different prognostic values seem to be the most biologically relevant. During the last decades, the treatment of CLL has been significantly changed. Different strategies such as monotherapy with chlorambucil and purine nucleoside analogues (PNA) used alone or in combination with cyclophosphamide have been introduced. Most recently, immunochemotherapy with anti-CD20 monoclonal antibody, rituximab, combined with fludarabine and cyclophosphamide, became a gold standard of first-line treatment in eligible CLL patients. Currently, new treatment strategies including new monoclonal antibodies, bendamustine, lenalidomide, or inhibitors of several cell signaling pathways are under clinical studies in resistant/relapsed CLL patients. Moreover, allogeneic stem cell transplantation has to be considered, especially in younger high risk patients, for example, those who are resistant to PNA or those with 17p deletion. In this paper, we present the most important recent advances in CLL biology and treatment.

scholarly journals Current Treatment Options in CLL

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2468
Author(s):  
Moritz Bewarder ◽  
Stephan Stilgenbauer ◽  
Lorenz Thurner ◽  
Dominic Kaddu-Mulindwa
Keyword(s):  
Treatment Options ◽  
Current Treatment ◽  
Lymphocytic Leukemia ◽  
Minor Role ◽  
Targeted Agents ◽  
Advantages And Disadvantages ◽  
New Therapeutic Approaches ◽  
Phosphoinositide 3 Kinase ◽  
Anti Cd20 ◽  
A Minor

After impressive developments in recent years with the rise of new targeted agents, chemoimmunotherapy (CIT) only plays a minor role in the treatment of patients with chronic lymphocytic leukemia (CLL). Inhibitors of the Bruton tyrosine kinase (BTK), such as ibrutinib or more recently acalabrutinib, are highly effective, even in poor-risk or chemo-refractory patients. Venetoclax, an inhibitor of the anti-apoptotic BCL2 protein and, to a lesser extent, phosphoinositide-3 kinase (PI3K) delta inhibitors, add to the armamentarium of targeted agents for the treatment of CLL. Furthermore, anti-CD20 monoclonal antibodies are used very successfully either alone or in combination with BTK, BCL2 or PI3K inhibitors. Despite these advances, there is still an ongoing pursuit for new therapeutic approaches in the treatment of CLL. An even bigger challenge poses the determination of the optimal combination and sequence of those drugs. Here, we give an overview of current treatment options in CLL, weighing the advantages and disadvantages of each approach in the light of different clinical settings.

scholarly journals Improvements in Health-Related Quality of Life and Symptoms in Patients with Previously Untreated Chronic Lymphocytic Leukemia: Final Results from the Phase II GIBB Study of the Combination of Obinutuzumab and Bendamustine

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3491-3491 ◽  
Author(s):  
Alexey Danilov ◽  
Habte A Yimer ◽  
Michael Boxer ◽  
John M Burke ◽  
Sunil Babu ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Health Status ◽  
Chronic Lymphocytic Leukemia ◽  
Global Health ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Future Health ◽  
Equity Ownership

Introduction: Longitudinal changes in health-related quality of life (HRQoL) are important in patients with chronic lymphocytic leukemia (CLL). GIBB (NCT02320487) is an open-label, single-arm phase II study of obinutuzumab (GA101; G) in combination with bendamustine (G-Benda) in patients with previously untreated CLL. A previous report from the GIBB study demonstrated an investigator-assessed objective response rate of 89.2%, a complete response rate of 49.0%, and no unexpected safety signals with G-Benda (Sharman et al. J Clin Oncol 2017). Here we report the final HRQoL data over 3 years from the GIBB study. Methods: Enrolled patients received G-Benda by intravenous infusion over six 28-day cycles: G 100mg on Day (D)1, 900mg on D2, and 1000mg on D8 and D15 of Cycle (C)1, then 1000mg on D1 of C2-6; benda 90mg/m2 on D2-3 of C1, and on D1-2 of C2-6. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) includes a global health status measure, 5 functional scales (physical, emotional, cognitive, social, and role functioning), 8 symptom scales/items (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, and diarrhea), and an item on financial difficulties (Aaronson et al. J Natl Cancer Inst 1993). The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) is a 16-item module, specific to CLL, containing 4 multi-item scales (fatigue, treatment side effects, disease symptoms, and infection) and 2 single items (social activities and future health worries). Both questionnaires were completed by patients on C1D1 (baseline), C3D1, and C6D1, at the end of induction (EOI) treatment (defined as +28 days from C6D1 or early treatment termination visit), at the response visit (defined as 2-3 months after the EOI treatment for all patients who received study treatment and had not experienced disease progression), and every 3 months thereafter at follow-up visits for up to 2 years. In total, there were 14 timepoints where data were collected. HRQoL scores were linear transformed to a 0-100-point scale. Mean baseline scores and mean score changes from baseline at each visit were evaluated. A threshold of ≥10-point change in score represents a clinically meaningful difference. For symptoms, negative change scores from baseline reflect an improvement in symptom burden. For global health status and functioning, positive change scores from baseline reflect improvements. Results: The trial enrolled 102 patients. Median age was 61 years and 68.4% of patients were male. Ninety-eight patients (96%) completed a questionnaire at baseline and at least 1 other questionnaire during a follow-up visit. Questionnaire completion rates at 14 time points ranged from 96% at baseline to 66% at 27 months follow-up (Table 1). According to the EORTC QLQ-C30 (Figure 1), improvements were observed for global health status at all follow-up visits, and clinically meaningful improvements were observed at the response visit, 3 months follow-up, and 27 months follow-up. Clinically meaningful improvements in role functioning were observed at EOI and persisted throughout the 27-month follow-up. For fatigue, clinically meaningful improvements were observed at every visit starting from the end of treatment (EOT) visit. Improvements were also observed for insomnia with mean reductions from baseline ≥10 points at various time points during follow-up. There was no worsening in other patient-reported symptoms or functional status over time. Similarly, with the EORTC QLQ-CLL16 (Figure 2), clinically meaningful improvements in symptoms were observed for fatigue, disease symptoms, and future health worries during treatment, at the EOT and/or throughout the follow-up. The largest improvement was observed for fatigue (-24.7) at the 24-month follow-up and future health worries (-25.4) at the 27-month follow-up. Conclusions: We previously reported that G-Benda is an effective regimen for first-line treatment of CLL with no unexpected safety signals. The HRQoL data from the GIBB trial suggest that G-Benda treatment consistently improved patient HRQoL over time. Several clinically meaningful improvements were observed in HRQoL, including global health status, functioning, symptoms, and future health worries. Disclosures Danilov: AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; MEI: Research Funding; Bristol-Meyers Squibb: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Aptose Biosciences: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Consultancy; Janssen: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Curis: Consultancy; Seattle Genetics: Consultancy; MEI: Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Abbvie: Consultancy. Yimer:AstraZeneca: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Honoraria; Celgene: Honoraria; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Amgen: Consultancy. Boxer:Gerson Lerman: Consultancy; Best Doctors: Consultancy; Takeda: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau. Burke:Celgene: Consultancy; Gilead: Consultancy; Roche/Genentech: Consultancy. Babu:Genentech: Research Funding. Li:Genentech: Employment; Roche: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Trask:Genentech: Employment, Equity Ownership. Masaquel:Roche: Equity Ownership; Genentech: Employment. Sharman:Acerta: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: GAZYVA (obinutuzumab) is a CD20-directed cytolytic antibody and is indicated: in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia; in combination with bendamustine followed by GAZYVA monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen

scholarly journals Phosphoinositide 3-Kinase Signaling in the Tumor Microenvironment: What Do We Need to Consider When Treating Chronic Lymphocytic Leukemia With PI3K Inhibitors?

2021 ◽  
Vol 11 ◽  
Author(s):  
Ebru Aydin ◽  
Sebastian Faehling ◽  
Mariam Saleh ◽  
Laura Llaó Cid ◽  
Martina Seiffert ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Treatment Strategies ◽  
Cell Receptor ◽  
Pi3k Pathway ◽  
Lymphocytic Leukemia ◽  
Pi3k Signaling ◽  
Extracellular Signals ◽  
Pi3k Inhibition

Phosphoinositide 3-kinases (PI3Ks) and their downstream proteins constitute a signaling pathway that is involved in both normal cell growth and malignant transformation of cells. Under physiological conditions, PI3K signaling regulates various cellular functions such as apoptosis, survival, proliferation, and growth, depending on the extracellular signals. A deterioration of these extracellular signals caused by mutational damage in oncogenes or growth factor receptors may result in hyperactivation of this signaling cascade, which is recognized as a hallmark of cancer. Although higher activation of PI3K pathway is common in many types of cancer, it has been therapeutically targeted for the first time in chronic lymphocytic leukemia (CLL), demonstrating its significance in B-cell receptor (BCR) signaling and malignant B-cell expansion. The biological activity of the PI3K pathway is not only limited to cancer cells but is also crucial for many components of the tumor microenvironment, as PI3K signaling regulates cytokine responses, and ensures the development and function of immune cells. Therefore, the success or failure of the PI3K inhibition is strongly related to microenvironmental stimuli. In this review, we outline the impacts of PI3K inhibition on the tumor microenvironment with a specific focus on CLL. Acknowledging the effects of PI3K inhibitor-based therapies on the tumor microenvironment in CLL can serve as a rationale for improved drug development, explain treatment-associated adverse events, and suggest novel combinatory treatment strategies in CLL.

How I treat chronic lymphocytic leukemia after venetoclax

Blood ◽  
2021 ◽  
Author(s):  
Thomas E Lew ◽  
Constantine S. Tam ◽  
John F. Seymour
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Treatment Options ◽  
Cell Receptor ◽  
Resistance Mechanisms ◽  
Lymphocytic Leukemia ◽  
Bcl2 Family ◽  
Clinical Scenarios ◽  
Car T

Venetoclax-based regimens have expanded the therapeutic options for patients with chronic lymphocytic leukemia (CLL), frequently achieving remissions with undetectable measurable residual disease (uMRD) and facilitating time-limited treatment without utilizing chemotherapy. Although response rates are high and durable disease control is common, longer-term follow-up of patients with relapsed and refractory (RR) disease, especially in the presence of TP53 aberrations, demonstrates frequent disease resistance and progression. Although the understanding of venetoclax resistance remains incomplete, progressive disease (PD) is typified by oligoclonal leukemic populations with distinct resistance mechanisms, including BCL2 mutations, upregulation of alternative BCL2 family proteins and genomic instability. Although most commonly observed in heavily pre-treated patients with disease refractory to fludarabine and harboring complex karyotype (CK), Richter transformation (RT) presents a distinct and challenging manifestation of venetoclax resistance. For patients with progressive CLL after venetoclax, treatment options include B-cell receptor pathway inhibitors (BCRis), allogeneic stem cell transplantation (SCT), chimeric antigen receptor (CAR) T-cells, and venetoclax re-treatment for those with disease relapsing after time-limited therapy. However, data to inform clinical decisions for these patients are limited. We review the biology of venetoclax resistance and outline an approach to the common clinical scenarios encountered after venetoclax-based therapy that will increasingly confront practising clinicians.

Sign in / Sign up

Export Citation Format

Share Document