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.

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.

scholarly journals Retreatment with obinutuzumab: An addition to the therapeutic landscape of chronic lymphocytic leukemia

2019 ◽  
Vol 7 ◽  
pp. 2050313X1882391 ◽  
Author(s):  
Sharad Khurana ◽  
Salman Ahmed ◽  
Victoria R Alegria ◽  
Sonikpreet Aulakh ◽  
Meghna Ailawadhi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Partial Remission ◽  
Single Agent ◽  
Chronic Lymphocytic Leukemia Patient ◽  
Lymphocytic Leukemia ◽  
Viable Option ◽  
Leukemia Patient ◽  
Therapeutic Landscape ◽  
Response Status ◽  
Anti Cd20

Obinutuzumab is used for the treatment of chronic lymphocytic leukemia. So far there are no data of using this for retreatment in patients who have received it previously. We introduced obinutuzumab for the retreatment in a chronic lymphocytic leukemia patient, who had first achieved partial remission with it and eventually relapsed over a course of 2.5 years. After retreatment with single-agent obinutuzumab, the patient achieved a partial remission again within one cycle and continues to maintain the response status. This case is a platform for considering obinutuzumab as a viable option for retreatment of chronic lymphocytic leukemia patients who have received it before, similar to the pattern of use for other anti-CD20 monoclonal antibodies in this disease, including rituximab.

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.

Chronic Lymphocytic Leukemia Treatment in México: Up to Half Patients May Not Requiere Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Luisa Fernanda Sánchez-Valledor ◽  
Carmina Alejandra Córdova-Ramírez ◽  
Gilberto David Elias-de-la-Cruz ◽  
Montserrat Rivera-Álvarez ◽  
Antonio Cruz-Mora ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Course ◽  
Conflicts Of Interest ◽  
Hematologic Malignancy ◽  
Stage Iv ◽  
The United States ◽  
Lymphocytic Leukemia ◽  
Malignant Cells ◽  
Simplified Approach ◽  
Anti Cd20

Introduction Chronic lymphocytic leukemia (CLL) is a lymphoid neoplasm which represents the most frequent hematologic malignancy in Caucasians. Every year, there are15,000 new diagnoses and 5000 CLL deaths in the United States. Its prevalence in México and other non-Caucasian populations is substantially lower and the clinical course of CLL patients has been described to be less aggressive Methods All consecutive patients seeking medical care after 1983 in our institution as a result of CLL and followed for at least 3 months were entered in the study. The study was approved by the institutional review board. The treatment of patients was withheld in: (a) Persons with CLL Rai stage 0 or 1, until progression; (b) Persons with CLL Rai stage 2-4, with a negative expression of ZAP-70 until progression. Progression was defined by: Anemia, thrombocytopenia, massive symptomatic or progressive splenomegaly and or adenopathy, progressive lymphocytosis (>50% increase in two months or lymphocyte doubling timeless than 6 months), autoimmune hemolytic anemia not responding to standard therapies, or constitutional symptoms: Weight loss greater than 10% in 6 months, unexplained night sweats or unexplained fever for 2 or more weeks. Refractoriness of the disease was defined as progression despite treatment for a minimum of 3 months. Results Among 98 patients with CLL who were accrued in the study between 1983 and 2019, 49 (50%) were followed for three or more months and accordingly, entered in the study. Median follow up time of the patients is 61 months (95% CI 46.1-75.8). There were 15 females and 34 males, the median age was 65 years (range 23-86). According to the Rai staging system, there were 24 stage 0, 7 stage I, 8 stageII, 0 stage III and 10 stage IV; 80% of patients were identified in stages 0-II. In 28 patients a complete immune phenotype of the malignant cells was analyzed: 89% of patients were ZAP-70 negative (ZAP expression in less than 20% of malignant cells), 79% expressed CD5, 100% CD19 and 86% CD23. Three patients were born in European countries, whereas 6 had an immediate European ancestor, indicating that a Caucasian background was identified in 9/49patients (18%). There were no instances of T-cell CLL. Median OS for all the patients has not been reached, being above 247 months (20 years). The OS of patients given or not any treatment was not statistically different (p= 0.09). It is clear that patients who needed treatment did worse than those not needing treatment but the differences were not significant. Patients with advanced stages (III and IV) had a worse outcome than those in early stages. Median OS for patients given no treatment at all has not been reached and is above 247 months; median OS for patients given CP was 115 months, median OS for those given FC has not been reached and is above 132 months, whereas median OS for persons given FCR has not been reached, being above 136 months; all these differences are not statistically significant. Eight of 49 patients were found to be refractory to treatment; they were receiving CP (5 cases); FC (2 cases) and FCR (one case); these refractory patients were given, FCR (7 cases) and rituximab/ifosfamide/carboplatin/etoposide (one case). No patient had to be given cladribine, pentostatin, alemtuzumab (anti-CD52), bendamustine, ofatumumab (anti-CD20), obinutuzumab (anti-CD20), lenalidomide, ibrutinib nor idelalisib. Conclusion In the era of novel anti-CLL drugs, we have found that the clinical course of these patients in México seems to be less aggressive than in Caucasian populations and that, in consequence, circa 50% of them do not need any treatment at all. In those needing treatment, the use of a simplified approach and taking advantage of improved supportive care measures, acceptable results are obtained even if all of the new CLL drugs are not employed. These observations may be critical in developing countries, where the cost of the drugs will continue to be a major factor in choosing therapies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

2017 ◽  
Vol 13 (01) ◽  
pp. 34
Author(s):  
Tarsheen K Sethi ◽  
Nishitha M Reddy ◽  
◽  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Treatment Options ◽  
Cell Receptor ◽  
Additional Treatment ◽  
Lymphocytic Leukemia ◽  
Duration Of Treatment ◽  
Immune Effector ◽  
Disease Biology ◽  
Immune Mediated ◽  
Asymptomatic Individuals

Until recently, chemoimmunotherapy has been the mainstay of treatment approach in chronic lymphocytic leukemia (CLL) patients requiring intervention. With the emergence of targeted treatments, there has been a shift in CLL therapy. With a better understanding of disease biology and risk stratification, a tailored approach based on patient age and comorbidities has evolved over time. The development of new and potent, next generation CD20 antibodies has refined therapy options especially for elderly unfit patients. Furthermore, agents targeting important pathways involved in proliferation and survival of CLL cells including B-cell receptor (BCR) signaling have provided additional treatment options in traditionally chemo-refractory CLL. Given the rapidly expanding repertoire of drugs, current research is focused on optimizing treatment sequence, duration of treatment and assessing long-term toxicities. Several immune mediated therapies are emerging and new combinations are being tested to re-establish antitumor immune effector response in CLL. While embracing the advances in CLL therapy, a few longstanding lessons remain. There is still little role of treatment of asymptomatic individuals. This review presents an overview of current and emerging drug therapies in the rapidly changing area of CLL treatment.

An update of venetoclax and obinutuzumab in chronic lymphocytic leukemia

2020 ◽  
Author(s):  
Ross Salvaris ◽  
Stephen Opat
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Novel Agents ◽  
Bruton Tyrosine Kinase ◽  
Phase Iii Trials ◽  
Treatment Naïve ◽  
Cd20 Antibody ◽  
Anti Cd20

In the last decade, the treatment of chronic lymphocytic leukemia (CLL) has shifted away from chemoimmunotherapy toward targeted novel agents such as small molecule inhibitors and antibodies. Here, we give an overview of the pharmacology of venetoclax and obinutuzumab and the evidence from early phase to Phase III trials that have shaped how they are used in the treatment of CLL. Venetoclax, an oral anti-apoptotic BCL-2 inhibitor, in combination with a CD20 antibody has shown superiority to chemoimmunotherapy in treatment-naive and relapsed/refractory CLL. Obinutuzumab is a novel anti-CD20 monoclonal antibody that has been safely combined with novel agents including venetoclax and Bruton tyrosine kinase inhibitors and has shown superiority over rituximab when combined with chlorambucil.

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 Entering the Era of Targeted Therapy for Chronic Lymphocytic Leukemia: Impact on the Practicing Clinician

2014 ◽  
Vol 32 (27) ◽  
pp. 3039-3047 ◽  
Author(s):  
John C. Byrd ◽  
Jeffrey J. Jones ◽  
Jennifer A. Woyach ◽  
Amy J. Johnson ◽  
Joseph M. Flynn
Keyword(s):  
Targeted Therapy ◽  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
Standard Of Care ◽  
Cell Receptor ◽  
Initial Therapy ◽  
Current Data ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Anti Cd20

PurposeChemoimmunotherapy has been the standard of care for chronic lymphocytic leukemia (CLL). However, the introduction of B-cell receptor (BCR) kinase inhibitors such as ibrutinib has the potential to eliminate the role of chemotherapy in the treatment of CLL. How to best incorporate old and new therapies for CLL in this landscape is increasingly complex.MethodsThis article reviews current data available to clinicians and integrates these data to provide a strategy that can be used to approach the treatment of CLL in the era of BCR signaling inhibitors.ResultsCurrent strategies separate patients based on age or functional status as well as genetics [presence or absence of del(17)(p13.1)]. In the era of targeted therapy, this will likely continue based on current available data. Phase III studies support chemoimmunotherapy as the initial standard therapy for patients without del(17)(p13.1). Choice of chemotherapy (fludarabine plus cyclophosphamide, bendamustine, or chlorambucil) and anti-CD20 antibody (rituximab, ofatumumab, or obinutuzumab) varies based on regimen and patient status. For patients with del(17)(p13.1), no standard initial therapy exists, although several options supported by phase II clinical trials (methylprednisolone plus alemtuzumab or ibrutinib) seem better than chemoimmunotherapy. Treatment of relapsed CLL seems to be best supported by ibrutinib-based therapy. Completion of trials with ibrutinib and other new agents in the near future will offer opportunity for chemotherapy-free treatment across all groups of CLL.ConclusionTherapy for CLL has evolved significantly over the past decade with introduction of targeted therapy for CLL. This has the potential to completely transform how CLL is treated in the future.

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