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 Chronic lymphocytic leukemia paradigm continues to be refined: news from the American Society of Hematology 2018 annual meeting

2019 ◽  
Vol 8 (2) ◽  
pp. IJH14
Author(s):  
Stefano Molica
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
Standard Of Care ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Phase Iii Trials ◽  
Prospective Phase ◽  
American Society ◽  
Anti Cd20

There were a number of important updates and advances presented at the 2018 Annual American Society of Hematology meeting. With respect to the treatment of chronic lymphocytic leukemia, the American Society of Hematology 2018 was notable for an improved understanding of ibrutinib-based therapies. In fact, three prospective Phase III trials presented at the meeting indicate, in turn, that ibrutinib alone, ibrutinib plus rituximab, or ibrutinib plus obinutuzumab, should be the new standard of care for chronic lymphocytic leukemia. However, additional clinical trials comparing chemo-immunotherapy with ibrutinib alone or in association with an anti-CD20 monoclonal antibody remain a reasonable avenue to complete results of these large studies.

scholarly journals Efficacy of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Chronic Lymphocytic Leukemia: A Serologic and Cellular Study

Chemotherapy ◽  
2021 ◽  
Author(s):  
Stefano Molica ◽  
Diana Giannarelli ◽  
Mirella Lentini ◽  
Daniela Zappala ◽  
Ada Mannella ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Antibody Response ◽  
Messenger Rna ◽  
Vaccine Dose ◽  
Lymphocytic Leukemia ◽  
Serological Response ◽  
Humoral Immune ◽  
Treatment Naïve ◽  
Cd20 Antibody ◽  
Anti Cd20

Background: Antibody response following SARS-CoV2 vaccination is somewhat defective in chronic lymphocytic leukemia (CLL). Moreover, the correlation between serologic response and status of cellular immunity has been poorly studied. Objective: This study was undertaken to assess humoral immune and cellular responses to the BNT162b2 messenger RNA (mRNA) COVID-19 vaccination in CLL. Methods: The presence of the spike antibodies was assessed at a median time of 14 days from the second vaccine dose of SARS-CoV2 in 70 CLL followed-up at a single institution. Results: The antibody response rate (RR) in CLL patients was 58.5%, compared to 100% of 57 healthy controls of the same sex and age (P< 0.0001). Patients treatment-naïve and those in sustained clinical remission after therapy had the highest RR (87.0% and 87.7%, respectively). In contrast, patients on therapy with a pathway inhibitor as monotherapy and those treated with an association of anti-CD20 antibody were unlikely to respond to the SARS-CoV-2 vaccine (52% and 10%, respectively). In multivariate analysis, early Rai stage (OR, 0.19 [0.05-0.79]; P=0.02) and no previous therapy (OR, 0.06[0.02-0.27]; P<0.0001) were found to be independent predictors of vaccination response. An increase in absolute NK cells (i.e., CD16/CD56 positive cells) in patients with a serological response was found following the second dose of vaccine (P=0.02). Conclusions: These results confirm that serological response to the BNT162b2 vaccine in patients with CLL is impaired. A third boosting vaccine dosage should be considered for these patients.

Rate of seroconversion for routine vaccinations in patients with chronic lymphocytic leukemia on ibrutinib.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19509-e19509
Author(s):  
Mohammad Ammad Ud Din ◽  
Saad Jamshed
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Seroconversion Rate ◽  
Geometric Mean ◽  
Humoral Response ◽  
Lymphocytic Leukemia ◽  
Post Vaccination ◽  
Bruton Tyrosine Kinase ◽  
Anti Cd20

e19509 Background: It is unclear whether Bruton tyrosine kinase inhibitors (BTKi) contribute to the humoral dysfunction in chronic lymphocytic leukemia. Methods: A literature search of PubMed, EmCare, and Google Scholar was performed on December 5, 2020. Five studies met inclusion criteria out of 249 studies per PRISMA guidelines (n = 244). Results: Pleyer et al. and Zent et al. showed an adequate recall humoral response to the shingle vaccine (41.5% and 75% seroconversion rate respectively), however, de novo response to hepatitis B vaccine was greatly reduced. Conflicting results were seen for the influenza vaccine as Sun et al. showed a significant increase in post-vaccination geometric mean titers for all three strains while only 7% of patients demonstrated seroconversion in the study by Douglas et al. None of the patients responded to the pneumococcal conjugate vaccine in a study by Andrick et al, though the results were not statistically significant (p = 0.029) (Table). Conclusions: Treatment with BTKi may not cause significant detrimental response to immunization but further studies are needed to elucidate longterm effects especially in patients with prior exposure to anti-CD20 antibodies.[Table: see text]

scholarly journals The role of acalabrutinib in adults with chronic lymphocytic leukemia

2021 ◽  
Vol 12 ◽  
pp. 204062072199055
Author(s):  
Bita Fakhri ◽  
Charalambos Andreadis
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Fda Approval ◽  
Phase Iii Trials ◽  
Treatment Naïve ◽  
Btk Inhibitor ◽  
Egfr Family ◽  
New Generation ◽  
Btk Inhibitors

The treatment landscape of chronic lymphocytic leukemia (CLL) has significantly changed in the past decade. This paradigm shift is due to the introduction of novel agents to the field. The two major classes of drugs that have contributed to this dramatic evolution include the Bruton tyrosine kinase (BTK) inhibitors and BCL2 inhibitors. Ibrutinib was the first-in-class drug which was initially approved by the US Food and Drug Administration (FDA) for the treatment of patients with relapsed/refractory and later for patients with treatment-naïve CLL. Despite encouraging efficacy outcomes, its use has been associated with cardiovascular and gastrointestinal toxicities likely due to off-target inhibition of ITK, TEC and EGFR family kinases. The next generation of BTK inhibitors was developed to be more selective with less off-target inhibition with the prospect to improve tolerability without compromising efficacy. Acalabrutinib, a selective covalent BTK inhibitor, is a second generation BTK inhibitor. The focus of this review is on two major phase III trials that resulted in the FDA approval of acalabrutinib in 2019. The ELEVATE TN trial investigated acalabrutinib with or without obintuzumab versus chlorambucil–obinutuzumab in older and frail patients with previously untreated CLL. The ASCEND trial explored acalabrutinib versus chemoimmunotherapy in patients with relapsed/refractory CLL. Both trials demonstrated superiority of the acalabrutinib-containing arms in terms of both efficacy and tolerability. Unfortunately, the availability of new generation BTK inhibitors has not resulted in mitigating the financial toxicities associated with these potentially life-long treatments.

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.

scholarly journals “Double-Hit” Chronic Lymphocytic Leukemia, Involving the TP53 and MYC Genes

2022 ◽  
Vol 11 ◽  
Author(s):  
Florence Nguyen-Khac
Keyword(s):  
Prognostic Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Targeted Therapies ◽  
Poor Prognosis ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Bruton Tyrosine Kinase ◽  
Treatment Naïve ◽  
Double Hit

Although the 17p deletion [del(17p)] is rare in cases of treatment-naive chronic lymphocytic leukemia (CLL), its frequency is higher in refractory/relapsed CLL – particularly in patients undergoing chemo(immuno)therapy. TP53 disruption (deletion and/or mutation) is the strongest prognostic factor for refractoriness to chemotherapy; the use of Bruton tyrosine kinase inhibitors and BCL2 inhibitors is then indicated. Rare cases of CLL can also harbor translocation or gain of the MYC oncogene. “Double-hit CLL” (with del(17p) and MYC gain) is associated with a very poor prognosis. The prognostic impact of TP53 disruption with MYC aberrations in patients receiving targeted therapies must now be evaluated.

Impact of Different Chemotherapy Regimen in Comorbid Patients with Advanced Chronic Lymphocytic Leukemia: Metaanalysis of Two Phase-III-Trials of the German CLL Study Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2840-2840 ◽  
Author(s):  
Paula Cramer ◽  
Valentin Goede ◽  
Petra Jenke ◽  
Raymonde Busch ◽  
Michael Hallek ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Chemotherapy Regimen ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Concomitant Disease ◽  
Two Phase ◽  
Phase Iii Trials ◽  
The Impact ◽  
Dose Reductions

Abstract Introduction: Since chronic lymphocytic leukemia (CLL) is a disease of elderly patients (pts) comorbidity is a frequent feature which has already been shown to be associated with survival-shortening in lymphoma patients. It has been hypothesized that intensity of chemotherapy may interfere with treatment outcome, but the precise mechanisms underlying the impact of comorbidity are still not understood. Consequently, comorbitity currently keeps away oncologists from administering intense combined (immuno−)chemotherapy to pts with CLL and concomitant diseases. Patients & methods: 554 pts treated in two different phase-III-trials of the GCLLSG were eligible for this analysis: 362 pts (65%) younger than 65 years were treated on the CLL4-protocol with Fludarabine (F) or Fludarabine-Cyclophosphamide (FC) and 192 pts (35%) aged 65 years and older on the CLL5-protocol with F or Chlorambucile (Clb). The mean age for all pts was 61 years; 68% of the pts were male. Results: Comorbidity was present in 53% of the pts, 25% had at least two comorbidities. The most common comorbidities were: hypertension (19%), lipometabolic disorders (16%), diabetes mellitus (10%) and coronary heart disease (7%). Progression free survival (PFS) and overall survival (OS) were significantly shorter in comorbid pts (median OS: 43,5 vs. 51,6 months, p=0,01; median PFS: 20,3 vs. 23,5 months, p=0,03). Survival was also impaired if pts had a higher number of comorbidities (PFS & OS: p=0,0001) or more severe concomitant diseases (PFS: p=0,007, OS: p=0,0000). Whereas this impact of comorbidity on OS was not significant in the FC- and Clb-arm, comorbid pts treated with F had a significantly shorter survival (median OS: 38,29 vs. 51,58 months, p=0,0452). Notably only the younger F-treated comorbid pts were affected by this disadvantage (CLL4: p=0,0221). Although myelotoxicity, infections and all grade III–IV adverse effects were not influenced by comorbidity, pts with concomitant disease had a higher rate of treatment terminations (38% vs. 25%, p=0,002). The higher percentage of dose reductions and treatment terminations for comorbid pts were only significant in the subgroup of F-treated pts (dose reduction: 31% vs. 19,1%, p=0,029; treatment termination in the younger CLL4-pts: 28,2% vs. 18,0%, p=0,023). Administration of more intense chemotherapy-regimen improved the survival of pts with concomitant disease (median OS: FC: not reached, F: 38,29 and Clb: 33,72 months, p=0,0248; median PFS: FC: not reached, F: 18,8 and Clb: 14,1 months, p=0,0000). A multivariate analysis on the prognostic impact of comorbidity and different chemotherapy regimen will be presented. Conclusions: Due to the here presented results the wide impact of comorbidity in CLL pts is apparent. It should be considered when it comes to treatment decisions eventhough this population was selected due to the strict criteria of the clinical trial. The mechanism of survival shortening in comorbid pts with CLL is not yet understood, but seems to be related with dose reductions and treatment terminations. Additional harm to these pts by an insufficient treatment and a poor control of the CLL ought to be avoided. As more intense chemotherapy-regimen, like FC are feasible for pts with comorbidity, more trials surveying these therapies in pts with more severe concomitant disease are needed.

Sign in / Sign up

Export Citation Format

Share Document