scholarly journals Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition

2021 ◽  
Author(s):  
Thomas E Lew ◽  
Victor S Lin ◽  
Edward Robert Scheffer Cliff ◽  
Piers Blombery ◽  
Ella R Thompson ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Unmet Need ◽  
Lymphocytic Leukemia ◽  
Second Line ◽  
Prior Therapy ◽  
Resistant Disease ◽  
Dismal Prognosis ◽  
Improved Outcomes ◽  
Bruton Tyrosine Kinase ◽  
Targeted Agent

Covalent Bruton tyrosine kinase inhibitors (BTKis) and the BCL2 inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n=5). The cohort was heavily pre-treated (median lines of prior therapy: 4) and enriched for adverse disease genetics (complex karyotype: 12/12 tested, 100%; del(17p)/TP53 mutations: 15/17, 88%). The median time to progression on prior venetoclax was 24 (range 6-94) months, and on prior BTKi was 25 (range 1-55) months. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in six. The median overall survival after progression on second-line TA was 3.6 (95%CI 2-11) months. Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.

Phase III AXIS trial for second-line metastatic renal cell carcinoma (mRCC): Effect of prior first-line treatment duration and axitinib dose titration on axitinib efficacy.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 354-354 ◽  
Author(s):  
Brian I. Rini ◽  
Bernard J. Escudier ◽  
M Dror Michaelson ◽  
Sylvie Negrier ◽  
Martin Eric Gore ◽  
...  
Keyword(s):  
Treatment Duration ◽  
Kinase Inhibitors ◽  
Performance Status ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Dose Titration ◽  
Second Line ◽  
First Line ◽  
Sunitinib Treatment ◽  
Prior Therapy

354 Background: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. In the phase 3 AXIS trial of axitinib vs sorafenib for second-line mRCC, axitinib significantly prolonged median progression-free survival (mPFS) (6.7 vs 4.7 months; hazard ratio 0.665; P<0.0001). Here, we evaluated the effect of prior sunitinib treatment duration and axitinib dose titration on subsequent axitinib efficacy. Methods: Eligible patients had clear-cell mRCC; measurable RECIST-defined progressive disease after 1 prior first-line systemic therapy; and Eastern Cooperative Oncology performance status (PS) 0/1. Patients were stratified by PS and prior therapy, and randomized 1:1 to either axitinib, at a starting dose of 5 mg twice daily (BID), or sorafenib, 400 mg BID. Patients without toxicity >grade 2 and BP <150/90 mmHg without antihypertensive medication for >2 weeks were eligible to increase axitinib dose to 7 mg BID and then to 10 mg BID. Results: The mPFS for patients receiving at least one total daily axitinib dose >10 mg (dose-titrated group; n=132) was 6.6 months [95% CI 4.7–8.3] and 8.3 months [95% CI 6.0–10.2] for patients receiving axitinib ≤10 mg (n=227). A total of 194 patients (53.7%) in the axitinib arm and 195 patients (53.9%) in the sorafenib arm had prior sunitinib treatment. The mPFS for patients with duration of prior sunitinib treatment ≥6 months and <6 months were 4.8 months [95% CI 4.5–6.5] and 4.6 months [95% CI 2.8–8.3] for axitinib patients; and 4.6 months [95% CI 2.9–4.9] and 2.9 months [95% CI 2.8–4.6), for sorafenib patients. The mPFS for duration of prior sunitinib ≥9 months and <9 months were 6.3 months [95% CI 4.6–6.7] and 4.5 months [95% CI 2.8–6.4] for axitinib patients; and 4.6 months [95% CI 2.8–4.9] and 2.9 months [95% CI 2.8–4.7]) for sorafenib patients. Conclusions: Duration of prior sunitinib ≥9 months may be associated with a longer PFS on second-line VEGFR tyrosine kinase inhibitors. Both axitinib dose-increased and non-increased patients had longer PFS compared with the sorafenib arm.

scholarly journals Standard treatment approaches for relapsed/refractory chronic lymphocytic leukemia after frontline chemoimmunotherapy

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 33-40
Author(s):  
Carol Moreno
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
Cellular Therapy ◽  
Negative Impact ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Phosphatidylinositol 3 Kinase ◽  
Bruton Tyrosine Kinase ◽  
Therapy Treatment

Abstract Despite the effectiveness of chemoimmunotherapy (CIT), in most cases the clinical course of chronic lymphocytic leukemia (CLL) is characterized by consecutive episodes of disease progression and need for therapy. Treatment possibilities for patients with CLL in whom CIT fails whose disease progresses after initial CIT include pathway inhibitors (PIs) and, for selected patients, cellular therapy (ie, allogeneic stem cell transplant, chimeric antigen receptor T cells). PIs (ie, Bruton tyrosine kinase inhibitors, phosphatidylinositol 3-kinase inhibitors, and BCL2 inhibitors) are revolutionizing the treatment of CLL. PIs have proved to be more effective than CIT, both as upfront therapy and for relapsed/refractory disease, largely because they may overcome the negative impact of adverse biomarkers (eg, TP53 aberrations, unmutated IGHV) on outcomes and because of their acceptable toxicity. In this article, the management of patients with relapsed/refractory CLL is discussed, with a particular emphasis on the role of PIs.

scholarly journals The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

Blood ◽  
2012 ◽  
Vol 119 (5) ◽  
pp. 1182-1189 ◽  
Author(s):  
Sabine Ponader ◽  
Shih-Shih Chen ◽  
Joseph J. Buggy ◽  
Kumudha Balakrishnan ◽  
Varsha Gandhi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Survival ◽  
Lymphocytic Leukemia ◽  
B Cell Malignancies ◽  
Bruton Tyrosine Kinase ◽  
Targeted Agent

Abstract B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in CLL, using in vitro and in vivo models, and performed correlative studies on specimens from patients receiving therapy with PCI-32765. PCI-32765 significantly inhibited CLL cell survival, DNA synthesis, and migration in response to tissue homing chemokines (CXCL12, CXCL13). PCI-32765 also down-regulated secretion of BCR-dependent chemokines (CCL3, CCL4) by the CLL cells, both in vitro and in vivo. In an adoptive transfer TCL1 mouse model of CLL, PCI-32765 affected disease progression. In this model, PCI-32765 caused a transient early lymphocytosis, and profoundly inhibited CLL progression, as assessed by weight, development, and extent of hepatospenomegaly, and survival. Our data demonstrate that PCI-32765 effectively inhibits CLL cell migration and survival, possibly explaining some of the characteristic clinical activity of this new targeted agent.

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]

Resistance to Bruton's Tyrosine Kinase Inhibitors: The Achilles Heel of Their Success Story in Lymphoid Malignancies

Blood ◽  
2021 ◽  
Author(s):  
Deborah M. Stephens ◽  
John C Byrd
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
Treatment Modalities ◽  
Bruton’S Tyrosine Kinase ◽  
B Cell Malignancies ◽  
Bruton's Tyrosine Kinase ◽  
Resistant Disease

Bruton's tyrosine kinase inhibitors (BTKi) have significantly changed the treatment landscape for patients with B-cell malignancies including chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Unfortunately, patients with BTKi resistant disease have shortened survival. Clinical and molecular risk factors, such as number of prior therapies and presence of TP53 mutations, can be used to predict patients at the highest risk of developing BTKi resistance. Many mechanisms of BTKi resistance have been reported with mutations in BTK and phospholipase C g 2 supported with the most data. The introduction of venetoclax has lengthened the survival of patients with BTKi resistant disease. Ongoing clinical trials with promising treatment modalities such as next-generation BTKi and chimeric antigen receptor T-cell therapy have reported promising efficacy in patients with BTKi resistant disease. Continued research focusing on resistance mechanisms and methods of how to circumvent resistance is needed to further prolong the survival of patients with BTKi resistant B-cell malignancies.

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.

Acute gout flare of bilateral first metatarsophalangeal joints due to ibrutinib use in chronic lymphocytic leukemia

2021 ◽  
pp. 107815522110297
Author(s):  
Jaspreet Kaur ◽  
Shahaf Tuler ◽  
Constantin A Dasanu
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitors ◽  
Oxidase Inhibitor ◽  
Lymphocytic Leukemia ◽  
Acute Gout ◽  
Xanthine Oxidase Inhibitor ◽  
Bruton Tyrosine Kinase ◽  
Metatarsophalangeal Joints ◽  
Mtp Joints ◽  
Gout Flare

Introduction Bruton tyrosine kinase inhibitors represent important tools in the therapeutic armamentarium against chronic lymphocytic leukemia (CLL) and other B-lymphoproliferative disorders. Case Report We describe herein a unique 65-year-old patient who presented with bilateral foot pain four months after starting treatment with ibrutinib for CLL. Of note, the patient had previously been diagnosed with gout, and was taking allopurinol prophylactically at the time of the event. Compliance with allopurinol was in excess of 99%. Yet, he was diagnosed with acute gout flare of bilateral first metatarsophalangeal (MTP) joints. Management & Outcome: Ibrutinib dose was reduced by one third, and the patient’s gout flare up was treated with ibuprofen as needed. After symptoms abated, ibrutinib was continued at 2/3rds of the dose, with an excellent CLL control. The patient tolerated this dose without any further adverse effects. Discussion/Conclusions: We have reported a unique side effect of acute bilateral first MTP joint gout flare likely triggered by ibrutinib use for CLL while the patient was taking a xanthine oxidase inhibitor. The mechanism by which ibrutinib caused this phenomenon remains to be elucidated.

scholarly journals The role of second generation Bruton tyrosine kinase inhibitors in the treatment of chronic lymphocytic leukemia. Resolution

2020 ◽  
Vol 21 (4) ◽  
pp. 45-47
Author(s):  
Irina V. Poddubnaya ◽  
Tatyana E. Bialik ◽  
Natalya N. Glonina ◽  
Olga B. Kalashnikova ◽  
Kamil D. Kaplanov ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Important Place ◽  
First Line Therapy ◽  
Line Therapy ◽  
Bruton Tyrosine Kinase ◽  
Adult Leukemia

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, with incidence rate of 4: 100 thousand per year, according to European data. CLL remains an incurable disease, with most patients over 60 years old. Immunochemotherapy schemes today remain the standard treatment approach for CLL. The advent of novel molecules expands possibilities of treating this disease. Targeted therapy with small molecule inhibitors of Bruton tyrosine kinase (BTK) occupies an important place in the treatment of patients with CLL, both for first-line therapy and for treatment of relapses. The drug acalabrutinib as a highly selective new generation of BTK inhibitor can be considered as an efficient and safe option for first-line therapy and for treatment of the disease relapse in patients with CLL, especially in patients with comorbidity, including cardiovascular diseases (CDV) or risk factors for CVD.

scholarly journals The TKI Era in Chronic Leukemias

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2201
Author(s):  
Danilo De Novellis ◽  
Fabiana Cacace ◽  
Valeria Caprioli ◽  
William G. Wierda ◽  
Kris M. Mahadeo ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Cell Receptor ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Pi3k Inhibitors ◽  
Cell Functions ◽  
Improved Outcomes ◽  
Btk Inhibitor

Tyrosine kinases are proteins involved in physiological cell functions including proliferation, differentiation, and survival. However, the dysregulation of tyrosine kinase pathways occurs in malignancy, including hematological leukemias such as chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Particularly, the fusion oncoprotein BCR-ABL1 in CML and the B-cell receptor (BCR) signaling pathway in CLL are critical for leukemogenesis. Therapeutic management of these two hematological conditions was fundamentally changed in recent years, making the role of conventional chemotherapy nearly obsolete. The first, second, and third generation inhibitors (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) of BCR-ABL1 and the allosteric inhibitor asciminib showed deep genetic and molecular remission rates in CML, leading to the evaluation of treatment discontinuation in prospective trials. The irreversible BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and spebrutinib) covalently bind to the C481 amino acid of BTK. The reversible BTK inhibitor pirtobrutinib has a different binding site, overcoming resistance associated with mutations at C481. The PI3K inhibitors (idelalisib and duvelisib) are also effective in CLL but are currently less used because of their toxicity profiles. These tyrosine kinase inhibitors are well-tolerated, do have some associated in-class side effects that are manageable, and have remarkably improved outcomes for patients with hematologic malignancies.

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