Ibrutinib (PCI 32765) Rapidly Improves Platelet Counts in Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma (CLL/SLL) Patients and Has Minimal Effects On Platelet Aggregation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1789-1789 ◽  
Author(s):  
Mohammed Farooqui ◽  
Jay Nelson Lozier ◽  
Janet Valdez ◽  
Nakhle Saba ◽  
Ajunae Wells ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Thrombus Formation ◽  
Lymphocytic Leukemia ◽  
Significant Activity ◽  
Small Lymphocytic Lymphoma ◽  
Open Label ◽  
Platelet Counts ◽  
Pre Treatment

Abstract Abstract 1789 INTRODUCTION: Ibrutinib (PCI 32765) is an orally administered covalent inhibitor of Bruton's Tyrosine Kinase (BTK). Ibrutinib has significant activity in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and is typically well tolerated (Byrd ASCO 2011, O'Brien ASH 2011). Rarely serious bleeding in patients concurrently on oral anticoagulation has been reported but was not related to thrombocytopenia (O'Brien ASH 2011). However, grade 1 or 2 ecchymosis/contusion is a frequent adverse event in patients on ibrutinib. In addition to being essential for B cell receptor signaling BTK is also involved in the signaling of the glycoprotein (GP)VI and GPIV von Willebrand (vW) receptors (Liu, Blood 2006). Thus, it is possible that ibrutinib could increase the bleeding risk by interfering with thrombus formation. In addition, lymphoproliferative disorders and some drugs have been associated with acquired vW-disease (AvWD). METHODS AND PATIENTS: In an ongoing single center, open label phase II trial we treat CLL/SLL patients with ibrutinib 420 mg daily on 28 day cycles (NCT01500733). We measured platelet (PLT) function on the PFA-100 instrument, vW-factor (vWF) antigen levels and activity (vWF-Ag/vWF-Act), and factor VIII (FVIII) on baseline, days 2 and 28. Here we report on effects of ibrutinib on platelet counts and function in 25 patients who completed >2 cycles. RESULTS: PLT counts prior to treatment ranged from 36 k/μl to 256 k/μl with a median of 102 k/μl. Twelve (48%) patients had a pre-treatment PLT count <100 k/μl. Median PLT counts for days 14, 28, and 56 increased to 140, 137, and 135 k/μl, respectively (P<.01). 76% of patients showed an increase after only 2 weeks on drug (median increase 25 k/μl (range 4–183 k/μl) that was sustained at subsequent timepoints. On day 14, 6 patients (24%) had a decrease in PLT count by a median of 13 k/μl from baseline; of these, 3 had a pre-treatment PLT count of <100 k/ul and 1 developed grade III thrombocytopenia (42 k/μl) that resolved to >100 k/μl by day 56. 20% (5 of 25) of patients reported grade 1 spontaneous ecchymosis with no correlation to platelet count, PFA testing, or vWF measurements. Of note we performed lymph node core biopsies in 35 patients taking ibrutinib with minimal bruising. Only 2 patients had more extensive local bruising/ecchymosis at the biopsy site. In 19 patients PFA-100 measurements of epinephrine (EPI) and adenosine diphosphate (ADP) stimulated platelet aggregation times were available (test requires PLT count >100 k/μl). Median changes in closure times with EPI and ADP on treatment were not significantly different from baseline (See table). Four (21%) patients started with abnormally prolonged EPI closure times (one on aspirin, one on ibuprofen; discontinued with the start of ibrutinib) which resolved by day 28 in 3 and decreased in 1. Three (16%) patients had a prolongation of EPI closure times on day 2 that resolved by day 28 in 2 and decreased in 1. All closure times on ADP were low or normal. No patients with abnormal PFA testing demonstrated spontaneous ecchymosis. From baseline to day 28 vWF-Act, vWF-Ag and FVIII decreased (P<0.05; n=24). All 3 values were high normal to elevated prior to treatment and decreased to normal on treatment. CONCLUSION: This preliminary report does not identify any significant ibrutinib effect on platelet function. PLT counts improved rapidly in the majority of patients and when seen transient decreases have been minimal. Three patients (16%) developed an abnormal reading in PLT function tests on treatment but none developed spontaneous echymosis or bleeding. The observed normalization of mildly elevated baseline levels of vWF and FVIII seems most consistent with a reduction in acute phase reactants and there was no evidence for AvWD on ibrutinib. The apparent functional tolerance of BTK inhibition in platelets is likely attributable to redundancy in the affected signaling pathways. This work was supported by the Intramural Research Program of NHLBI, NIH. We thank our patients for participating in these research studies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase 3 iLLUMINATE trial

Haematologica ◽  
2022 ◽  
Author(s):  
Carol Moreno ◽  
Richard Greil ◽  
Fatih Demirkan ◽  
Alessandra Tedeschi ◽  
Bertrand Anz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Final Analysis ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
First Line Therapy ◽  
Line Therapy ◽  
Open Label Phase

iLLUMINATE is a randomized, open-label phase 3 study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or

Mapping the Targets of Dasatinib in Chronic Lymphocytic Leukemia Reveals Distinct Roles for Abl and Btk in Drug Resistance and Adhesion, and Explains Clinical Effects On Lymph Node Reduction

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3900-3900
Author(s):  
Eric Eldering ◽  
Christian R Geest ◽  
Martin FM de Rooij ◽  
Nora Liu ◽  
Bogdan I Florea ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Lymph Node ◽  
Chronic Lymphocytic Leukemia ◽  
Broad Spectrum ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Clinical Effects ◽  
Open Label

Abstract Abstract 3900 In the lymph node (LN) microenvironment, chronic lymphocytic leukemia (CLL) cells are protected from apoptosis by upregulation of anti-apoptotic proteins. In vitro, this can be mimicked via CD40-stimulation of CLL cells, which also provides resistance to various chemotherapeutics. Novel drugs that target kinases involved in B cell signalling, including the broad spectrum kinase inhibitor dasatinib, are currently in clinical development for CLL. We have shown previously that dasatinib prevents CD40-mediated anti-apoptotic changes in CLL (Hallaert et Blood 2008). However, the kinase(s) involved remain unidentified. Here, we coupled dasatinib to an affinity matrix and pulled down its targets from CD40-stimulated CLL cells. By mass-spectrometry and Western blotting, Abl and Btk were identified as dominant targets of dasatinib. Functional analysis revealed that CD40-mediated anti-apoptotic signals and drug-resistance could be overcome both by dasatinib and the Abl inhibitor imatinib, but not by the novel Btk inhibitor PCI-32765 (ibrutinib), whereas BCR- and chemokine-controlled adhesion could be abolished by dasatinib and ibrutinib, but not by imatinib. Thus, dasatinib combines two key aspects that are clinically relevant: inhibition of Abl overrides chemoprotective survival signals, whereas inhibition of Btk impairs integrin-mediated adhesion of CLL cells in the microenvironmental niche. This combined inhibition of Abl and Btk was put to an initial test in an open-label phase 2 trial of dasatinib combined with fludarabine in twenty refractory CLL patients. As might be expected based on the in vitro data, reductions in lymph node size were observed in most patients. A LN reduction of ≥20% provided a significant improved PFS (256 days) and OS (510 days) as compared to non-responders (80 days and 158 days respectively). Details of the clinical study will be presented separately. In conclusion, in agreement with in vitro molecular studies, dasatinib seems to have clinical efficacy in heavily pretreated refractory CLL patients. Combined, these data encourage further studies on a broad-spectrum kinase inhibitor like dasatinib in combination with other classes of drugs in relapsed and refractory CLL. Disclosures: No relevant conflicts of interest to declare.

Immune Thrombocytopenia Associated to Low-Dose Alemtuzumab Therapy in Chronic Lymphocytic Leukemia: A Single Retrospective Center Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4598-4598
Author(s):  
Gianluigi Reda ◽  
Francesco Maura ◽  
Giuseppe Gritti ◽  
Daniele Vincenti ◽  
Mariarita Sciumé ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Disease Progression ◽  
Cumulative Dose ◽  
Immune Thrombocytopenia ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Autoimmune Disorder ◽  
Intravenous Immunoglobulins ◽  
Lymphocytic Leukemia ◽  
Platelet Counts

Abstract Abstract 4598 Immune thrombocytopenia (ITP) is a common autoimmune complication in chronic lymphocytic leukemia (CLL), occurring in up to 5% of patients. The occurrence of alemtuzumab-associated ITP have been rarely reported in CLL and it has never been reported so far as a significant event complicating alemtuzumab treatment in clinical trials. Recently, a new distinctive form of secondary ITP occurring in 6 out of 215 patients with relapsing-remitting multiple sclerosis treated with alemtuzumab in a randomized, controlled phase II trial has been reported (Cuker et al, Blood 2011). We investigated the incidence of ITP in a cohort of 64 consecutive patients treated with low-dose alemtuzumab for relapsed/refractory CLL from 2003 to 2010. Subcutaneous alemtuzumab was administered at the dose of 10 mg three times a week, up to 18 weeks. ITP was documented in 12/64 patients: in 3 patients (4.7%) ITP developed before alemtuzumab treatment and no relapses of the autoimmune disorder were observed during the treatment; in 9 patients (14.8%, with an incidence of 5.7 events/100 patient-year) ITP developed after alemtuzumab treatment. Median time to ITP from initial alemtuzumab exposure was 12 months (range 1–42 months). Concomitant hemolytic anemia (Evans syndrome) was observed in one patient. At ITP onset, median platelet counts were 11×109/L (range 3–70) and anti-platelet antibodies (Capture P® Method, ImmucorGamma, Norcross GA, USA) were found in 7 of the 8 patients tested. No patients showed severe or life-threatening bleeding. Three of nine patients who developed ITP after alemtuzumab therapy, experienced CLL progression requiring chemo-immunotherapy after 3, 4 and 13 months from ITP onset, respectively. One patient achieved a partial remission of CLL with ITP resolution, while the other two died of disease progression. In the remaining six cases, ITP was not associated with disease progression and was treated with corticosteroids and/or intravenous immunoglobulins. Five patients achieved normal platelet counts, while one patient did not respond. Low-dose alemtuzumab (theoretical cumulative dose 540 mg, equal to half of the classic cumulative dose and one-third of the individual dose) is an effective, safe and well tolerated treatment for CLL, as reported by several recent studies (Cortelezzi et al, Leukemia 2009; Brit J Haematol 2011). In our cohort of CLL patients treated with alemtuzumab, the incidence of ITP was 14.8% that is almost three times higher than previously reported in CLL. These data may indicate a role of T-lymphocyte dysregulation induced by alemtuzumab in the pathogenesis of ITP. Our data also suggested the importance of monitoring platelet counts during follow-up in patients treated with low-dose alemtuzumab for both haematological and non-haematological diseases. Disclosures: No relevant conflicts of interest to declare.

Trial in progress: a phase II, multicenter, single-arm study of zanubrutinib (BGB-3111) in patients with previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma intolerant of prior treatment with ibrutinib.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS8066-TPS8066
Author(s):  
Ian Flinn ◽  
Mazyar Shadman ◽  
Benjamin Bruce Freeman ◽  
Dih-Yih Chen ◽  
Xiaoping Zhang ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
International Workshop ◽  
Lymphocytic Leukemia ◽  
Clinical Effects ◽  
Small Lymphocytic Lymphoma ◽  
Open Label ◽  
Patient Reported

TPS8066 Background: Ibrutinib (ibr), a Bruton tyrosine kinase inhibitor (BTKi), was shown to improve patient outcomes in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); however, adverse events (AEs) were the most common reason for discontinuing ibr (50% and 63% of discontinuations in relapse/refractory (R/R) and frontline patients, respectively; Haematologica. 2018:103:874). Zanubrutinib, an approved BTKi for mantle cell lymphoma, was specifically engineered to optimize selectivity. Pooled clinical data from 6 zanubrutinib monotherapy trials in B-cell malignancies (N=682 patients; R/R CLL/SLL [n=91]) suggested that zanubrutinib monotherapy was well tolerated and demonstrated a low rate of treatment discontinuation from AEs (9%; Tam, EHA 2019). Presented here is a trial-in-progress that will evaluate whether zanubrutinib monotherapy may serve as a therapeutic option for patients with CLL/SLL who have become ibr intolerant. Methods: The ongoing phase II, multicenter, US, single-arm, open-label study (NCT04116437, BGB-3111-215) will evaluate zanubrutinib monotherapy (160mg twice daily) as a treatment option for patients with CLL/SLL intolerant to prior ibr treatment. Approximately 60 patients will be enrolled from ~30 community medical centers. Key inclusion criteria include CLL/SLL requiring treatment per International Workshop on CLL criteria ( Blood. 2018;131:2745) before ibr therapy, intolerance to ibr (defined as an unacceptable AE for which, per investigator’s opinion, ibr treatment should be discontinued despite optimal supportive therapy), resolution of ibr-related AEs to grade ≤1 or baseline, and an ECOG PS 0-2. Key exclusion criteria include having an intervening cancer therapy between ibr and zanubrutinib, a documented disease progression during ibr treatment up to the time of enrollment, and a history of central nervous system (CNS) hemorrhage. The primary endpoint is frequency and severity of protocol-specified treatment-emergent AEs (diarrhea, myalgia, muscle spasm, arthralgia, hypertension, fatigue, rash, atrial fibrillation, and hemorrhage excluding CNS hemorrhage). The secondary endpoints include overall response rate, progression-free survival, and patient-reported outcomes. An exploratory endpoint was added to evaluate clinical effects (physical activity, treatment-related symptoms, and quality of life) using a smartphone app. Recruitment is ongoing. Clinical trial information: NCT04116437 .

scholarly journals Efficacy of Ibrutinib in Newly Diagnosed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Combined Analysis of Four Phase III Randomized Controlled Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5481-5481
Author(s):  
Anita Sultan ◽  
Chandler Graf ◽  
Donald P. Quick ◽  
Sriman Swarup ◽  
Jonathan Kopel ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Disease Stage ◽  
Newly Diagnosed ◽  
Small Lymphocytic Lymphoma ◽  
Presenting Symptoms

Introduction: Chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), the most common adult lymphoproliferative disorder in western countries, is a B-cell malignancy that is treated based on presenting symptoms and stage. The treatment response is highly variable depending on disease stage and mutation profile of the malignant B cells. Bruton tyrosine kinase (BTK) is a downstream B-cell signaling kinase that has been shown to play a major role in B cell survival and proliferation. Hence, BTK inhibitors have become an attractive therapeutic strategy for treatment of CLL/SLL in both newly diagnosed and relapse/refractory setting. Ibrutinib is a potent oral, covalent inhibitor of BTK that has gained wide acceptance in treatment of CLL/SLL. We analyzed phase III trials where ibrutinib was used in newly diagnosed untreated CLL/SLL to examine treatment effects based on disease staging and molecular profiling. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with newly diagnosed/ untreated CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Four phase III RCTs (RESONATE-2, iLLUMINATE, E1912 and A041202 studies) with a total of 1,574 patients with newly diagnosed CLL/SLL were eligible. Studies compared ibrutinib+ obinutuzumab vs chlorambucil+ obinutuzumab, ibrutinib vs chlorambucil, bendamustine+ rituximab vs ibrutinib vs ibrutinib+ rituximab, ibrutinib+ rituximab vs fludarabine+ cyclophosphamide+ rituximab, were included in the analysis. The randomization ratio was 2:1 in E1912 study and 1:1 in other studies. The I2 statistic for heterogeneity was 75, suggesting moderate heterogeneity among RCT. The pooled HR for PFS was statistically significant at 0.28 (95% CI: 0.19-0.41; P < 0.0001). The PFS benefit was observed in all Rai stages, either del11q or del17p and unmutated or mutated IGHV status; Rai stage ≤ 2 cohort (HR, 0.29; 95% CI: 0.21- 0.41; P < 0.0001), Rai stage >2 cohort (HR, 0.31; 95% CI: 0.21- 0.46; P < 0.0001), either del11q or del17p cohort (HR, 0.19; 95% CI: 0.12- 0.31; P < 0.0001), unmutated IGHV cohort (HR, 0.18; 95% CI: 0.12- 0.27; P < 0.0001), and mutated IGHV cohort (HR, 0.27; 95% CI: 0.15- 0.49; P < 0.0001). Conclusions: Our meta-analysis showed that ibrutinib maintains activity in newly diagnosed untreated CLL/SLL, across all Rai stages, in del11q or del17p and in unmutated and mutated IGHV. The use of ibrutinib should be further explored considering other factors such as overall survival rates, detrimental side effects, and health-related quality of life for the patients. Ibrutinib clearly outlines an effective treatment option, ultimately increasing the quality of care. Disclosures No relevant conflicts of interest to declare.

scholarly journals Risk of Serious Adverse Events, Infection and Sepsis in Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Treated with Idelalisib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5489-5489
Author(s):  
Jonathan Kopel ◽  
Sriman Swarup ◽  
Anita Sultan ◽  
Lukman Tijani ◽  
Ei Moe Phyu ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Conflicts Of Interest ◽  
Group Versus ◽  
Lymphocytic Leukemia ◽  
Control Group ◽  
Study Group ◽  
Small Lymphocytic Lymphoma ◽  
Phase 3 ◽  
Serious Adverse Events

Introduction: Idelalisib is a first-in-class potent, oral, selective small-molecule inhibitor of δ isoform of phosphatidylinositol 3-kinase (PI3Kδ), which involves in the signaling of B-cell receptor pathways via activation of downstream serine threonine kinases AKT and mammalian target of rapamycin (mTOR), and has been implicated in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL). Yet, there are considerable safety concerns. We undertook a systematic review and combined analysis of phase 3 randomized controlled trials to determine the risk of serious adverse events, infection and sepsis in patients with relapsed/ refractory CLL/SLL treated with idelalisib. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase 3 RCTs utilizing idelalisib in patients with relapsed and refractory CLL/SLL that mention serious adverse events, infection and sepsis as adverse effects were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results: Three phase 3 RCTs with a total of 892 patients with relapsed and refractory CLL/SLL were eligible for analysis. Studies compared ofatumumab vs idelalisib+ofatumumab, rituximab vs idelalisib+rituximab, bendamustine+ rituximab vs idelalisib+bendamustine+rituximab and ofatumumab vs duvelisib. The randomization ratio was 2:1 in Jones et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 83, suggesting moderate heterogeneity among RCTs. The incidence of serious adverse events was 341 (69.59%) in study group vs 177 (44.03%) in control group with RR of 1.50 (95% CI: 1.28-1.75; p < 0.0001). Pneumonitis was noted in 14 (2.86%) vs 1 (0.25%) in control group (RR, 5.42; 95% CI: 1.22-24.13; p = 0.03). The incidence of any-grade pneumonia was 78 (15.92%) in study group vs 45 (11.19%) in control group (RR, 1.38; 95% CI: 0.98 - 1.96; P = 0.07). High-grade pneumonia was reported in 59 (12.04%) in idelalisib arm versus 33 (8.21%) in control group with RR of 1.36 (95% CI: 0.82 - 2.27; P = 0.23). Pneumocystis jiroveci (PJP) pneumonia rate was 2.56% higher in study group compared to control arm (RR, 4.25; 95% CI: 1.10 - 16.34; P = 0.04). Febrile neutropenia was noted in 13.47% in study group versus 4.73% in control arm (RR, 2.39; 95% CI: 0.90-6.34; p = 0.08). Sepsis rate was 3.36% higher in idelalisib group compared to control arm and the pooled RR was statistically significant at 2.64 (95% CI 1.10-6.30; p = 0.03). Treatment-related deaths were 45 (6.92%) in idelalisib arm vs 21 (3.74%) in control arm according to analysis of 2 trials. The pooled RR was not statistically significant at 1.64 (95% CI: 0.99 -2.71; P = 0.06). Conclusion: Patients on idelalisib experienced higher risk of serious adverse events, pneumonitis, PJP pneumonia, and sepsis, with RR of 1.50 for serious adverse events, RR of 5.42 for pneumonitis, RR of 4.25 for PJP pneumonia and RR of 2.64 for sepsis respectively. Nevertheless, there was no significant increase in treatment-related deaths due to TRAE in the idelalisib group, compared to control arm. Preemptive measures with proper supportive care are required to reduce those toxicities which can ultimately improve patients' quality of life and may probably affect patients' compliance. Disclosures No relevant conflicts of interest to declare.

scholarly journals BRUIN CLL-313: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3732-3732
Author(s):  
Wojciech Jurczak ◽  
Caroline Dartigeas ◽  
Marta Coscia ◽  
Peter S. Ganly ◽  
Ghassan Al-Jazayrly ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
Publicly Traded ◽  
Open Label ◽  
Phase 3 ◽  
Advisory Committees ◽  
Mutation Status

Abstract Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and the majority of patients will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In a phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397, 10277:892-901). Study Design and Methods: BRUIN CLL-313 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus bendamustine plus rituximab (BR) in treatment naïve CLL/SLL patients with retained 17p. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by IGHV mutation status (mutated vs unmutated), and Rai stage (low/intermediate vs high). Patients in the BR arm are eligible to crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 and confirmed by an independent review committee (IRC). Eligible patients are adults with confirmed diagnosis of CLL/SLL and who require therapy per iwCLL 2018 criteria. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation to DLBCL, prolymphocytic leukemia or Hodgkin lymphoma any time pre-enrollment, presence of 17p deletion, prior systemic therapy for CLL/SLL, and significant cardiovascular disease. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an IRC. Secondary endpoints include investigator-assessed PFS, overall survival (OS), overall response rate (ORR), duration of response (DoR), safety and tolerability, and patient reported outcomes. The global study is currently enrolling patients. Disclosures Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Coscia: Gilead: Honoraria; AbbVie: Honoraria, Other; Janssen: Honoraria, Other, Research Funding; AstraZeneca: Honoraria. Wang: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Bao: Loxo Oncology at Lilly: Current Employment; Genentech: Ended employment in the past 24 months. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Zinzani: Eusapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Celtrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau.

Lymphoplasmacytic Differentiation Associated with Lenalidomide Therapy in Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4412-4412
Author(s):  
Marays Veliz ◽  
Lynn C. Moscinski ◽  
Ling Zhang ◽  
Eduardo M. Sotomayor ◽  
Javier Pinilla-Ibarz
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
Mechanism Of Action ◽  
Conflicts Of Interest ◽  
Selection Effect ◽  
Lymphocytic Leukemia ◽  
Significant Activity ◽  
Immune Mediated ◽  
Immune Synapses ◽  
Initiation Of Therapy

Abstract Abstract 4412 Background Due to significant activity of lenalidomide in chronic lymphocytic leukemia (CLL), research is ongoing to better characterize its mechanism of action. Recent laboratory studies of cells from CLL patients have shown that lenalidomide could exert its antiproliferative activity by decreasing the presence of survival-promoting cytokines. It has also been shown to facilitate immune-mediated ADCC by restoring the defective ability of T- and NK-cells to form immune synapses with tumor B-cells (Ramsay et al JCI 2008). However, no direct cytotoxic effect of lenalidomide has yet been demonstrated in CLL cells. Here, we suggest a new potential mechanism of action based on morphologic evaluation of bone marrow samples from patients with CLL receiving treatment with lenalidomide. Methods Bone marrow biopsy and aspirations from 13 patients with relapsed or refractory CLL, who are participating in a phase II clinical trial of lenalidomide and rituximab, and 1 patient who received lenalidomide outside of study, were reviewed before initiation of therapy and every 2 months thereafter. Results Of 14 CLL samples evaluated, 3 samples contained cells with lymphoplasmacytoid features in both bone marrow (figure 1) and peripheral blood, which had not been present prior to initiation of treatment. Of the 3 samples containing lymphocytes with plasmacytoid features, 2 were obtained from patients who received more than 6 months of therapy with the lenalidomide/rituximab combination, and 1 was taken from the patient receiving lenalidomide, after one month of therapy. Long term morphologic effects of lenalidomide therapy on lymphocytes from patients with CLL remain unknown. However, we hypothesize that the observed changes in morphology after lenalidomide treatment could represent either a differentiation phenomenon, as a potential antitumor mechanism in CLL cells, or perhaps represent just a selection effect. Conclusions An exact direct antitumor mechanism of lenalidomide on CLL cells remains unknown. Our observations suggest that lenalidomide may promote terminal differentiation of lymphocytes thus proposing an additional mechanism by which lenalidomide exerts its anti-tumor activity in CLL. Disclosures: No relevant conflicts of interest to declare.

Quercetin Therapy for Selected Patients with PIM1 Kinase-Positive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Pilot Study

2018 ◽  
Vol 139 (2) ◽  
pp. 132-139 ◽  
Author(s):  
Beverly W. Baron ◽  
Michael J. Thirman ◽  
Mihai C. Giurcanu ◽  
Joseph M. Baron
Keyword(s):  
Pilot Study ◽  
Chronic Lymphocytic Leukemia ◽  
Small Sample ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
Open Label ◽  
Translational Study ◽  
Pim1 Kinase ◽  
Institutional Review

We reported that PIM1 kinase is expressed in the lymphocytes of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Quercetin, a naturally occurring flavonoid, is a dietary supplement and inhibits many kinases, including PIM1, in vitro. Under an Institutional Review Board-approved protocol, we performed an open-label, single-arm pilot study to evaluate the antitumor activity of quercetin in patients with CLL/SLL. Q-ForceTM chews were administered orally, 500 mg twice daily, for 3 months. Eligible patients had failed prior therapies, had had no other standard treatment, or refused other therapies. Response was assessed based on objective change in disease parameters. Patients were included if their lymphocyte counts were rising and ≥10,000/µL but not > 100,000/µL. Three patients received quercetin treatment. There was no toxicity. Two responded with stabilization of rising lymphocyte counts (p < 0.001 for each), which remained stable during their follow-up (5 and 11 months after cessation of treatment, respectively). The CLL cells in the nonresponder harbored a TP53 mutation. Although our data from this pilot translational study are based on a small sample, further studies of quercetin as a potential therapeutic agent in selected patients with CLL/SLL appear warranted.

Sign in / Sign up

Export Citation Format

Share Document