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1. SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib versus Bendamustine + Rituximab (BR) in Patients with Treatment-Naive (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL).

Author

Tam C.S., Giannopoulos K., Jurczak W., Simkovic M., Shadman M., Osterborg A., Laurenti L., Walker P., Opat S., Chan H., Ciepluch H., Greil R., Tani M., Trneny M., Brander D.M., Flinn I.W., Grosicki S., Verner E., Brown J.R., Kahl B.S., Ghia P., Tian T., Marimpietri C., Paik J.C., Cohen A., Huang J., Robak T., Hillmen P., Tam C.S., Giannopoulos K., Jurczak W., Simkovic M., Shadman M., Osterborg A., Laurenti L., Walker P., Opat S., Chan H., Ciepluch H., Greil R., Tani M., Trneny M., Brander D.M., Flinn I.W., Grosicki S., Verner E., Brown J.R., Kahl B.S., Ghia P., Tian T., Marimpietri C., Paik J.C., Cohen A., Huang J., Robak T., and Hillmen P.

Abstract

Background: Zanubrutinib (zanu) is a selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimize off-target effects (Guo, J Med Chem 2019;62:7923-40). In a phase 1/2 study, zanu demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and was associated with durable clinical responses in patients (pts) with CLL/SLL (Tam, Blood 2019;134:851-9). Here, we present interim results for the phase 3 SEQUOIA (BGB-3111-304; NCT03336333) trial, which evaluated the efficacy and safety of zanu vs BR in TN pts with CLL/SLL. Method(s): SEQUOIA is an open-label, global phase 3 study that randomized TN pts with CLL/SLL without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m 2 on day 1 and 2 and rituximab 375 mg/m 2 in cycle 1, 500 mg/m 2 in cycles 2-6 for 6 x 28-day cycles. Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Hallek, Blood 2008;111:5446-56) were eligible if they were either >=65 y or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridization was required. Pts were stratified by age (<65 y vs >=65 y), Binet Stage (C vs A/B), IGHV mutational status, and geographic region. The primary endpoint was independent...Copyright © 2021 American Society of Hematology

Published
2022

2. SEQUOIA : Results of a Phase 3 Randomised Study of Zanubrutinib versus Bendamustine + Rituximab in Patients with Treatment-Naive Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma.

Author

Munir T., Giannopoulos K., Jurczak W., Simkovic M., Shadman M., Osterborg A., Laurenti L., Walker P., Opat S., Chan H., Ciepluch H., Greil R., Tani M., Trneny M., Brander D.M., Flinn I.W., Grosicki S., Verner E., Kahl B.S., Ghia P., Li J., Tian T., Zhou L., Marimpietri C., Paik J.C., Cohen A., Huang J., Brown J.R., Robak T., Tam C.S., Munir T., Giannopoulos K., Jurczak W., Simkovic M., Shadman M., Osterborg A., Laurenti L., Walker P., Opat S., Chan H., Ciepluch H., Greil R., Tani M., Trneny M., Brander D.M., Flinn I.W., Grosicki S., Verner E., Kahl B.S., Ghia P., Li J., Tian T., Zhou L., Marimpietri C., Paik J.C., Cohen A., Huang J., Brown J.R., Robak T., and Tam C.S.

Abstract

Zanubrutinib (zanu) is a selective nextgeneration Bruton tyrosine kinase (BTK) inhibitor designed to have high specificity for BTK and minimal off-target effects. SEQUOIA (NCT03336333) is an open-label, global phase 3 study that randomised treatment naive (TN) patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) without del(17p) to receive zanu 160 mg twice daily until progressive disease or unacceptable toxicity, or bendamustine 90 mg/m2 on day 1 and 2 and rituximab 375 mg/m2 in cycle 1, 500 mg/m2 in cycles 2-6 for 6 x 28-day cycles (BR). Adult patients who met International Workshop on CLL (iwCLL) criteria for treatment were eligible if they were >= 65 years or unsuitable for treatment with fludarabine, cyclophosphamide and rituximab. Central verification of del(17p) status by fluorescence in situ hybridisation was required. Patients were stratified by age (<65 years vs. >=65 years), Binet Stage (C vs. A/B), immunoglobulin heavy chain gene (IGHV) mutational status and geographical region. The primary end-point was independent review committee (IRC)-assessed progression-free survival (PFS). Secondary end-points included PFS by investigator assessment (INV), overall response rate (ORR; by IRC and INV), overall survival (OS) and safety. Responses for CLL and SLL were assessed per modified iwCLL criteria and Lugano criteria respectively. Adverse events (AEs) were recorded until disease progression. From 31 Oct 2017-22 Jul 2019, 479 patients without del(17p) were randomised to zanu ( n = 241) and BR ( n = 238). Treatment groups were well balanced for demographical and disease characteristics (zanu vs. BR): median age, 70.0 years vs. 70.0 years; unmutated IGHV, 53.4% (125/234) vs. 52.4% (121/231); and del(11q), 17.8% vs. 19.3%. At median followup (26.2 months), PFS was significantly prolonged with zanu versus BR as assessed by IRC (hazard ratio [HR] 0.42, 95% CI 0.28-0.63, 2-sided p < 0.0001), and INV (HR 0.42, 95% CI 0.27-0.66, 2-sided p = 0

Published
2022

3. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial.

Author

Tam C.S., Brown J.R., Kahl B.S., Ghia P., Giannopoulos K., Jurczak W., Simkovic M., Shadman M., Osterborg A., Laurenti L., Walker P., Opat S., Chan H., Ciepluch H., Greil R., Tani M., Trneny M., Brander D.M., Flinn I.W., Grosicki S., Verner E., Tedeschi A., Li J., Tian T., Zhou L., Marimpietri C., Paik J.C., Cohen A., Huang J., Robak T., Hillmen P., Tam C.S., Brown J.R., Kahl B.S., Ghia P., Giannopoulos K., Jurczak W., Simkovic M., Shadman M., Osterborg A., Laurenti L., Walker P., Opat S., Chan H., Ciepluch H., Greil R., Tani M., Trneny M., Brander D.M., Flinn I.W., Grosicki S., Verner E., Tedeschi A., Li J., Tian T., Zhou L., Marimpietri C., Paik J.C., Cohen A., Huang J., Robak T., and Hillmen P.

Abstract

Background: Zanubrutinib is a next-generation, selective Bruton tyrosine kinase inhibitor with efficacy in relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). We compared zanubrutinib with bendamustine-rituximab to determine its effectiveness as frontline therapy in patients with CLL or SLL. Method(s): We conducted an open-label, multicentre, phase 3 study at 153 academic or community hospitals in 14 countries and regions. Eligible patients had untreated CLL or SLL requiring treatment as per International Workshop on CLL criteria; were aged 65 years or older, or 18 years or older and had comorbidities; and had an Eastern Cooperative Oncology Group performance status score of 0-2. A central interactive web response system randomly assigned patients without del(17)(p13.1) to zanubrutinib (group A) or bendamustine-rituximab (group B) by sequential block method (permutated blocks with a random block size of four). Patients with del(17)(p13.1) were enrolled in group C and received zanubrutinib. Zanubrutinib was administered orally at 160 mg twice per day (28-day cycles); bendamustine at 90 mg/m2 of body surface area on days 1 and 2 for six cycles plus rituximab at 375 mg/m2 of body surface area the day before or on day 1 of cycle 1, and 500 mg/m2 of body surface area on day 1 of cycles 2-6, were administered intravenously. The primary endpoint was progression-free survival per independent review committee in the intention-to-treat population in groups A and B, with minimum two-sided alpha of 0.05 for superiority. Safety was analysed in all patients who received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, NCT03336333, and is closed to recruitment. Finding(s): Between Oct 31, 2017, and July 22, 2019, 590 patients were enrolled; patients without del(17)(p13.1) were randomly assigned to zanubrutinib (group A; n=241) or bendamustine-rituximab (group B; n=238). At median follow-up of 26.2 months (IQR 23.7

Published
2022

4. CLL-137 SEQUOIA: Results of a Phase 3 Randomized Study of Zanubrutinib Versus Bendamustine + Rituximab (BR) in Patients With Treatment-Naïve (TN) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/ SLL)

Author

Kahl, B. S., Giannopoulos, K., Jurczak, W., Simkovic, M., Shadman, M., Osterborg, A., Laurenti, Luca, Walker, P., Opat, S., Chan, H., Ciepluch, H., Greil, R., Tani, M., Trneny, M., Brander, D. M., Flinn, I. W., Grosicki, S., Verner, E., Brown, J. R., Ghia, P., Li, J., Tian, T., Zhou, L., Marimpietri, C., Paik, J. C., Cohen, A., Robak, T., Hillmen, P., Tam, C. S., Laurenti L. (ORCID:0000-0002-8327-1396), Kahl, B. S., Giannopoulos, K., Jurczak, W., Simkovic, M., Shadman, M., Osterborg, A., Laurenti, Luca, Walker, P., Opat, S., Chan, H., Ciepluch, H., Greil, R., Tani, M., Trneny, M., Brander, D. M., Flinn, I. W., Grosicki, S., Verner, E., Brown, J. R., Ghia, P., Li, J., Tian, T., Zhou, L., Marimpietri, C., Paik, J. C., Cohen, A., Robak, T., Hillmen, P., Tam, C. S., and Laurenti L. (ORCID:0000-0002-8327-1396)

Abstract

Context: The Bruton tyrosine kinase (BTK) inhibitor, zanubrutinib, was designed for high BTK specificity and minimal toxicity. SEQUOIA (NCT03336333) is a global, open-label, randomized phase 3 study in treatment-naïve patients with CLL/SLL without del(17p) who were unsuitable for fludarabine/cyclophosphamide/rituximab. Design: Patients were randomized to receive zanubrutinib (160 mg twice daily) or bendamustine (day 1-2: 90 mg/m2) and rituximab (cycle 1: 375 mg/m2; cycles 2-6: 500 mg/m2); stratification factors were age (<65 years vs ≥65 years), Binet Stage, IGHV mutation, and geographic region. Main Outcome Measures: Primary endpoint was an independent review committee (IRC)-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed (INV) PFS, overall response rate (ORR), overall survival (OS), and safety. Results: From October 31, 2017, to July 22, 2019, 479 patients were enrolled (zanubrutinib=241; BR=238). Baseline characteristics (zanubrutinib vs BR): median age, 70.0 years versus 70.0 years; unmutated IGHV, 53.4% versus 52.4%; del(11q), 17.8% versus 19.3%. With median follow-up of 26.2 months, PFS was significantly prolonged with zanubrutinib by IRC (HR 0.42; 2-sided P<.0001) and INV (HR 0.42; 2-sided P=.0001). Zanubrutinib treatment benefit occurred across age, Binet stage, bulky disease, del(11q) status, and unmutated IGHV (HR 0.24; 2-sided P<.0001), but not mutated IGHV (HR 0.67; 2-sided P=.1858). For zanubrutinib versus BR, 24-month PFS-IRC=85.5% versus 69.5%; ORR-IRC=94.6% versus 85.3%; complete response rate=6.6% versus 15.1%; ORR-INV=97.5% versus 88.7%; and 24-month OS=94.3% versus 94.6%. Select adverse event (AE) rates (zanubrutinib vs BR): atrial fibrillation (3.3% vs 2.6%), bleeding (45.0% vs 11.0%), hypertension (14.2% vs 10.6%), infection (62.1% vs 55.9%), and neutropenia (15.8% vs 56.8%). Treatment discontinuation due to AEs (zanubrutinib vs BR)=20 patients (8.3%) versus 31 patients (13.7%); AEs leading

Published
2022

5. Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naive Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with Del(17p): Initial Results from Arm C of the Sequoia (BGB-3111-304) Trial.

Author

Tam C.S., Robak T., Ghia P., Kahl B.S., Walker P., Janowski W., Simpson D., Shadman M., Ganly P.S., Laurenti L., Opat S., Tani M., Ciepluch H., Verner E., Simkovic M., Osterborg A., Trneny M., Tedeschi A., Paik J., Marimpietri C., Feng S., Huang J., Hillmen P., Brown J.R., Tam C.S., Robak T., Ghia P., Kahl B.S., Walker P., Janowski W., Simpson D., Shadman M., Ganly P.S., Laurenti L., Opat S., Tani M., Ciepluch H., Verner E., Simkovic M., Osterborg A., Trneny M., Tedeschi A., Paik J., Marimpietri C., Feng S., Huang J., Hillmen P., and Brown J.R.

Abstract

Background: Patients with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Several new options targeting B-cell receptor signaling have emerged as potential effective therapies in this high-risk group. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It has been shown to be highly potent, selective, and bioavailable with potentially advantageous pharmacokinetic and pharmacodynamic properties. In an early phase study, zanubrutinib demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and has been associated with durable clinical responses in patients with CLL/SLL (Tam, Blood 2019). Here, we present safety and efficacy data in treatment-naive (TN) patients with del(17p) CLL/SLL who are enrolled in the non-randomized Arm C of the SEQUOIA (BGB-3111-304) trial. Method(s): The SEQUOIA trial is an open-label, global, multicenter, phase 3 study that includes a non-randomized cohort (Arm C) of TN patients with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult patients with CLL/SLL who met iwCLL criteria for treatment (Hallek, Blood 2008) were eligible if they were either >= 65 y of age or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response assessment was evaluated by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008; Cheson, J Clin Oncol 2012) and for SLL per Lugano criteria (Cheson, J Clin Oncol 2014). Result(s): In total, 109 patients with centrally confirmed del(17p) were enrolled into Arm C

6. Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naive Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with Del(17p): Initial Results from Arm C of the Sequoia (BGB-3111-304) Trial.

Author

Tam C.S., Robak T., Ghia P., Kahl B.S., Walker P., Janowski W., Simpson D., Shadman M., Ganly P.S., Laurenti L., Opat S., Tani M., Ciepluch H., Verner E., Simkovic M., Osterborg A., Trneny M., Tedeschi A., Paik J., Marimpietri C., Feng S., Huang J., Hillmen P., Brown J.R., Tam C.S., Robak T., Ghia P., Kahl B.S., Walker P., Janowski W., Simpson D., Shadman M., Ganly P.S., Laurenti L., Opat S., Tani M., Ciepluch H., Verner E., Simkovic M., Osterborg A., Trneny M., Tedeschi A., Paik J., Marimpietri C., Feng S., Huang J., Hillmen P., and Brown J.R.

Abstract

Background: Patients with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Several new options targeting B-cell receptor signaling have emerged as potential effective therapies in this high-risk group. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor, designed to maximize BTK occupancy and minimize off-target inhibition of TEC- and EGFR-family kinases. It has been shown to be highly potent, selective, and bioavailable with potentially advantageous pharmacokinetic and pharmacodynamic properties. In an early phase study, zanubrutinib demonstrated complete and sustained BTK occupancy in both peripheral blood mononuclear cells and lymph nodes and has been associated with durable clinical responses in patients with CLL/SLL (Tam, Blood 2019). Here, we present safety and efficacy data in treatment-naive (TN) patients with del(17p) CLL/SLL who are enrolled in the non-randomized Arm C of the SEQUOIA (BGB-3111-304) trial. Method(s): The SEQUOIA trial is an open-label, global, multicenter, phase 3 study that includes a non-randomized cohort (Arm C) of TN patients with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult patients with CLL/SLL who met iwCLL criteria for treatment (Hallek, Blood 2008) were eligible if they were either >= 65 y of age or unsuitable for treatment with fludarabine, cyclophosphamide, and rituximab. Use of long-term anticoagulation was permitted. Central verification of del(17p) by fluorescence in situ hybridization with a minimum of 7% aberrant nuclei present was required for entry into Arm C. Response assessment was evaluated by investigator for CLL per modified iwCLL criteria (Hallek, Blood 2008; Cheson, J Clin Oncol 2012) and for SLL per Lugano criteria (Cheson, J Clin Oncol 2014). Result(s): In total, 109 patients with centrally confirmed del(17p) were enrolled into Arm C

7. Effects of ibrutinib on in vitro platelet aggregation in blood samples from healthy donors and donors with platelet dysfunction.

Author

Ninomoto J, Mokatrin A, Kinoshita T, Marimpietri C, Barrett TD, Chang BY, Sukbuntherng J, James DF, and Crowther M

Subjects
Adenine analogs & derivatives, Adult, Aged, Female, Humans, Male, Middle Aged, Piperidines, Platelet Aggregation Inhibitors pharmacology, Pyrazoles pharmacology, Pyrimidines pharmacology, Tissue Donors, Young Adult, Blood Platelets drug effects, Platelet Aggregation Inhibitors therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use
Abstract

Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase (BTK), is approved in the US and EU for the treatment of various B-cell malignancies. In clinical studies, BTK inhibitors have been associated with increased bleeding risk, which may result from BTK inhibition in platelets. Methods: To better understand the mechanism of ibrutinib in bleeding events, we isolated platelet-rich plasma from healthy donors ( n  = 8) and donors with conditions associated with impaired platelet function or with potentially increased bleeding risk (on hemodialysis, taking aspirin, or taking warfarin; n  = 8 each cohort) and used light transmission aggregometry to assess platelet aggregation in vitro after exposure to escalating concentrations of ibrutinib, spanning and exceeding the pharmacologic range of clinical exposure. Results: Platelet aggregation was induced by agonists of 5 major platelet receptors: adenosine diphosphate (ADP), thrombin receptor-activating peptide 6 (TRAP6), ristocetin, collagen, or arachidonic acid (AA). Platelet aggregation induced by ADP, TRAP6, ristocetin, and AA was not meaningfully inhibited by the maximal concentrations of ibrutinib (10 µM). In contrast, collagen-induced platelet aggregation was dose-dependently inhibited by ibrutinib in all donor cohorts (maximum aggregation % with 10 μM ibrutinib, -64% to -83% of agonist activity compared to control agonist samples but without ibrutinib). Conclusion: These results confirm prior reports and support a mechanistic role for the inhibition of collagen-induced platelet aggregation in bleeding events among susceptible individuals receiving ibrutinib therapy.

Published
2020
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8. Cell signaling-based classifier predicts response to induction therapy in elderly patients with acute myeloid leukemia.

Author

Cesano A, Willman CL, Kopecky KJ, Gayko U, Putta S, Louie B, Westfall M, Purvis N, Spellmeyer DC, Marimpietri C, Cohen AC, Hackett J, Shi J, Walker MG, Sun Z, Paietta E, Tallman MS, Cripe LD, Atwater S, Appelbaum FR, and Radich JP

Subjects
Aged, Aged, 80 and over, Area Under Curve, Blood Cells cytology, Bone Marrow Cells cytology, Female, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute pathology, Male, Metabolic Networks and Pathways, Middle Aged, Prognosis, ROC Curve, Remission Induction, Signal Transduction, Single-Cell Analysis, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Blood Cells metabolism, Bone Marrow Cells metabolism, Leukemia, Myeloid, Acute drug therapy
Abstract

Single-cell network profiling (SCNP) data generated from multi-parametric flow cytometry analysis of bone marrow (BM) and peripheral blood (PB) samples collected from patients >55 years old with non-M3 AML were used to train and validate a diagnostic classifier (DXSCNP) for predicting response to standard induction chemotherapy (complete response [CR] or CR with incomplete hematologic recovery [CRi] versus resistant disease [RD]). SCNP-evaluable patients from four SWOG AML trials were randomized between Training (N = 74 patients with CR, CRi or RD; BM set = 43; PB set = 57) and Validation Analysis Sets (N = 71; BM set = 42, PB set = 53). Cell survival, differentiation, and apoptosis pathway signaling were used as potential inputs for DXSCNP. Five DXSCNP classifiers were developed on the SWOG Training set and tested for prediction accuracy in an independent BM verification sample set (N = 24) from ECOG AML trials to select the final classifier, which was a significant predictor of CR/CRi (area under the receiver operating characteristic curve AUROC = 0.76, p = 0.01). The selected classifier was then validated in the SWOG BM Validation Set (AUROC = 0.72, p = 0.02). Importantly, a classifier developed using only clinical and molecular inputs from the same sample set (DXCLINICAL2) lacked prediction accuracy: AUROC = 0.61 (p = 0.18) in the BM Verification Set and 0.53 (p = 0.38) in the BM Validation Set. Notably, the DXSCNP classifier was still significant in predicting response in the BM Validation Analysis Set after controlling for DXCLINICAL2 (p = 0.03), showing that DXSCNP provides information that is independent from that provided by currently used prognostic markers. Taken together, these data show that the proteomic classifier may provide prognostic information relevant to treatment planning beyond genetic mutations and traditional prognostic factors in elderly AML.

Published
2015
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