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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. Zanubrutinib monotherapy for patients with treatment naive chronic lymphocytic leukemia and 17p deletion.

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.C., Kuwahara S.B., Feng S., Ramakrishnan V., Cohen A., 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.C., Kuwahara S.B., Feng S., Ramakrishnan V., Cohen A., Huang J., Hillmen P., and Brown J.R.

Abstract

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naive patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade >= 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

Published
2021

6. Zanubrutinib monotherapy for patients with treatment-naïve chronic lymphocytic leukemia and 17p deletion

Author

Tam, C. S., Robak, T., Ghia, P., Kahl, B. S., Walker, P., Janowski, W., Simpson, D., Shadman, M., Ganly, P. S., Laurenti, Luca, Opat, S., Tani, M., Ciepluch, H., Verner, E., Simkovic, M., Osterborg, A., Trneny, M., Tedeschi, Alessandra, Paik, J. C., Kuwahara, S. B., Feng, S., Ramakrishnan, V., Cohen, A., Huang, J., Hillmen, P., Brown, J. R., Laurenti L. (ORCID:0000-0002-8327-1396), Tedeschi A., Tam, C. S., Robak, T., Ghia, P., Kahl, B. S., Walker, P., Janowski, W., Simpson, D., Shadman, M., Ganly, P. S., Laurenti, Luca, Opat, S., Tani, M., Ciepluch, H., Verner, E., Simkovic, M., Osterborg, A., Trneny, M., Tedeschi, Alessandra, Paik, J. C., Kuwahara, S. B., Feng, S., Ramakrishnan, V., Cohen, A., Huang, J., Hillmen, P., Brown, J. R., Laurenti L. (ORCID:0000-0002-8327-1396), and Tedeschi A.

Abstract

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase III SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42–86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0–26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI: 79.0–94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI: 88.4–98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered as clinicaltrials.gov Identifier: NCT03336333.

Published
2021

7. Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion.

Author

Tam, CS, Robak, T, Ghia, P, Kahl, BS, Walker, P, Janowski, W, Simpson, D, Shadman, M, Ganly, PS, Laurenti, L, Opat, S, Tani, M, Ciepluch, H, Verner, E, Šimkovič, M, Österborg, A, Trněný, M, Tedeschi, A, Paik, JC, Kuwahara, SB, Feng, S, Ramakrishnan, V, Cohen, A, Huang, J, Hillmen, P, Brown, JR, Tam, CS, Robak, T, Ghia, P, Kahl, BS, Walker, P, Janowski, W, Simpson, D, Shadman, M, Ganly, PS, Laurenti, L, Opat, S, Tani, M, Ciepluch, H, Verner, E, Šimkovič, M, Österborg, A, Trněný, M, Tedeschi, A, Paik, JC, Kuwahara, SB, Feng, S, Ramakrishnan, V, Cohen, A, Huang, J, Hillmen, P, and Brown, JR

Abstract

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 – 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 – 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

Published
2020

8. An evaluation of factors predicting long-term response to thalidomide in 234 patients with relapsed or resistant multiple myeloma.

Author

Hus, I, Dmoszynska, A, Manko, J, Hus, M, Jawniak, D, Soroka-Wojtaszko, M, Hellmann, A, Ciepluch, H, Skotnicki, A, Wolska-Smolen, T, Sulek, K, Robak, T, Konopka, L, and Kloczko, J

Subjects
MULTIPLE myeloma, SERUM, BLOOD plasma, PLASMACYTOMA, THALIDOMIDE, PIPERIDINE, MULTIPLE myeloma diagnosis, SURVIVAL, ALBUMINS, PREDICTIVE tests, BLOOD proteins, HEMOGLOBINS, TIME, CANCER relapse, PROGNOSIS, TREATMENT effectiveness, IMMUNOSUPPRESSIVE agents, GLOBULINS, DRUG resistance in cancer cells
Abstract

The aim of this study was to assess the prognostic value of pretreatment clinical and laboratory parameters in refractory or relapsed multiple myeloma (MM) patients who have a long-term response to thalidomide (THAL), lasting at least 18 months. The study was carried out on 234 patients who received THAL for relapsed/refractory myeloma. Out of the 234 patients, 129 patients (55.1%) responded to THAL with a mean response duration of 11.9 months (ranging from 1 to 48) and an overall survival rate of 20.3 months (ranging 1-55 months). In 64 patients (27.4% of the whole group), the response to THAL lasted > or =18 months with a mean response lasting 24 months. Statistical analysis of the group of nonresponders and patients with long-term response to THAL showed a significantly higher serum albumin level (P=0.0003) and haemoglobin level (P=0.05), as well as a lower beta2 microglobulin (beta2M) (P=0.022), LDH (P=0.045) serum level in patients with long-term response. In this study, the LDH and serum albumin level were predictors for response to THAL therapy. The beta2M serum level was not a predictor for response to THAL. The albumin serum level was the best parameter distinguishing the group of patients with long-term response to THAL from the entire responding group (P=0.02). [ABSTRACT FROM AUTHOR]

Published
2004
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9. 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

10. Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Follow-up Results from Arm C of the SEQUOIA (BGB-3111-304) Trial.

Author

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

Abstract

Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenstrom macroglobulinemia, zanubrutinib was associated with important safety advantages compared to ibrutinib, especially regarding cardiovascular toxicity (Blood; in press). The initial results from Arm C of the SEQUOIA (BGB-3111-304) trial of zanubrutinib in a large cohort of TN CLL/SLL pts with del(17p) were recently presented with a median follow-up of 10 months (Blood 2019;134:851). Presented here is an updated analysis for safety and efficacy in this cohort. Method(s): The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm C) of TN pts with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446) were eligible if they were aged >=65 y 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 was evaluated by investigator for CLL...Copyright © 2020 American Society of Hematology

11. 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

12. Efficacy and Safety of Zanubrutinib in Patients with Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) with del(17p): Follow-up Results from Arm C of the SEQUOIA (BGB-3111-304) Trial.

Author

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

Abstract

Background: Patients (pts) with CLL/SLL whose tumor exhibits the deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib (BGB-3111) is an investigational, next-generation Bruton tyrosine kinase (BTK) inhibitor. In the ASPEN study of pts with Waldenstrom macroglobulinemia, zanubrutinib was associated with important safety advantages compared to ibrutinib, especially regarding cardiovascular toxicity (Blood; in press). The initial results from Arm C of the SEQUOIA (BGB-3111-304) trial of zanubrutinib in a large cohort of TN CLL/SLL pts with del(17p) were recently presented with a median follow-up of 10 months (Blood 2019;134:851). Presented here is an updated analysis for safety and efficacy in this cohort. Method(s): The SEQUOIA trial (NCT03336333) is an open-label, global, multicenter, phase 3 study that includes a nonrandomized cohort (Arm C) of TN pts with del(17p) CLL/SLL treated with zanubrutinib (160 mg twice daily). Adult pts with CLL/SLL who met International Workshop on CLL (iwCLL) criteria for treatment (Blood 2008;111:5446) were eligible if they were aged >=65 y 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 was evaluated by investigator for CLL...Copyright © 2020 American Society of Hematology

13. Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion

Author

Tam CS, Robak T, Ghia P, Kahl BS, Walker P, Janowski W, Simpson D, Shadman M, Ganly PS, Laurenti L, Opat S, Tani M, Ciepluch H, Verner E, Šimkovič M, Österborg A, Trněný M, Tedeschi A, Paik JC, Kuwahara SB, Feng S, Ramakrishnan V, Cohen A, Huang J, Hillmen P, and Brown JR

Subjects
Aged, Humans, Piperidines, Pyrazoles, Pyrimidines adverse effects, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
Abstract

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

Published
2021
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14. Modulation of the activity of calcium-activated neutral proteases (calpains) in chronic lymphocytic leukemia (B-CLL) cells.

Author

Witkowski JM, Zmuda-Trzebiatowska E, Swiercz JM, Cichorek M, Ciepluch H, Lewandowski K, Bryl E, and Hellmann A

Subjects
Adult, Aged, Aged, 80 and over, Apoptosis, CD3 Complex, Calcium metabolism, Enzyme Activation, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Calpain metabolism, Leukemia, Lymphocytic, Chronic, B-Cell enzymology, Signal Transduction
Abstract

Decreased susceptibility to apoptosis and impaired proliferative control are thought to be responsible for prolonged life span and accumulation of chronic lymphocytic leukemia (B-CLL) cells. The activity of calpains (calcium-dependent, neutral proteases, active in the cells responding to signals inducing a rise of cytoplasmic Ca(++)) is involved in the regulation of apoptosis of some cell types by interaction with caspase-3. This work verifies the hypothesis of the abnormal activity of calpains and its role in reduced apoptosis of the B-CLL cells. Casein zymography, reverse transcriptase-polymerase chain reaction, and Western blotting were used for identification and quantification of the activity and expression of calpains in B-CLL cells and purified normal B lymphocytes. The activity and expression of mu-calpain (requiring micromolar Ca(++) for activation) are significantly higher in the leukemic than in nonmalignant cells. Contrarily, the activity and expression of m-calpain (requiring millimolar Ca(++)) as well as the expression of calpastatin (an endogenous inhibitor of calpains) are unchanged or reduced in the B-CLL lymphocytes. Correspondingly, the activity of caspase-3 is many times lower in the B-CLL cells than in normal B lymphocytes. Inhibition of overexpressed mu-calpain in living B-CLL cells in vitro results in doubling of the proportion of the cells undergoing spontaneous apoptosis. This observation suggests a possible role for calpains in longer survival of the B-CLL cells and may open new therapeutic possibilities.

Published
2002
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