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In: Environmental Management, Springer Science and Business Media LLC, Vol. 1, No. 1 ( 1977-1), p. 67-96

Type of Medium: Online Resource

ISSN: 0364-152X , 1432-1009

URL: Article

DOI: 10.1007/BF01867402

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 1977

detail.hit.zdb_id: 1478932-2

detail.hit.zdb_id: 131372-1

SSG: 12

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 8 ( 2017-03-10), p. 826-833

Abstract: B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2016.70.4320

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2017

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 254-254

Abstract: Introduction: BCL-2 is an anti-apoptotic protein that is commonly overexpressed in hematologic malignancies, including Non-Hodgkin Lymphoma (NHL). Venetoclax is a selective, potent, orally bioavailable BCL-2 inhibitor. Patients (pts) with relapsed/refractory (R/R) NHL were enrolled in a phase 1, open-label, dose-escalation, multicenter study to determine the safety, pharmacokinetics, and efficacy of venetoclax monotherapy. We present updated data on the safety profile and efficacy as of June 10, 2015. Methods: Venetoclax was administered once-daily until progressive disease or unacceptable toxicity. To mitigate the risk of tumor lysis syndrome (TLS), a 3-week period with a stepwise, intrapatient dose ramp-up was used, starting at 200 mg and reaching a maximum dose level of 1,200 mg in the dose escalation cohorts. In a safety expansion cohort, stepwise escalation from 400 mg to 800 mg to 1200 mg was evaluated. Adverse events (AEs) were graded according to NCI-CTCAE version 4.0. Responses were assessed using 2007 Cheson IWG response criteria including CT scans beginning at week 6. Results: Accrual is complete with 106 pts enrolled. NHL subtypes included in the dose escalation cohorts (200-1200 mg/day) were diffuse large B-cell lymphoma (DLBCL, n=20), follicular lymphoma (FL, n=14), mantle cell lymphoma (n=28), Waldenström macroglobulinemia (n=4), marginal zone lymphoma (n=3), and multiple myeloma (n=1). NHL subtypes enrolled in the safety expansion cohort (1200 mg/day) were DLBCL (n=21) and FL (n=15). The current analysis focuses on pts with DLBCL and FL from the dose escalation and safety expansion cohorts. Data on other subtypes will be presented at the meeting. In total, 57/70 pts with DLBCL and FL have discontinued (n=49 due to PD, n=3 due to AE, n=2 withdrew consent, n=2 proceeded to transplant and n=1 due to non-compliance). Treatment emergent-AEs of any grade in ≥20% of the 70 pts with DLBCL or FL were diarrhea and fatigue (each 44%), nausea (33%) and vomiting (23%). Treatment-emergent grade 3/4 AEs in ≥5 pts, were anemia (14%), fatigue (9%) and thrombocytopenia (7%). Serious adverse events in ≥2 pts were hyponatremia (4%), and dehydration, diarrhea, and febrile neutropenia (each 3%). Two events of laboratory TLS were previously reported. There were no new events of laboratory TLS and no pts had clinical TLS. Among 41 pts with DLBCL, 7 were DLBCL-Richter's transformation (RT) and 2 had primary mediastinal large B-cell lymphoma (PMBCL). The median age was 68 (range: 25-86). The median number of prior therapies was 3 (range: 1-8). Five (12%) had rituximab-refractory disease. The median time on venetoclax for pts with DLBCL was 5 months (range: 0.4-9). The overall response rate (ORR) was 15% [3 (9%) CR and 2 (6%) PR] for pts with DLBCL (n=34). The median duration of response for DLBCL was 3.3 months (range: 2-4) with no responses ongoing and the median duration of SD was 2.3 months (range: 1-15). One pt with SD remains on study at 9 months of venetoclax. Two responders (1 with DLBCL who achieved CR and 1 with PMBCL who achieved PR) proceeded to allogeneic hematopoietic stem cell transplant. The ORR was 43% (3 PR) for pts with DLBCL-RT (n=7). One pt with PR remains on study at 18 months of venetoclax. Among 29 pts with FL, the median age was 64 (range: 46-75). The median number of prior therapies was 3 (range: 1-10). Eight (28%) had rituximab-refractory disease. The median time on venetoclax was 7 months (range: 1-19). The ORR was 34% [3 (10%) CR and 7 (24%) PR] for pts with FL (n=29). All 3 patients with CR were enrolled in the dose escalation cohorts. The median duration of response was 10 months (range: 1-30) and the median duration of SD was 4.2 months (range: 2-18). Eleven patients remain on study. Response rates are summarized in the table. Conclusions: Venetoclax monotherapy demonstrated a tolerable safety profile in pts with R/R NHL. Several pts with DLBCL had an initial response to venetoclax, but this response was not sustained. In FL, venetoclax monotherapy achieved an ORR of 34% indicating clinical benefit, as evidenced by long durations on therapy. These results suggest that the optimal role of venetoclax for treatment of DLBCL and FL will be in combination therapies. Venetoclax is currently being evaluated in combination with bendamustine and rituximab and in combination with R or obinutuzumab plus CHOP in phase 2 studies of pts with FL. Table 1. Table 1. Disclosures Gerecitano: Genentech: Consultancy, Other: Advisory Board; AbbVie: Consultancy, Other: Advisory Board. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Roberts:Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax: Employment; AbbVie and Genentech: Research Funding. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Consultant and speaker bureau for Genentech: Consultancy; AbbVie and Genentech: Research Funding. Kahl:Genentech: Consultancy; AbbVie: Research Funding; Teva: Consultancy. Pagel:Actinium Pharmacetuicals, Inc.: Equity Ownership. Puvvada:AbbVie and Genentech: Research Funding. Kipps:AbbVie: Consultancy, Research Funding. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Dunbar:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Gressick:AbbVie: Employment, Equity Ownership. Wagner:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Heitner Enschende:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.254.254

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 374, No. 4 ( 2016-01-28), p. 311-322

Type of Medium: Online Resource

ISSN: 0028-4793 , 1533-4406

URL: Article

DOI: 10.1056/NEJMoa1513257

Language: English

Publisher: Massachusetts Medical Society

Publication Date: 2016

detail.hit.zdb_id: 1468837-2

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1789-1789

Abstract: New treatment options are needed for patients (pts) with R/R NHL, particularly in MCL where there are no curative options. Dysregulation of the anti-apoptotic protein Bcl-2 is a hallmark of NHL pathogenesis and contributes to chemotherapy resistance. ABT-199 is a selective, potent, orally bioavailable small molecule Bcl-2 inhibitor that is a promising agent for the treatment of pts with NHL. Methods The primary objectives of this phase I, dose-escalation study were to evaluate the safety and pharmacokinetics (PK), and to determine a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ABT-199. Secondary objectives were to assess the efficacy of ABT-199 and to explore biomarkers for response. Adult pts requiring therapy, with ECOG performance status ≤1 and adequate marrow function (ANC ≥1.0 x 109/L, Plt ≥50 x 109/L) received ABT-199 on Week 1 Day -7 (W1D-7), followed by continuous, once-daily dosing from W1D1 until progressive disease or unacceptable toxicity. A 2 to 3 week lead-in period with stepwise escalation starting with lower doses to final cohort doses of 200, 300, 400, 600, and 900 mg was implemented. Evaluations include adverse events (AE; NCI-CTCAE-V4), PK parameters and disease responses (IWG 2007 criteria). Results As of July 4, 2013, 32 pts were enrolled, 11 (34%) with follicular (FL), 8 (25%) with MCL, 8 (25%) with diffuse large B-cell (DLBCL), 1 (3%) with marginal zone (MZL), 3 (9%) with Waldenström macroglobulinemia (WM), and 1 (3%) multiple myeloma (MM). The median age was 68 (range 35-85), 63% were male with a median of 3.5 prior therapies (range 1-7), and the median time on study was 6.0 months (range 0.5-15.0). 44% of the pts had bulky disease ≥5 cm, including ≥10 cm in 16%. 22 pts have discontinued (D/C) drug: 18 due to progressive disease, 2 due to AEs, and 2 who proceeded to stem cell transplant in ongoing response. The most common AEs of any grade (G) occurring in ≥20% of pts were nausea (41%), diarrhea (31%), vomiting (22%), fatigue (22%), and upper respiratory tract infection (22%). G 3/4 AEs occurring in 〉 3 pts were anemia (15%), neutropenia (13%), and thrombocytopenia (13%). G 3/4 thrombocytopenia was not dose-dependent or dose-limiting. Two of 10 pts in cohort 5 experienced a DLT (G3 febrile neutropenia and G4 neutropenia) at the target dose of 600 mg. G3 laboratory tumor lysis syndrome was seen after the initial dose in 1 pt with bulky MCL (elevations in phosphate and potassium only) and 1 pt with DLBCL (elevations in phosphate and uric acid only). After a single dose with food, ABT-199 had Tmax and T1/2 of approximately 8 and 15 hours, respectively. Food increased ABT-199 bioavailability by 3-4 fold. Preliminary efficacy data are summarized in the table. Conclusions ABT-199 showed anti-tumor activity as monotherapy for several NHL subtypes, with an overall response rate of 53% in this R/R population. Anti-tumor activity was seen in all MCL and WM pts treated across the range of ABT-199 cohort doses, and responses in DLBCL and FL pts were observed at doses ≥600 mg. Dose escalation is continuing to determine the MTD and RP2D. Biomarker studies are also underway in various NHL subtypes to explore a potential correlation with response. Disclosures: Seymour: Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Gerecitano:AbbVie: Research Funding; Genentech: Research Funding. Kahl:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding. Wierda:AbbVie, Inc.: Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau. Anderson:Genentech: Research Funding; AbbVie, Inc.: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, which recieves commercial income related to ABT-199, Employee, which recieves commercial income related to ABT-199 Other. Rudersdorf:AbbVie, Inc.: Employment, Stock Other. Gressick:AbbVie, Inc: Employment, Stock Other. Montalvo:AbbVie, Inc.: Employment, Stock Other. Yang:AbbVie, Inc.: Employment, Stock Other. Busman:AbbVie, Inc.: Employment, Stock Other. Dunbar:AbbVie, Inc.: Employment, Stock Other. Cerri:AbbVie, Inc.: Employment, Stock Other. Enschede:AbbVie, Inc.: Employment, Stock Other. Humerickhouse:AbbVie, Inc.: Employment, Stock Other. Roberts:AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1789.1789

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 304-304

Abstract: Abstract 304 Background: BCL-2 is highly expressed in indolent non-Hodgkin lymphomas (NHL), mantle cell lymphoma (MCL) and other selected aggressive lymphomas, and is a promising target for therapeutic intervention. The first-generation BCL-2 inhibitor navitoclax showed some activity in indolent lymphoma, but its co-inhibition of BCL-xL resulted in dose-limiting thrombocytopenia, precluding the full exploration of the potential of BCL-2 inhibition with this drug in NHL. ABT-199 is an orally bioavailable, second-generation BH3-mimetic that inhibits BCL-2 (Ki 〈 0.10 nM), but has 500-fold less activity for BCL-xL (Ki=48 nM). ABT-199 demonstrated antitumor activity against a variety of human cell lines and xenograft models that include B cell NHL, follicular lymphomas (FL), diffuse large B-cell Lymphoma (DLBCL) and MCL. Methods: This is a phase-I dose-escalation trial using a modified Fibonacci design in patients with relapsed/refractory NHL. The primary objectives of this study are to determine the safety, pharmacokinetics (PK) and maximum tolerated dose (MTD) of ABT-199; to recommend a phase-2 dose; and to assess efficacy and biomarkers in patients with relapsed/refractory NHL. Adult patients requiring therapy, with ECOG performance status £1, and adequate marrow function received ABT-199 on Week 1 Day −7 (W1D-7), followed by continuous once-daily dosing from W1D1, until progressive disease (PD) or unacceptable toxicity. Due to concerns of potential tumor lysis, a strategy of commencing with a 2 to 3 week lead-in period with step-wise increases to the target cohort dose is being evaluated. In the first four cohorts, the starting dose increased from 50 to 200 mg (50, 100, 200, and 200 mg, respectively), with target cohort doses of 200 mg [n=3], 300 mg [n=3] , 400 mg [n=4], and 600 mg [n=7] . Evaluations include: adverse events (AE; NCI-CTCAE-V4) and tumor response (IWG 2007 criteria). Results: To date, 17 patients (median age, 71 [35–85]) have been treated with ABT-199. Median prior therapies were 3 (range, 1–7) and 6 patients had bulky adenopathy ( 〉 5cm). Most common AEs (experienced by 〉 2 patients) were nausea (41%), diarrhea (24%), dyspepsia (24%), fatigue (24%), extremity pain (24%); and anemia, constipation, upper respiratory tract infection and cough (18% each). Grade 3 or 4 AEs occurring in 〉 1 patient were anemia (18%) and neutropenia (12%). Treatment-related thrombocytopenia has not been reported and no dose-limiting toxicities (DLTs) have been identified to date. After a single dose administration with a high-fat meal, ABT-199 reached Cmax at approximately 7 hrs with a terminal half-life of about 15 hrs. Food increased ABT-199 exposure by approximately 3-fold. With a median follow-up of 2.8 months (range, 1.2 to 10.8), 14 patients remain on study and 3 have discontinued due to PD. In patients who have completed at least a W6 assessment, reductions of 〉 50% in target lesions have been observed in 8/15 patients (53%); 6/6 patients with MCL, 1/2 patients with WM and 1/2 patients with DLBCL. Additionally, 5 FL patients have been evaluated (3 with rituxan-refractory disease) with a median time on study of 6.4 months (range, 3.5 to 10.8). 4/5 FL patients had nodal disease reductions ranging from 18% to 40%. Conclusions: ABT-199 shows single agent anti-tumor activity in patients with NHL; particularly in MCL. Activity is also observed in DLBCL and WM. To date, no DLTs have been identified and tumor lysis syndrome related to ABT-199 has not been reported. Dose escalation is continuing to identify the optimal dosing regimen and MTD of ABT-199 in NHL. Updated results will be presented. Disclosures: Roberts: Abbott: Research Funding; Genentech: Research Funding. Anderson:Genentech: Research Funding; Abbott: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 Other. Kahl:Genentech: Consultancy, Research Funding; Abbott: Research Funding. Darden:Abbott: Employment, owner of Abbott stock Other. Nolan:Abbott: Employment, own Abbott stock Other. Gressick:Abbott: Employment, stock owner Other. Yang:Abbott: Employment, own Abbott stock Other. Chyla:Abbott: Employment, Stock owner Other. Busman:Abbott: Employment, Stock owner Other. Graham:Abbott: Employment, Stock owner Other. Cerri:Abbott: Employment, Stock owner Other. Enschede:Abbott: Employment, own Abbott stocks Other. Humerickhouse:Abbott: Employment, own Abbott stocks Other. Seymour:Roche: Advisory board member, Advisory board member Other, Consultancy; Genentech: Advisory board member, Advisory board member Other, Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.304.304

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: British Journal of Haematology, Wiley, Vol. 195, No. 1 ( 2021-10), p. 113-118

Abstract: Richter syndrome (RS), an aggressive lymphoma occurring in the context of chronic lymphocytic leukaemia/small lymphocytic lymphoma, is associated with poor prognosis when treated with conventional immunochemotherapy, therefore, improved treatments are required. Immune checkpoint blockade has shown efficacy in some B‐cell malignancies and modest responses in early clinical trials for RS. We investigated the immune checkpoint profile of RS as a basis to inform rational therapeutic investigations in RS. Formalin‐fixed, paraffin‐embedded biopsies of RS ( n  = 19), de novo diffuse large B‐cell lymphoma (DLBCL; n  = 58), transformed indolent lymphomas (follicular [tFL], n  = 16; marginal zone [tMZL], n  = 24) and non‐transformed small lymphocytic lymphoma (SLL; n  = 15) underwent gene expression profiling using the NanoString Human Immunology panel. Copy number assessment was performed using next‐generation sequencing. Immunohistochemistry (IHC) for LAG3 and PD‐1 was performed. LAG3 gene expression was higher in RS compared to DLBCL ( P  = 0·0002, log2FC 1·96), tFL ( P   〈  0·0001, log2FC 2·61), tMZL ( P  = 0·0004, log2FC 1·79) and SLL ( P  = 0·0057, log2FC 1·45). LAG3 gene expression correlated with the gene expression of human leukocyte antigen Class I and II, and related immune genes and immune checkpoints. IHC revealed LAG3 protein expression on both malignant RS cells and tumour‐infiltrating lymphocytes. Our findings support the investigation of LAG3 inhibition to enhance anti‐tumour responses in RS.

Type of Medium: Online Resource

ISSN: 0007-1048 , 1365-2141

URL: Issue

URL: Article

DOI: 10.1111/bjh.v195.1

DOI: 10.1111/bjh.17789

Language: English

Publisher: Wiley

Publication Date: 2021

detail.hit.zdb_id: 1475751-5

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 18 ( 2018-09-15), p. 4371-4379

Abstract: Purpose: The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as chromosome 17p deletion [del(17p)] or progressive disease following B-cell receptor pathway inhibitors. Patients and Methods: We conducted a comprehensive analysis of the safety of 400 mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase I/II studies. Results: Median age was 66 years and 60% had del(17p). Patients had received a median of three prior therapies (range: 0–15); 42% previously received ibrutinib or idelalisib. Median duration of exposure to venetoclax was 16 months (0–56). In the pooled analysis, the most common adverse events (AE) of any grade were diarrhea (41%), neutropenia (40%), nausea (39%), anemia (31%), fatigue (28%), and upper respiratory tract infection (25%). The most common grade 3/4 AEs were neutropenia (37%), anemia (17%), and thrombocytopenia (14%). With the current 5-week ramp-up dosing, the incidence of laboratory TLS was 1.4% (2/166), none had clinical sequelae, and all of these patients were able to ramp-up to a daily dose of 400 mg. Grade 3/4 neutropenia was manageable with growth factor support and dose adjustments; the incidence of serious infections in these patients was 15%. Ten percent of patients discontinued venetoclax due to AEs and 8% died while on study, with the majority of deaths in the setting of disease progression. Conclusions: Venetoclax as a long-term continuous therapy is generally well tolerated in patients with R/R CLL when initiated with the current treatment algorithm. Clin Cancer Res; 24(18); 4371–9. ©2018 AACR.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-17-3761

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2018

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4395-4395

Abstract: Background: Venetoclax (VEN) is a potent, highly selective, orally bioavailable small-molecular BCL2 inhibitor that is FDA-approved for patients (pts) with chronic lymphocytic leukemia (CLL) that harbors del(17p) and who have received ≥1 prior therapy. VEN monotherapy induces objective response in ~80% of pts (16-20% complete remission by investigator) with relapsed/refractory (R/R) CLL, including del(17p) CLL (Roberts et al, 2016; Stilgenbauer et al, 2016). Safety of VEN monotherapy was evaluated using an integrated dataset from pts with CLL. Methods: Pts were included if they received at least one dose of 400 mg VEN as target dose in the M12-175 (first in human), M13-982 (del[17p] CLL), or M14-032 (prior ibrutinib or idelalisib) Phase I or II studies. All started with weekly dose ramp up to 400 mg daily over 4-5 weeks and continued VEN until disease progression/discontinuation. Results: Overall, 296 pts were included in the analysis: median age was 66 years (range: 29-85), 94% had ECOG score 0-1, 53% had Binet stage A, 27% B, and 19% C. 66% had del(17p) CLL, 77% had unmutated IGHV, and 69% had β-2 microglobulin 〉 3 mg/L. Pts had received a median of 3 prior therapies (range: 0-12) and 94 (32%) had received prior ibrutinib or idelalisib. A history of cytopenias was common, with neutropenia in 52 (18%) pts, anemia in 118 (40%), and thrombocytopenia in 80 (27%). Forty-six (16%) pts were on G-CSF support prior to enrollment. At the time of analysis, median duration on VEN was 13 months (range: 0-50), with 55% pts receiving VEN daily for 〉 1 year. Common AEs (any grade) were neutropenia (41%), diarrhea (39%), nausea (36%), anemia (29%), fatigue (26%), and upper respiratory tract infection (23%). The most common Grade 3/4 AEs were neutropenia (37%), anemia (15%), and thrombocytopenia (14%). Grade 3/4 infections were reported for 19% of pts. Common serious AEs were pneumonia and febrile neutropenia (5% each); most serious AEs occurred within the first 3 months on VEN. Twenty-five deaths were reported: 13 due to disease progression and 12 were treatment-emergent AEs due to complications related to underlying CLL (most common were infections [4]); none were attributed by the investigator to VEN. The safety profile was similar when analyzed by subgroups, including age, sex, race, or prior ibrutinib/idelalisib. Four pts had AEs of TLS, though only one met Howard criteria for laboratory TLS (decreased calcium and increased phosphate). No clinical TLS was observed. All events occurred during the 5-week dose ramp up and pts interrupted VEN dosing for median of 3 days (range: 1-5), though all restarted VEN to reach 400 mg. Events were managed by IV hydration and standard of care for laboratory abnormalities. A major reason for VEN interruptions/reductions was neutropenia, with most dose adjustments occuring within the first 3 months on study. Neutropenia was managed by standard supportive care measures, including G-CSF support for 136 (46%) pts during this time. Time of first onset for most hematologic toxicities (any grade) occurred during dose ramp up (Figure). First onset of new AEs within or after 3 months on VEN (shown as within/after 3 months) was 34%/7% for neutropenia, 27%/3% anemia, and 14%/5% thrombocytopenia. This temporal pattern is likely due to improving CLL disease control though for some pts this may be the result of increasing time off prior myelosuppresive chemotherapy. Grade 4 neutropenia was reported in 71 (24%) pts and median time to event was 28 days (range: 2-416); 48/71 (67%) had Binet C at screening and median time to event was 23 days (range: 2-415). Grade 4 neutropenia required dose reductions for 21% of pts, 80% received G-CSF support, and 1 event led to study discontinuation. Grade 4 thrombocytopenia occurred in 32 (11%) pts (23 had Binet C) and Grade 4 anemia in 2 (2%) pts (both Binet C). Gastrointestinal toxicities were mainly Grade 1/2, with 60% new events reported in the first 3 months vs 11% reported 〉 3 months (Figure). No late toxicity signal has been observed in pts receiving 〉 1 year of therapy. Conclusions: The safety profile of 400 mg VEN daily was consistent across pts with CLL pooled from 3 studies and remains acceptable with longer follow up in this larger population. No clinical TLS was observed and one event of laboratory TLS was manageable. The majority of AEs, including cytopenias (most common Grade 3/4 AEs), occurred during the first months of VEN and onset of AEs decreased over time in pts with emergent toxicities. Figure Figure. Disclosures Seymour: AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Davids:Genentech: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Infinity: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Roberts:AbbVie: Research Funding; Genentech: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; Janssen: Research Funding; Servier: Research Funding. Hallek:GSK: Research Funding; Mundipharma: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Gilead: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria. Wierda:Genentech: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Gerecitano:Samus: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Cerri:AbbVie: Employment. Potluri:AbbVie: Employment. Kim:AbbVie: Employment. Busman:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Humerickhouse:AbbVie: Employment. Best:AbbVie: Employment. Desai:AbbVie: Employment. Stilgenbauer:Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4395.4395

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Advances, American Society of Hematology, Vol. 6, No. 2 ( 2022-01-25), p. 503-508

Abstract: The genomic landscape of resistance to targeted agents (TAs) used as monotherapy in chronic lymphocytic leukemia (CLL) is complex and often heterogeneous at the patient level. To gain insight into the clonal architecture of acquired genomic resistance to Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors in CLL, particularly in patients carrying multiple resistance mutations, we performed targeted single-cell DNA sequencing of 8 patients who developed progressive disease (PD) on TAs (either class). In all cases, analysis of single-cell architecture revealed mutual exclusivity between multiple resistance mutations to the same TA class, variable clonal co-occurrence of multiple mutations affecting different TAs in patients exposed to both classes, and a phenomenon of multiple independent emergences of identical nucleotide changes leading to canonical resistance mutations. We also report the first observation of established BCL2 resistance mutations in a patient with mantle cell lymphoma (MCL) following PD on sequential monotherapy, implicating BCL2 as a venetoclax resistance mechanism in MCL. Taken together, these data reveal the significant clonal complexity of CLL and MCL progression on TAs at the nucleotide level and confirm the presence of multiple, clonally independent, mechanisms of TA resistance within each individual disease context.

Type of Medium: Online Resource

ISSN: 2473-9529 , 2473-9537

URL: Article

DOI: 10.1182/bloodadvances.2021006211

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 2876449-3