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In: Molecular and Cellular Biology, Informa UK Limited, Vol. 25, No. 21 ( 2005-11-01), p. 9576-9585

Type of Medium: Online Resource

ISSN: 1098-5549

URL: Article

DOI: 10.1128/MCB.25.21.9576-9585.2005

Language: English

Publisher: Informa UK Limited

Publication Date: 2005

detail.hit.zdb_id: 1474919-1

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 356-356

Abstract: The first two authors contributed equally. Introduction: VenR (2 years of Ven, plus R during the first 6 months) improved progression-free/overall survival (PFS/OS) vs bendamustine + R (BR) in patients (pts) in with R/R CLL in MURANO (Seymour et al. N Eng J Med 2018). MURANO also showed early, sustained and durable undetectable minimal residual disease (uMRD) status with VenR, which is associated with prolonged survival in CLL (Kater et al. J Clin Oncol 2019). Here we explore associations between baseline molecular characteristics and VenR-induced MRD responses and PFS based on the 4-year follow-up of MURANO. Methods: DNA specimens from CD19-enriched baseline samples (313/389 enrolled pts) were analyzed with whole-exome sequencing (WES). Genetic complexity (GC) was assessed by array comparative-genomic hybridization. Gene expression data were generated by RNA sequencing from matched RNA samples (209 pts). Univariate analysis determined the impact of gene mutations, GC, and BCL-2 (family) expression on MRD and PFS at end of combination therapy (EOCT) and end of treatment (EOT). MRD (peripheral blood only) was categorized as uMRD & lt;1 CLL cell/10,000 leukocytes ( & lt;10-4), low MRD (≥10-4 to & lt;10-2) or high MRD (≥10-2). Array-based GC status was non-complex = 0-2, low GC = 3-4 and high GC = ≥5 aberrations. Results: Mutation frequencies/GC status at baseline were equally distributed between arms. All 313 pts had CLL cells with non-silent, deleterious mutations by WES (mean 47/pt; 0.97±0.3 mutations/megabase). Of 44 frequently mutated genes, 202/313 (65%) pts had ≥1 frequent mutation; 69/313 (22%) pts had ≥2. Frequencies (%) of deleterious mutations were TP53 21.7, ATM 18.8, NOTCH1 17.9, SF3B1 12.5, XPO1 9.9, BIRC3/POT1/BRAF/EGR2 5.1-5.4, rest & lt;5%; ELF4, HISTIH1B, MED12 or PIM1 = 0. Deleterious gene mutations were more frequent in CLL pts with unmutated (91.9%) vs mutated (65.5%) IGHV (p=0.08). Of 288 pts with GC data, 113 (39.2%) = non-complex, 64 (22.2%) = low GC and 27 (9.4%) = high GC. Further in-text analyses refer to VenR only. WES data: BIRC3 mut and BRAF mut tended to be enriched in pts with detectable MRD at EOCT (% MRD+ in mutation vs wild type: 62.5% vs 23.7% [p=0.146] and 55.6% vs 21.4% [p=0.027] respectively) (Table 1). At EOT, NOTCH1 mut and TP53 mut were negatively associated with uMRD (35.3% vs 63.5% [p=0.10]; 41.7% vs 63.9% [p=0.028] ) (Table 1). These observations were concordant with observed PFS outcomes (Figure 1). Array data: Negative effects on MRD status were seen in pts with either del17p at EOCT (p=0.055) and at EOT (p=0.054) or del13q14bi at EOCT (p=0.018) (Table 1). Trends were seen for gain 2p, loss 18p/4q/trisomy 12 at EOCT and gain 2p/8q, loss 14q/18p/4q and trisomy 12 at EOT. High MRD+ at EOT was also associated with low and high GC vs non-complex GC (p=0.042) (Figure 2). PFS was shorter in high but not low GC pts at 36-mo follow-up (HR 3.2, p=0.0055; HR 1.1, p=0.77). Conversely, after 4-years follow-up, low GC pts had reduced PFS benefit vs non-complex GC (HR 2.0, p=0.025; Figure 3), differing from previously reported findings (Lugano, 3-year follow-up). The delayed deterioration in PFS benefit in low GC pts was unprecedented, and warrants further investigation into prognostic risks associated with this subgroup. RNA expression data: Gene-specific and pathway-level enrichment analyses are ongoing to explore associations between RNA sequencing data and MRD status. Preliminary gene expression analyses showed that pts with MRD+ at EOCT expressed higher BCL-2 than those with uMRD (p=0.028), but not at EOT (Table 1). There was a trend towards increased MCL-1 expression from high MRD to low MRD and uMRD at EOT. Conclusions: We identified genomic alterations having impact on MRD response at EOCT and EOT (i.e. BIRC3, BRAF, NOTCH1, TP53): mutations mostly were associated with increased MRD and del17p tended to lead to increase in high and low clones of MRD+. Low/high GC negatively impacted long-term PFS with VenR and may represent high-risk pt subgroups. High BCL-2 may associate with MRD+ at EOCT but not at EOT. Given the small size of the genomic alteration cohort, further validation of these findings are needed. Studying the large CLL clinicogenomic data in MURANO helped determine whether VenR combinations overcome challenges posed by CLL/SLL with unfavorable clinical characteristics, and further identify biomarkers that may predict clinical benefits in these pts. Disclosures Kater: AbbVie: Consultancy, Honoraria, Research Funding; Roche: Other: Travel funding, Research Funding; Genentech: Research Funding. Wu:Genentech, Inc.: Employment, Equity Ownership. Bolen:F. Hoffmann-La Roche: Equity Ownership; Genentech, Inc.: Employment. Assaf:Genentech, Inc.: Employment, Equity Ownership. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Apellis: Research Funding; Gilead: Research Funding; Roche: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Eichhorst:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, 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; BeiGene: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Eldering:Genetech, Roche, AbbVie: Research Funding. Kipps:AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: 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, Research Funding; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Langerak:Gilead: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding. Mellink:Roche/Genentech: Research Funding. Van Der Kevie-Kersemaekers:Array analysis is financed by Roche/Genentech: Research Funding. Owen:AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Teva: Honoraria; Merck: Honoraria; Acerta: Research Funding. Chyla:Abbvie, Inc: Employment, Other: Stock or options. Punnoose:Roche: Other: Stock/stock options; Genentech, Inc.: Employment. Wang:Roche: Equity Ownership; Genentech, Inc.: Employment. Lefebure:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Boyer:F. Hoffmann-La Roche Ltd: Employment. Humphrey:F. Hoffmann-La Roche Ltd: Employment. Jiang:Genentech: Employment, Equity Ownership; F. Hoffman-La Roche: Equity Ownership. Seymour:Roche: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding; Acerta: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123678

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 19-21

Abstract: Introduction: The randomized Phase III MURANO study (NCT02005471) compared fixed-duration VenR with standard bendamustine-rituximab (BR) in R/R CLL. Deep responses with uMRD were associated with superior progression-free survival (PFS) of VenR vs BR with 48 months (mo) follow-up (f/u). We now report long-term MRD kinetics and updated efficacy outcomes, including re-exposure to VenR (to be presented), with a 5 year (yr) median follow-up (clinical cutoff date May 8, 2020). Methods: As published, pts were randomized to VenR (Ven 400 mg daily for 2 yrs + standard dose R for the first 6 mo) or B (70 mg/m2)R (6 mo). A sub-study was introduced in 2018, allowing pts who developed progressive disease (PD) following Tx with BR or VenR to receive the MURANO VenR regimen. PFS was based on investigator assessment. Peripheral blood MRD was analyzed centrally by allele-specific oligonucleotide polymerase chain reaction and/or flow cytometry. Pts were categorized by MRD status as previously reported, using & lt;10-4 threshold for uMRD. MRD conversion was defined as 2 consecutive assays detecting MRD or PD in pts who previously had uMRD. Genomic complexity (GC) and del(17p) status were assessed by array comparative genomic hybridization. GC was defined as ≥3 copy number variations (CNV). All p-values are descriptive. Results: 389 pts were enrolled (VenR, n=194; BR, n=195). With a median f/u of 59.2 (range, 0-71.5) mo, the PFS benefit with VenR over BR was sustained (HR, 0.19 [95% CI: 0.15-0.26]; p & lt;0.0001). Median PFS was 53.6 (95% CI: 48.4-57.0) mo for VenR and 17.0 (95% CI: 15.5-21.7) mo for BR. For pts who completed the full 2 yrs of Ven Tx (n=130), PFS estimates 36 mo post-end of treatment (EOT) were ~51.1% (95% CI: 40.2-61.9). Overall survival (OS) benefit was maintained for pts treated with VenR vs BR (HR, 0.40 [95% CI: 0.26-0.62]; p & lt;0.0001), with 5-yr OS estimates of 82.1% (95% CI: 76.4-87.8) for VenR and 62.2% (95% CI: 54.8-69.6) for BR. Improved OS outcome was observed among the VenR pts that reached EOT without PD and had uMRD (83/118) compared with those with MRD (35/118), with 3-yr post-EOT survival estimates of 95.3% (95% CI: 90.0-100.0) vs 85.0% (95% CI: 72.8-97.2), respectively (Figure 1). Of the pts with uMRD at EOT, 32/83 had not shown PD and remained uMRD at the 5-yr update, 4/83 had PD without prior confirmed MRD conversion and 47/83 had MRD conversion. Median time to MRD conversion from EOT was 19.4 (95% CI: 8.7-28.3) mo. Of the 47/83 pts with confirmed MRD conversion, 19 subsequently developed PD by International Workshop on CLL criteria with a median time to PD from MRD conversion of 25.2 (95% CI: 19.4-30.4) mo. These 19 pts exhibited more rapidly increasing rates of MRD post-EOT than pts that had MRD conversion but were PD-free (Figure 2). Among pts that were uMRD at EOT, the baseline presence of del(17p), GC and unmutated immunoglobulin heavy chain gene (IGVH) were each associated with increased risk of MRD conversion and subsequent PD post-EOT (Table 1). All 4 pts with del(17p) experienced MRD conversion with subsequent PD. 8/18 (44%) pts with GC vs 8/40 (20%) pts without GC eventually converted to MRD and developed PD. The rate of MRD conversion with eventual PD was also higher among those with unmutated IGVH (21/56; 37%) than those without (1/23; 4%). Once uMRD at EOT was achieved, pts without del(17p) or GC, or with mutated IGVH, were more likely to maintain uMRD or experience MRD conversion without subsequent PD at this follow-up (Table 1). No new safety signals were identified. Excluding non-melanoma skin cancers, 2 second primary malignancies (VenR [acute myeloid leukemia and multiple myeloma]) were reported since the previous update. Rates of Richter transformation remained balanced between treatment arms (7 on VenR, 6 on BR). Following PD on the main study, 29 pts were enrolled in the sub-study (re-treatment; n=21, crossover; n=8). Further data on their biologic profile, updated response rates, and MRD in the re-treatment cohort will be presented. Conclusions: Five-yr data from MURANO demonstrate sustained PFS and OS benefit with VenR vs BR. In the VenR cohort, uMRD at EOT is associated with improved OS. Unmutated IGVH, del(17p) and GC (≥3 CNV) are associated with higher rates of MRD conversion and subsequent PD after attaining uMRD at EOT. Overall, a substantial proportion of pts who completed Ven Tx retained uMRD 36 mo after treatment cessation, displaying durable response following 2-yr fixed-duration VenR. Disclosures Kater: Janssen: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Roche: Research Funding; Genentech: Research Funding. Kipps:Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees. Eichhorst:F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding. Hillmen:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Astra Zeneca: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding. D'Rozario:F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Owen:AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. Assouline:AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding. Lamanna:MingSight: Other: Institutional research grants, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Other: Institutional research grants, Research Funding; Loxo: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Octapharma: Research Funding; Columbia University Medical Center: Current Employment; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Robak:Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria; Sandoz, Janssen, AbbVie, Roche, Gilead: Consultancy. de la Serna:F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; Abbvie, AstraZeneca: Other: Travel, Accommodations, Expenses; Abbvie, Janssen: Speakers Bureau; Gilead, AstraZeneca, Abbvie, Janssen, Sandoz, F. Hoffmann-La Roche: Consultancy; Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding. Cartron:Celgene: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead: Honoraria; Jansen: Honoraria; Abbvie: Honoraria. Montillo:Gilead: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria; Verastem: Honoraria. Mellink:Genentech, Inc: Research Funding; Amsterdam University Medical Centre: Current Employment. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Wilson:Roche Products Limited: Current Employment. Wu:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Jiang:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Lefebure:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Boyer:Roche: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Seymour:Mei Pharma: Consultancy, Honoraria; Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-136109

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Pharmacology Research & Perspectives, Wiley, Vol. 3, No. 5 ( 2015-10)

Abstract: The Bcl‐2 family inhibitors venetoclax and navitoclax demonstrated potent antitumor activity in chronic lymphocytic leukemia patients, notably in reducing marrow load and adenopathy. Subsequent trials with venetoclax have been initiated in non‐Hodgkin's lymphoma and multiple myeloma patients. Traditional preclinical models fall short either in faithfully recapitulating disease progression within such compartments or in allowing the direct longitudinal analysis of systemic disease. We show that intravenous inoculation of engineered RS4;11 (acute lymphoblastic leukemia) and Granta 519 (mantle cell lymphoma) bioluminescent reporter cell lines result in tumor engraftment of bone marrow, with additional invasion of the central nervous system in the case of Granta 519. Importantly, apoptosis induction and response of these systemically engrafted tumors to Bcl‐2 family inhibitors alone or in combination with standard‐of‐care agents could be monitored longitudinally with optical imaging, and was more accurately reflective of the observed clinical response.

Type of Medium: Online Resource

ISSN: 2052-1707 , 2052-1707

URL: Article

DOI: 10.1002/prp2.178

Language: English

Publisher: Wiley

Publication Date: 2015

detail.hit.zdb_id: 2740389-0

SSG: 15,3

In: American Journal of Hematology, Wiley, Vol. 97, No. 2 ( 2022-02)

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Issue

URL: Article

DOI: 10.1002/ajh.v97.2

DOI: 10.1002/ajh.26411

Language: English

Publisher: Wiley

Publication Date: 2022

detail.hit.zdb_id: 1492749-4

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3923-3923

Abstract: Abstract 3923 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: Seymour: Roche: Advisory Board member Other, Consultancy; Genentech: Advisory Board member, Advisory Board member Other, Consultancy. Anderson:Abbott: Research Funding; Genentech: 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. Kipps:Abbott: Consultancy, Research Funding. Wierda:Abbott: Research Funding; Genentech: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; AmGen: Research Funding; Merck: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; Genzyme: Consultancy. Kahl:Abbott: Research Funding; Genentech: Consultancy, Research Funding. Miller:Abbott: Research Funding; Genentech: Research Funding. Darden:Abbott: Employment, owner of Abbott stock Other. Nolan:Abbott: Employment, own Abbott stock Other. Gressick:Abbott: Employment, stock owner Other. Xiong:Abbott: Employment, own Abbott stock Other. Huang:Genentech: Research Funding; Abbott: Research Funding; Walter and Eliza Hall Institiute of Medical Research: Employment, receives commercial income related to ABT-199, receives commercial income related to ABT-199 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. Roberts:Abbott: Research Funding; Genentech: 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.3923.3923

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 12, No. 11_Supplement ( 2013-11-01), p. C249-C249

Abstract: Leukemias and lymphomas are characterized by disseminated disease burden in the circulation, lymphoid tissues and bone marrow. Although anti-cancer agents that can effectively target all of these compartments are associated with better prognosis, there is a paucity of established, longitudinal pre-clinical models that can faithfully reproduce the system-wide disease state of these malignancies. To address this limitation, we induced stable expression of the fusion construct of luc2, a firefly luciferase optimized for expression in mammalian cells, and mCherry, a far red fluorescent protein (named LMC), in an acute lymphoblastic leukemia (ALL) cell line, RS4;11, and a mantle cell lymphoma (MCL) cell line, Granta 519. Intravenous (IV) inoculation of these engineered lines in mice results in reliable tumor engraftment of the bone marrow and other tissues. Additionally, we demonstrate that Granta 519, a cell line harvested from a patient with a highly aggressive blastoid lymphoma, invades the central nervous system (CNS) similar to that observed in some MCL patients. Administration of the Bcl-2 inhibitors ABT-199 or navitoclax to established RS4;11-LMC tumor bearing mice significantly reduced tumor load in all compartments. This reflected the clinical activity achieved with navitoclax and, in particular, ABT-199, in recent clinical trials. Further, ABT-199 and navitoclax combined with bendamustine-rituximab (BR) induces significant regression of Granta 519-LMC tumors in the bone marrow and CNS, demonstrating that the Bcl-2 agents can access MCL cells which have invaded the CNS. Taken together, these data demonstrate that IV inoculation of RS4;11-LMC and Granta 519-LMC leads to engraftment of tumor cells in clinically relevant sites. The ability to both model systemic disease and monitor drug treatment in a longitudinal fashion constitutes a translational advantage for the study and development of anticancer therapeutics. Disclosures: SA, AO, JChen, BJC, JClarin, KF, TM, SM, SS, MLS, SKT, JL, AJS, ERB and JH are employees of AbbVie. This study was sponsored by AbbVie. AbbVie contributed to the study design, research and interpretation of data, writing, reviewing and approving the publication. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C249. Citation Format: Scott L. Ackler, Anatol Oleksijew, Jun Chen, Brenda J. Chyla, Jerry Clarin, Kelly Foster, Thomas McGonigal, Sasmita Mishra, Sally Schlessinger, Morey L. Smith, Stephen K. Tahir, Joel Leverson, Andrew J. Souers, Erwin R. Boghaert, Jonathan Hickson. Detection of tissue and bone marrow clearance of systemically engrafted hematologic tumors by ABT-199 and navitoclax using bioluminescent imaging. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C249.

Type of Medium: Online Resource

ISSN: 1535-7163 , 1538-8514

URL: Article

DOI: 10.1158/1535-7163.TARG-13-C249

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2013

detail.hit.zdb_id: 2062135-8

SSG: 12

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 546-546

Abstract: Background Acute myeloid leukemia (AML) is a highly heterogeneous disease with multiple prognostic indicators of outcomes to conventional treatments; including age, cytogenetic risk, and presence of genomic abnormalities (NPM1, TP53, FLT3 and IDH1/2). Additionally, overexpression of BCL-2 is a predictor for poor response to chemotherapy and can lead to therapeutic resistance in AML (Campos et. al. Blood, 1993). Venetoclax (Ven), an oral selective BCL-2 inhibitor, in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC), was recently approved for treatment naive patients (pts) with AML who were not fit for standard induction therapy on the basis of two phase 1b/2 studies (DiNardo et.al, Lancet Onclogy, 2018; Wei et.al., J Clin. Oncol., 2019). Here, we present clinical outcome results from the phase 1b/2 study populations in subgroups defined by molecular markers and correlations with BCL-2 family expression. Methods: The data cut-off dates were 31-Aug-2018 (VEN+HMA study M14-358, NCT02203773) and 22-Aug-2018 (VEN+LDAC study M14-387 NCT02287233). Pt responses were assessed according to the IWG criteria for AML (Cheson et.al., J Clin. Oncol.,2003). The presence of AML associated mutations (NPM1, IDH1, IDH2, TP53 and FLT3) were determined centrally in bone marrow aspirates (BMA) at baseline. BCL-2 (BCL2) gene expression was defined centrally by quantitative polymerase chain reaction (qPCR) using the deltaCt (ΔCt) method. BCL2 expression normalized to a reference gene (2-ΔCt) was evaluated for pts with & gt; 50% AML blasts in baseline BMA (median 75%; range 50-99%). The composite complete remission (CR) and CR with incomplete marrow recovery (CRi) rate, overall survival (OS), time to first response (TTR), and duration of response (DOR), and BCL-2 gene expression were correlated with presence of baseline molecular markers. Results: Data from 209 pts who received Ven 400 mg or 600 mg in combination with either HMA or LDAC are reported here. The median age was 74 years (range: 61-90 years) and 61% (n=127) were male (Table 1). Of the 167 pts with centrally assessed molecular markers, IDH1 or IDH2 mutations were detected in 25.7%, NPM1 mutations in 15.6%, TP53 mutations in 22.2%, and FLT3 mutations in 18.0% pts. Pts may have more than one of these mutations (i.e co-mutations of NPM1 and IDH1or IDH2, NPM1 with FLT3, or NPM1 with TP53) identified in baseline BMA. The CR/CRi rates were 83.7% for pts with IDH1/IDH2 mutations, 84.6% for pts with NPM1 mutations, 59.5% for pts with TP53 mutations, and 53.3% for pts with FLT3 mutations (Table 2). The median OS was not reached (NR) for pts with IDH1, IDH2 or NPM1 mutations, while the median OS for pts with detectable TP53 mutations or FLT3 mutations was 8.9 mos and 12.4 mos respectively. The remissions (CR or CRi) were rapid (median TTR between 1.1 mos to 1.8 mos) for each group (Table 2) and durable responses were observed for pts with IDH1, IDH2, NPM1, or FLT3 mutations (median DOR was either NR for IDH and NPM1 and 19.9 mos for FLT3). Pts with TP53 mutations are known to have poor prognosis and the DOR in this cohort was 5.6 mos. The median time on study was 11.6 mos (range: 0.3-44 mos). The range of BCL2 mRNA expression (2-ΔCt) in bone marrow blasts was 0.03 to 2.93, with a median of 0.86. The Cox hazard ratio for OS was 1.06, p=0.8565 based on BCL2 above the median ( & gt; 0.86 2-ΔCt). The multivariate analysis included age, cytogenetic risk, AML type (primary vs secondary) and trial (M14-387 vs M14-358). Albeit not statistically significant and small sample sets, pts with either IDH1 or IDH2 mutations (N = 21) tended to have higher BCL2 expression (median 2-ΔCt 1.1 ; range 0.19 -2.93) while pts with TP53 mutations (N = 7) had lower levels of BCL2 expression (median 2-ΔCt 0.55; range 0.03 - 1.27). Determination of baseline expression of other family members (BCL2L1, MCL1, BCL2A1, BCLw, NOXA, etc) is ongoing and additional univariate and multivariate analyses will be presented at the meeting. Conclusions: These analyses demonstrate that VEN + HMA or LDAC has efficacy across multiple molecular markers in AML. This activity is rapid and durable, and is observed across different levels of BCL2 expression in AML blasts. Disclosures Chyla: Abbvie, Inc: Employment, Other: Stock or options. Harb:AbbVie Inc: Employment, Other: Stock/stock options. Mantis:AbbVie Inc: Employment, Other: Stock/stock options. Riehm:AbbVie Inc.: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Sun:AbbVie: Employment, Other: Stock/stock options. Huang:AbbVie Inc: Employment, Other: Stock/stock options. Jiang:AbbVie Inc.: Employment, Other: Stock/stock options. Dail:Genentech: Employment, Equity Ownership. Peale:Genentech Inc.: Employment, Other: Stock/stock options. Potluri:AbbVie, Inc.: Employment, Other: Stock/stock options. Hayslip:AbbVie Inc: Employment, Other: Stock/stock options. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment in acute myeloid leukemia, which is not an approved indication.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-128373

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 8520-8520

Abstract: 8520 Background: BCL-2 is highly expressed in NHL, including mantle cell lymphoma (MCL), and is a promising therapeutic target as it is involved in NHL pathogenesis and mediates resistance to many cytotoxics. ABT-199 is a second generation inhibitor with 500-fold higher affinity for BCL-2 (K i 〈 0.10 nM) than BCL-X L (K i =48 nM). Methods: Objectives of this Ph 1 dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy in patients (pts) with relapsed or refractory (R/R) NHL. A single oral dose (50-400 mg) was administered followed by 6 days off drug prior to the initiation of continuous once daily dosing. Due to concerns of potential tumor lysis syndrome (TLS), a 2 to 3 wk lead-in period with step-wise escalation to the target cohort dose was implemented. Dose cohorts up to 900 mg have been evaluated to date. Results: As of January 2013, 31 pts have been enrolled (median age 68 y (range 35-85); 20 males; median prior therapies 3 (range 1-7). 13 (42%) and 4 (13%) had bulky adenopathy ( 〉 5 and 〉 10 cm, respectively). The most common AEs (≥15% of patients) were nausea (36%), diarrhea (26%), dyspepsia, vomiting, fatigue, pyrexia and cough (16% each). Gr 3/4 AEs occurring in 〉 1 patient were anemia, neutropenia (4 pts each), and febrile neutropenia (2 pts). Two of 14 pts in cohort 5 experienced DLTs at the target dose of 600 mg: Gr 3 febrile neutropenia and Gr 4 neutropenia. Although Gr 3/4 thrombocytopenia was observed in 3 pts, it was not dose dependent. Gr 3 TLS was seen after the initial dose in 1 pt with very bulky MCL ( 〉 10 cm). With a median follow-up of 5 months (range 0.5-15), 17 have discontinued: 13 due to PD, 2 due to AEs and 2 who received a BMT. Of the 29 pts evaluable for efficacy, the overall best response rate was 55% with 1 DLBCL pt achieving a CR and 15 (52%) a PR (8/8 MCL, 3/3 Waldenstrom macroglobulinemia, 2/7 follicular lymphoma and 2/7 DLBCL pts). Conclusions: ABT-199 is highly active in R/R NHL, particularly in MCL. Additional dosing and scheduling modifications are currently being explored to optimize the efficacy/safety profile of this active new agent. ABT-199 warrants further single-agent and combination trials in NHL. Clinical trial information: NCT01328626.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2013.31.15_suppl.8520

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2013

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1349-1349

Abstract: Germline deletion of bcl-x demonstrated the importance of this gene for hematopoiesis. Bcl-x deficient embryos failed to thrive due to massive apoptosis of immature hematopoietic and neural cells. Deletion of this gene in the adult has uncovered its requirement for the final maturation of erythroid cells, the transition of pre-B cells to the pro-B cell stage and recently, we showed an important role in the development of natural killer cells. While the role of bcl-x in hematopoietic stem cells (HSC) has yet to be addressed, a role for other members of anti-apoptotic bcl-2 family of proteins has been established. Overexpression of bcl-2 led to accumulation of HSC, whereas genetic deletion of mcl-1 resulted in ablation of HSC. In the present study, we determined by quantitative Real-Time PCR, that in addition to mcl-1, bcl-x is also highly expressed in hematopoietic stem cells, whereas the level of bcl-2 is threefold lower. Moreover, we found the expression of bcl-x to be down regulated with differentiation of HSC into progenitor populations (i.e. GMP, CMP and MEP). Therefore, we established a model to delete bcl-x in the stem cells of adult mice. We bred the Mx1-cre transgenic line with mice that carry the bcl-x gene flanked by loxP sites. Deletion of bcl-x occurred following administration of pIpC. A total of 10 bcl-x deficient mice and 7 age-matched control animals (Mxi-cre/wildtype bcl-x) were examined. Quantitative real-time PCR revealed a 55 – 95% reduction of bcl-x mRNA in Lin−, Sca-1+, c-kit+ cells 8 days post the first administration of pIpC. This population consists of phenotypically and functionally defined long-term HSC (LT-HSC), short-term HSC (ST-HSC) and multipotent progenitors. We used FACS analysis to identify LT-HSC versus ST-HSC populations and to further assess the effects of bcl-x deletion. LT-HSC were defined by staining, for the following cell surface markers as Lin−, Sca-1+, c-kit+, Flt3−, CD34−; ST-HSC were characterized as Lin−, Sca-1+, c-kit+, Flt3−, CD34+. We found a 2 fold shift in the ratio of LT-HSC versus ST-HSC in bcl-x deficient mice compared to the ratio in control animals. This result raises the hypothesis that bcl-x regulates entry of HSC into the cell cycle. A notion that is supported by the observation that overexpression of bcl-x in fibroblasts delays transition from the Go/G1 to the S phase of the cell cycle. Future experiments will determine if the observed phenomenon is mediated through the anti-apoptotic function or cell cycle activity of the bcl-x protein.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.1349.1349

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7