Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 140, No. 8 ( 2022-08-25), p. 839-850

Abstract: The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5 years’ follow-up. Survival benefits with VenR vs BR were sustained (median PFS [95% confidence interval] : 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P & lt; .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], P & lt; .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9% (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with VenR (93 days) vs BR (53 days; P = 1.2 × 10−7). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2021015014

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 355-355

Abstract: Introduction: Venetoclax (Ven) is a highly selective oral inhibitor of key apoptosis regulator BCL-2, which is overexpressed in CLL. MURANO (a randomized Phase III study) compared fixed-duration VenR with standard bendamustine-rituximab (BR) in R/R CLL. The superior progression-free survival (PFS) of VenR versus BR was established in the first pre-planned analysis (Seymour et al. N Engl J Med 2018); continued PFS benefit was seen with longer follow-up and after all patients (pts) had completed therapy (Kater et al. J Clin Oncol 2019). We now present data from a further analysis (median follow-up 48 months) when all pts had been off Ven treatment for median 22 months. Methods: As previously published, pts were randomized to 6 cycles of VenR then Ven 400mg once daily for 2 years in total, or 6 cycles of BR. PFS status was based on investigator assessment. Central analysis of minimal residual disease (MRD) status in peripheral blood (PB) was performed at Cycle 4, end of combination treatment (EOCT) then every 3-6 months. Pts were categorized as undetectable MRD (uMRD; & lt;1 CLL cell/10,000 leukocytes [ & lt;10-4]), low-MRD (≥10-4 - & lt;10-2), or high-MRD (≥10-2) status. All p-values are descriptive. Safety data collected for the current analysis period were pre-specified adverse events (AEs) of concern, serious AEs (SAEs) related to study drug, and development of a second primary malignancy. Results: 389 pts were enrolled: VenR (n=194), BR (n=195). At data cutoff (May 8, 2019), all pts were off treatment and with a median follow-up from enrolment of 48 months. With a median follow-up period of 22 months since Ven completion (1-35 months), the PFS benefit of VenR over BR was sustained (HR, 0.19 [95% CI 0.14, 0.25]; p & lt;0.0001; Figure 1). The 4-year PFS estimates were 57.3% (95% CI 49.4, 65.3) versus 4.6% (95% CI, 0.1, 9.2), respectively. For the pts who completed 2 years of Ven (n=130), the 18- and 24-month post-treatment cessation PFS estimates were 75.5% (95% CI 67.4, 83.7) and 68.0% (95% CI 57.6, 78.4), respectively. Thirty-five of 130 pts had developed progressive disease (PD, defined by International Workshop on Chronic Lymphocytic Leukemia criteria) after completion of Ven. Sustained overall survival (OS) benefit was demonstrated with VenR over BR (HR, 0.41 [95% CI 0.26, 0.65]; p & lt;0.0001; 4-year rate: 85.3% vs 66.8%; Figure 2). This OS benefit was seen despite 103/142 (73%) BR pts receiving treatment after progression; 81/103 (79%) pts in the BR arm received novel targeted agents (Bruton tyrosine kinase inhibitors [BTKis; n=60], PI3K inhibitors [PI3Kis; n=9] , BH3-only mimetics [n=10] or investigational medicinal products [IMPs; n=2] ). The response rate to novel targeted agents in the BR arm was 47/81 (58%; Figure 3). Forty-two of 64 (66%) pts in the VenR arm received anti-CLL therapy after PD. Of these, 28 received novel targeted therapies (BTKis, n=12; PI3Kis, n=1; BH3-only mimetics, n=14; IMPs, n=1) and the response rate to these treatments was 9/28 (32%; Figure 3). Fourteen of the VenR arm pts with PD subsequently received Ven or were re-treated with VenR, producing an overall response rate of 2/14 (14%); 10/14 pts (71%) were without an evaluable or available response. Updated response data for these pts will be presented. In both treatment arms, the previously reported association between uMRD in PB at the EOCT response visit with improved PFS was maintained with this extended follow-up (Figure 4A). In the VenR cohort, improved PFS was observed for pts who were uMRD at end of treatment (EOT; Figure 4B). Among VenR pts who had detectable PB MRD at the EOCT response visit and at EOT, low-MRD pts continued to show improved PFS versus high-MRD pts. There were no new SAEs considered related to study drug. Excluding non-melanoma skin malignancies, 3 second primary malignancies were detected (1 who received BR [melanoma] and 2 who received VenR [melanoma and breast cancer] ) since the previous update. There were no new reported events of Richter's transformation. Conclusions: Four-year data from MURANO demonstrate sustained PFS and OS benefits with VenR versus BR. 24-month post-treatment cessation PFS was 68.0% in pts completing 2 years of Ven, and pts who attained PB uMRD showed particularly durable responses. These follow-up data provide further support for the application of time-limited VenR in R/R CLL. Disclosures Seymour: Celgene: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy; Acerta: Consultancy; Janssen: Consultancy, Research Funding. Kipps: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; 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; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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. Eichhorst:ArQule: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding; 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: 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. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; Apellis: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. D'Rozario:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. 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. Robak:Takeda: Consultancy, Research Funding; UCB: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grant, Research Funding; Amgen: Consultancy, Other: Travel grant; Roche: Consultancy, Other: Travel grant, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grant, Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta: Research Funding; Morphosys AG: Research Funding. de la Serna:Roche, AbbVie, Janssen, Gilead: Speakers Bureau; Roche, AbbVie, Gilead, Janssen, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jaeger:Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. Cartron:Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria; Roche, Celgene: Consultancy. Montillo:Versatem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Kim:AbbVie: Employment, Other: Stock or options. Wu:Genentech, Inc.: Employment, Equity Ownership, Other: Stock options. Jiang:F. Hoffman-La Roche: Equity Ownership; Genentech: Employment, Equity Ownership. Wang:Genentech, Inc.: Employment; Roche: Equity Ownership. Lefebure:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Boyer:F. Hoffmann-La Roche Ltd: Employment. Humphrey:F. Hoffmann-La Roche Ltd: Employment. Kater:Genentech: Research Funding; Roche: Other: Travel funding, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123930

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. 130, No. Suppl_1 ( 2017-12-07), p. LBA-2-LBA-2

Abstract: Introduction Venetoclax (V), an orally administered, highly selective, potent BCL-2 inhibitor, induces high ORR when given as monotherapy to pts with relapsed/refractory (R/R) CLL, including high-risk populations, e.g. del(17p). V is also well tolerated when combined with rituximab (R) and achieves improved CR rates and minimal residual disease negativity (MRD-). Here, we provide first released data from the primary analysis of MURANO (NCT02005471), the first Phase 3 study of V in pts with R/R CLL, which assessed efficacy/safety of VR vs standard chemoimmunotherapy, bendamustine (B) + rituximab (BR). Methods Eligibility for this open-label, randomized, Phase 3 study included R/R CLL requiring treatment (iwCLL guidelines), 1-3 prior lines of therapy (including ≥1 chemo-containing) and ECOG PS ≤1. Prior B was allowed provided response duration was ≥24 mo. Pts were randomized (1:1) to VR or BR. Stratification factors were del(17p), responsiveness to prior therapy and geographic region. In the VR arm, a 4- or 5-wk graduated dose ramp-up of V from 20-400 mg daily was used to mitigate potential tumor lysis syndrome (TLS) risk. Beginning at Wk 6, R was then given monthly for six 28-day cycles (IV 375 mg/m2 first dose, then 500 mg/m2) in combination with V daily. Pts continued with V 400 mg for a maximum of 2 yr or until disease progression (whichever first). In the BR arm, pts were given B (IV 70 mg/m2) on Days 1 and 2 of each of six 28-day cycles in combination with R using same R dosing schedule. MRD was centrally assessed by ASO-PCR and/or flow cytometry in peripheral blood at screening, Mo. 4 and 9, and 3-monthly follow-up visits. The primary endpoint was investigator (INV)-assessed PFS. An interim analysis was preplanned at ~140 INV-assessed PFS events. On data review, an Independent Data Monitoring Committee recommended study arms to be unblinded to the sponsor as pre-specified statistical boundaries for early stopping were crossed for PFS in favor of VR. Results 389 pts were enrolled in VR (n=194) and BR (n=195) arms, which were well balanced: median (range) age, 64.5 (28-83) vs 66.0 (22-85) yr; 1 prior therapy, 57.2% vs 60.0%; fludarabine refractory, 14.1% vs 15.5%; del(17p), 26.6% vs 27.2%. At data cut-off (8 May 2017; median follow-up, 23.8 mo. [range 0.0-37.4]), INV-assessed PFS was superior for VR vs BR with HR 0.17, 95% CI 0.11-0.25, P & lt;0.0001; median not reached vs 17.0 mo. (Fig 1). 24-mo. PFS estimates were 84.9% vs 36.3%, respectively. Consistent treatment effects on PFS were observed in all subgroups assessed (Fig 2). With HR 0.19, 95% CI 0.13-0.28, P & lt;0.0001, Independent Review Committee-assessed PFS showed a similar magnitude of benefit. Key secondary efficacy endpoints showed consistent improvements for VR vs BR including a notable improvement in OS (HR 0.48, 95% CI 0.25-0.90). INV-assessed ORR was 93.3% with VR vs 67.7% with BR (Δ=25.6%, 95% CI 17.9-33.3%); CR/CRi was achieved in 26.8% vs 8.2% of pts, respectively (Table 1). Higher peripheral blood MRD- rates attained at any time were seen with VR vs BR (83.5% vs 23.1%; Δ=60.4%, 95% CI 52.3-68.6%) by ITT analysis. MRD negativity was more durable in the VR arm. Consistent with known safety profiles of the regimens, Grade 3-4 neutropenia was higher in VR arm but there was no increase in febrile neutropenia or Grade 3-4 infection (Table 2). There were 6 (3.1 %) and 2 (1.1%) Grade ≥3 AEs of TLS reported for VR and BR, respectively; one clinical TLS event in each arm (a Grade 4 acute renal failure in BR, transient increase in creatinine in VR; VR event occurred on an earlier 4-week ramp-up schedule). Richter transformation was confirmed in 6 pts and 5 pts for VR vs BR, respectively. AEs leading to death were seen in 5.2% vs 5.9% of pts. Median relative V dose intensity was 97% of protocol-specified drug exposure. Conclusion The primary analysis of MURANO, the first Phase 3 study of V in R/R CLL, shows a profound improvement in PFS vs standard BR chemoimmunotherapy, with consistent effects in all-risk subsets. Key secondary endpoints, including OS, ORR and CR rate, also showed consistent improvements with remarkable rates of peripheral blood MRD- that exceed those previously attained in treatment of R/R CLL. This enhanced disease control was achieved in a multinational setting with an acceptable safety profile, without significant TLS, demonstrating that treatment with VR resulted in outcomes superior to that of BR for pts with R/R CLL. Disclosures Seymour: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: 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, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps:Celgene: Consultancy; Oncternal: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Eichhorst:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Hillmen:Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. D'Rozario:Roche: Consultancy. Assouline:Lundbeck: Other: Advisory Board; Paladin: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myer Squibb: Speakers Bureau; Roche Canada: Consultancy. Owen:AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Merck: Honoraria. Gerecitano:Merck: Consultancy; Mass Medical International: Consultancy; Incyte: Consultancy; Arcus Medica: Consultancy; Aratana: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Samus Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Orexo: Consultancy. Robak:AbbVie: Honoraria, Research Funding; Akari Therapeutics Plc: Honoraria, Research Funding; Roche: Honoraria, Research Funding. De la Serna:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jaeger:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria; AOP Orphan: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; GSK: Honoraria; Infinity: Honoraria; Millennium: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding. Cartron:Gilead: Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Montillo:Novartis: Honoraria; Roche: Research Funding; Abbvie: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Humerickhouse:AbbVie: Employment, Equity Ownership. Punnoose:Genentech: Employment. Li:Genentech: Employment. Boyer:Roche: Employment. Humphrey:F-Hoffmann-La Roche: Employment, Equity Ownership. Mobasher:Roche: Equity Ownership; Genentech: Employment. Kater:Roche: Consultancy; Acerta/Astra Zeneca: Consultancy, Research Funding; Roche/Genentech: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Research Funding; Sandoz: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V130.Suppl_1.LBA-2.LBA-2

Language: English

Publisher: American Society of Hematology

Publication Date: 2017

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 4393-4393

Abstract: Introduction: The anti-apoptotic protein BCL2 is overexpressed in a number of hematological malignancies, including chronic lymphocytic leukemia (CLL). Venetoclax (VEN) is a selective, oral BCL2 inhibitor with demonstrated activity and an acceptable safety profile both as monotherapy and in combination regimens in relapsed/refractory (R/R) CLL patients (pts). VEN has demonstrated preclinical activity with bendamustine/rituximab (BR), a standard treatment in this population, as well as clinical efficacy with R. The anti-CD20 mAb obinutuzumab (G) has demonstrated improved efficacy in combination with chlorambucil compared with R. Here we present an interim analysis of an ongoing phase 1b study (GO28440) evaluating the maximum tolerated dose (MTD) of both VEN+BR and VEN+BG, plus safety, tolerability, efficacy and optimal order of administration in both R/R or 1L CLL pts (NCT01671904). Methods: Pts with ECOG PS ≤1, 0-3 prior chemotherapy lines, and adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts (VEN 100-400mg/day +BR or +BG in a 3+3 dose escalation design) and subsequent safety expansion cohorts (400mg). Dose finding occurs in one of two dosing schedules: Schedule A (VEN introduced before BR or BG) or Schedule B (BR or BG introduced before VEN), with one chosen for expansion per unique population/drug grouping. Both schedules include a gradual VEN dose ramp-up and other prophylactic measures based on risk stratification to reduce the risk of tumor lysis syndrome (TLS). Following completion of 6 months of combination therapy, pts continue single-agent VEN until unacceptable toxicity, disease progression, or (for 1L pts only) up to 1 year total VEN. Dose-limiting toxicity (DLT) data are reviewed after all pts in a cohort have completed 21 days of combination treatment at the target VEN dose and focus on TLS and cytopenias. Efficacy is assessed by iwCLL guidelines; Hallek et al. 2008. Results: At data cutoff (May 2, 2016), 55 pts (baseline characteristics and disposition in Table 1) have been treated; 47 pts received VEN+BR: 30 R/R (12 on Schedule A at doses 100-400mg, 18 on Schedule B all at 400mg) and 17 1L (all at 400mg: 6 on Schedule A, 11 on Schedule B). Eight pts received VEN+BG: all on Schedule B at 400mg. Safety is summarized for VEN+BR (R/R and 1L) and VEN+BG (1L) in Table 2. The most common AEs across all groups were neutropenia, thrombocytopenia, and nausea. Most G3-4 AEs across all groups were hematological toxicities; common non-hematological AEs included diarrhea and fatigue. Platelet transfusions occurred in 4 (13%) R/R VEN+BR and 1 (13%) 1L VEN+BG pts. There were serious AEs in 21 pts (43% R/R VEN+BR, 35% 1L VEN+BR, 25% 1L VEN+BG) including febrile neutropenia, nausea, vomiting, erythema, and infection. No deaths were reported. No TLS events (laboratory or clinical) were observed. Dose interruptions or modifications for VEN and/or BR/BG occurred in 35 (75%) of VEN+BR pts (22 R/R, 13 1L) and 7 (88%) VEN+BG pts, mainly due to neutropenia. Early VEN discontinuations for toxicity: 7 pts VEN+BR (R/R), 2 pts VEN+BR (1L), 1 pt VEN+BG. Early B and/or R/G discontinuations for toxicity: 10 pts VEN+BR (R/R), 4 pts VEN+BR (1L), 2 pts VEN+BG. Common reasons for discontinuations (≥1 pt) included neutropenia and thrombocytopenia. Across all pts, a median of 4 cycles of B were completed. Best overall response and minimal residual disease (MRD) status for evaluated pts are presented in Table 3. All but one R/R pt (off study early for disease transformation) responded across all groups. Conclusion: This study is the first to evaluate both VEN+BR and VEN+BG in pts with CLL. VEN 400mg daily can be combined with BR or BG in patients with either R/R or 1L CLL; neutropenia and thrombocytopenia are manageable with an otherwise acceptable safety profile. Administration schedules (VEN or BR first) appear to have similar toxicity profiles, with no DLT or lab/clinical TLS reported for either during dose finding. As expected, due to the known safety profile of VEN and B, hematologic toxicity was observed with VEN+BR; early VEN+BG safety data appears similar. Events appeared manageable, although early discontinuations contributed to a median of 4 completed cycles of B across all pts. Even with median of 〈 6 cycles of BR, all evaluated pts responded, with more than half showing CR and/or undetectable MRD. Responses may continue to deepen as more data is collected; the study is still enrolling. Disclosures Stilgenbauer: Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding. Morschhauser:Gilead Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Servier: Consultancy, Honoraria. Wendtner:Novartis: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Glaxo-SmithKline: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Cartron:Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Hallek:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Eichhorst:Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau. Kozloff:AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Lozanski:Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding. Punnoose:Genetech, Inc.: Employment. Wang:Genetech, Inc.: Employment. Hilger:Genetech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Salles:Celgene: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.4393.4393

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 487-487

Abstract: Numerous molecular approaches have been taken to elucidate the regulation of the human β-like globin genes, and particularly the “fetal” (γ- to β-) globin switch, given the role of fetal hemoglobin (HbF) levels on disease severity in the β-hemoglobin disorders. Despite these efforts, no developmental stage-specific nuclear regulators of HbF expression have been identified and validated. Recent genome-wide single nucleotide polymorphism (SNP) association studies by us and others have revealed novel loci that are significantly associated with HbF levels in normal, sickle cell, and thalassemia populations. One variant, lying within intron 2 of the chromosome 2 gene BCL11A, accounts for & gt;10% of the variation in HbF levels. We have now tested the hypothesis that BCL11A, a zinc-finger transcription factor, serves as a stage-specific regulator of HbF expression, rather than merely a genetic marker of HbF status. We found that BCL11A is expressed as two major isoforms (termed XL and L) in human erythroid progenitors. The level of BCL11A expression is inversely correlated with the expression of the HbF gene, γ-globin, in human erythroid cell types representative of different developmental stages. Expression of BCL11A is negligible in embryonic, and high in adult, erythroid cells. Correlation of SNP genotypes with levels of BCL11A RNA in cells derived from individuals of known genotypes indicates that the “high HbF” genotype is associated with reduced BCL11A expression. To better characterize its potential role in erythropoiesis and globin gene regulation, we identified interacting protein partners of BCL11A in erythroid cells through affinity purification and protein microsequencing. We found that the BCL11A protein exists in complexes with the nucleosome remodeling and histone deacetylase (NuRD) corepressor complex, as well as the erythroid transcription factors GATA-1 and FOG-1. Taken together, the genetic, developmental, and biochemical data are most consistent with a model in which BCL11A functions as a repressor of γ-globin gene expression. To directly test this possibility, we modulated expression of BCL11A in primary human erythroid precursors expanded from adult CD34+ progenitors. Transient or persistent knockdown of BCL11A accomplished by siRNA or lentiviral shRNA delivery, respectively, led to robust induction of γ-globin gene expression. Importantly, down-regulation of BCL11A expression did not alter the differentiation state or global transcriptional profile of the cells, suggesting an effect on a limited number of targets, including the γ-globin gene. In summary, these studies establish BCL11A as a potent regulator of human globin switching. As an adult-stage repressor, BCL11A represents a primary target for therapy aimed at reactivating HbF expression in patients with β-hemoglobin disorders. Our studies illustrate the power of an integrative approach to reveal the functional connection between a common genetic variant and a trait that serves as a prominent modifier of disease severity.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.487.487

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3341-3341

Abstract: Abstract 3341 Poster Board III-229 Allo-SCT procedures are currently undergoing a profound evolution. The spectra of patients and diseases for which this approach is now considered have increased considerably over the past years. This is mainly due to the introduction in routine practice of the so-called nonmyeloablative or RIC regimens. While it is well established that fludarabine is the backbone drug to secure engraftment, there is a wide variability in the degree of myeloablation between the different RIC protocols, and the toxicity profile might vary significantly from one protocol to another. The combination of fludarabine and Busulfan (usually 8 mg/Kg total dose) with or without ATG, is among the most widely used RIC protocols worldwide. In an attempt to further decrease the toxicity of the transplant procedure, we hypothesized that further reduction (50%) of the Busulfan dose can allow improving transplant outcome. With this background, this pilot study tested the combination of Fludarabine (120 mg/m2), Busulfan (4 mg/Kg total dose administered orally over a single day) and ATG (Thymoglobuline®, 2.5 mg/Kg/d for 2 days) as a RIC regimen prior to allo-SCT in a single centre series of 46 patients. The cohort included 27 males (59%) and 19 females (41%) with a median age at time of allo-SCT of 57 (range, 12-64) y. Diagnoses included 21 cases of AML (46%), 12 NHL (26%), 6 Hodgkin diseases (13%), 3 ALL (6.5%), 2 myeloproliferative syndromes (4%), 1 MDS (2%) and 1 CLL (2%). Before allo-SCT, 23 patients (50%) underwent and failed previous stem cell transplantation (auto or allo). PBSCs were used as stem cell source in 42 patients (91%), while 4 patients (9%) received classical bone marrow. A matched-related donor was used in 18 cases (39%) and an unrelated donor in 28 cases (61%). With a median follow-up of 30.4 (range, 23.7-50.8) months, the median peripheral blood chimerism of donor origin at day 30 after allo-SCT was 99%. 20 patients (43.5%) experienced grade 2-4 acute GVHD, including 13 cases (28.3%) of grade 3-4 acute GVHD. Nine patients (19.6%) experienced some form of chronic GVHD (5 extensive and 4 limited). At time of last follow-up, 26 patients (56.5%) were still alive. Relapse or disease progression occurred in 13 patients at a median of 3.5 (range, 0.6-18) months after allo-SCT. Disease progression accounted for 7 deaths, while transplant-related causes (acute GVHD, n=5; MOF, n=3; infections, n=2; other causes, n=3) were observed in 13 cases, for a TRM rate of 28.3%. The KM estimates of disease-free survival (DFS) and overall survival (OS) at 3 years after allo-SCT were 46.9% and 56.5% respectively. Interestingly, OS was lower in the AML subgroup (n=21) as compared to the remaining 25 patients with other diagnoses (42.9% vs. 68%, p=0.09). We conclude that low dose Busulfan (4 mg/kg total dose) combined with fludarabine and ATG is a feasible RIC regimen that can allow engraftment after allo-SCT in heavily pre-treated patients. The toxicity profile of this regimen is acceptable. However, in the setting of AML, disease control may be a matter of concern, especially in the early period after allo-SCT, suggesting that this type of RIC should be reserved for patients with lymphoid or indolent malignancies. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.3341.3341

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 184-184

Abstract: Introduction Venetoclax (Ven) is a highly selective oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway, which is constitutively overexpressed in CLL. Efficacy and safety of VenR given for a fixed duration in R/R CLL was evaluated in the randomized Phase III MURANO study compared with standard bendamustine + rituximab (BR). A first pre-planned analysis, when the majority of patients (pts) were still on study treatment (median follow-up 23.8 mo), established a superior PFS of VenR over BR (Seymour et al. NEJM 2018). With all pts having completed therapy, we analysed long-term outcome with a median follow up of 36.0 mo. Methods Pts were randomized to receive 6 cycles of VenR followed by Ven 400mg once daily for a total of 2 yrs, or 6 cycles of BR. Disease status was assessed by CT scan at screening, Cycle (C) 4 and 2−3 mo after end of combination therapy (EOCT). During Ven single agent and at follow-up visits, response was determined by clinical assessment every 3 mo until 3 yrs of follow-up, then every 6 mo thereafter or until PD. PFS status was based on investigator assessment. Peripheral blood (PB) minimal residual disease (MRD) was analysed centrally by ASO-PCR and/or flow cytometry at C4, EOCT and every 3/6 mo thereafter. All p values are descriptive. Results In total, 389 pts were enrolled in VenR (n=194) or BR (n=195) arms. As of May 8 2018, all pts were off treatment. For BR, 154 (79%) had completed 6 cycles. In the VenR arm, 174 (90%) completed the VenR combination phase and 130 (67%) had completed 2 yrs of Ven. The remainder had PD (11%), died (1%), or withdrew due to AEs (15%) or other reason (6%). Median Ven exposure duration and relative dose intensity were 24.4 (range 0-27.9) mo and 97.4% (26-100%), respectively, overall and 17.7 (0.5-21.9) mo and 99% during Ven single-agent therapy. With a median time off Ven after 2 yrs treatment of 9.9 (1.4-22.5) mo, PFS with VenR remains superior to BR (HR, 0.16 [95% CI 0.12, 0.23]; p 〈 0.0001; median not reached vs 17.0 mo; Figure 1). 3-year PFS estimate was 71.4% (95% CI 64.8%, 78.1%) vs 15.2% (95% CI 9.1%, 21.4%) respectively. Consistent magnitude of treatment effect on PFS with VenR was observed in all clinical and biological subgroups (Figure 2). For pts who completed 2 yrs of Ven (n=130), 6 and 12 mo PFS estimates were 92% (95% CI 87.3, 96.8) and 87% (95% CI 81.1, 93.8), respectively (Figure 3). 16/130 pts developed PD after completion of Ven; of these, 14 were MRD-positive at 〉 1% in PB at Mo 24 (when Ven single agent was scheduled to cease) and 10/16 pts had del(17p)/TP53 mutation at baseline. Clinical and cytogenetic risk factors in pts with and without PD after Mo 24 are in Table 1. In this analysis, OS improvement was seen with VenR over BR (HR, 0.50 [95% CI 0.30, 0.85]; p=0.0093; 3-yr rate: 87.9% vs 79.5%; Figure 4). Subsequent CLL-directed treatment was given after PD in 91 pts in the BR arm. 71/91 (78%) BR arm pts received novel targeted agents, including 45 who had ibrutinib and 7 who had Ven. 27/194 (14%) pts in the VenR arm received subsequent therapy: 13/27 (44%) had novel targeted agents as next treatment, including 8 pts who had ibrutinib and 3 who were re-treated with Ven. See Table 2 for a safety overview for VenR combination and Ven single-agent periods. During Ven single agent: 17/171 pts (10%) had an AE leading to drug withdrawal; 7/171 pts (4%) had an AE leading to dose reduction; 44/171 pts (26%) had a Ven dose interruption due to an AE; 7/171 pts (4%) had a fatal AE (4 other cancers, 2 cardiac, 1 pneumonia). Grade 3-4 AEs occurred in 59/171 pts (35%); the most frequent were neutropenia (20 pts, 12%), anemia (5 pts, 3%), and thrombocytopenia (3 pts, 2%). 12/171 (7%) pts had a grade 3-4 infection in the Ven single-agent phase. The total number of Richter transformation events was 7 with VenR and 6 with BR. Conclusions With all pts off treatment and 3 yrs' median follow-up, continued substantial benefit was observed with VenR, with PFS and OS superior to BR. There were no new safety signals; most pts were able to complete treatment. The rate of CLL progression in the first 12 mo after Ven completion was modest (13%), supporting the feasibility and safety of a time-limited VenR duration. The protocol has been amended to include assessment of response and durability of disease control with VenR reintroduction at PD. This updated analysis of this Phase III global randomized study demonstrates clinically meaningful benefit of the VenR chemotherapy-free regimen with a fixed duration in all pts with R/R CLL. Disclosures Seymour: AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy. Kipps:Genentech Inc: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Gilead Sciences, Inc.: Honoraria, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Assouline:Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau. Owen:Teva: Honoraria; Celgene: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Merck: Honoraria; AbbVie: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Honoraria, Research Funding. Robak:Janssen: Consultancy, Honoraria; Gilead: Consultancy; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria. de la Serna:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jaeger:Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Bioverativ: 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; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cartron:Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Montillo:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Lamanna:Acerta: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Punnoose:Genentech Inc: Employment; Roche: Equity Ownership. Jiang:Genentech Inc: Employment, Equity Ownership. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Boyer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Kater:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-184

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. 21 ( 2021-11-25), p. 2148-2152

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2021011121

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 829-829

Abstract: Introduction BCL2 is an anti-apoptotic protein overexpressed in CLL and critical in the pathogenesis of the disease; venetoclax (VEN) is an orally available, selective BCL2 inhibitor. Bendamustine (B) and rituximab (R) combination has demonstrated efficacy in relapsed/refractory (R/R) and previously untreated (frontline, 1L) patients (pts) with CLL. Preclinical data suggest that VEN+BR may provide synergistic activity in pts with CLL. Clinical data from VEN, both as a single-agent and in combination with R, support VEN+BR combination in CLL. We report an ongoing phase 1b study (NCT01671904) that is evaluating as primary objectives the maximum tolerated dose (MTD) of VEN when combined with BR, plus safety, tolerability, and order of administration to reduce toxicities of this combination in R/R or 1L CLL pts. Methods Pts with ECOG PS ≤1, 0-3 prior chemotherapy lines, and adequate marrow, hepatic, renal and coagulation function are being enrolled in dose finding cohorts and subsequent safety expansion cohorts, ranging from VEN 100 to 400 mg/day (3+3 dose escalation design). Pts are assigned to one of two dosing schedules (Fig 1) with VEN (Schedule A) or BR (Schedule B) introduced first; both include a gradual VEN dose ramp-up and other prophylactic measures to reduce the risk of tumor lysis syndrome (TLS) and risk stratification for TLS (high, intermediate and low). On completing combination therapy, pts continue single-agent VEN until disease progression (R/R CLL) or up to 18 months (1L CLL). Dose-limiting toxicity (DLT) data are reviewed after all pts in a cohort have completed 21 days of combination treatment at the target VEN dose and focus on TLS and cytopenias. Efficacy is assessed by investigators (iwCLL guidelines; Hallek et al. 2008). Results At data cutoff (April 30, 2015), 30 pts have been treated; 20 R/R pts, 12 on Schedule A (3 at 100 mg, 3 at 200 mg, and 6 at 400 mg) and 8 on Schedule B (all at 400 mg), and 10 1L pts, 6 on Schedule A and 4 on Schedule B (all at 400 mg). Baseline characteristics are shown in Fig 2. Of 10 pts with reported cytogenetics, 2 have del(17p). Median time on study is 5.5 (range, 0.03-15.2) months. No safety difference between Schedules A and B was seen in the DLT observation period for R/R CLL pts; neither schedule exhibited any toxicities precluding choice of the highest administered dose of 400 mg daily VEN. Schedule B was chosen for R/R safety expansion due to potential for tumor debulking prior to VEN. Dose finding in 1L Schedule A also selected 400 mg; dose finding for Schedule B is ongoing. Of 30 safety-evaluable, 27 (90%) pts experienced any adverse event (AEs; Fig 3). Most common AEs were neutropenia and nausea. Most G3 AEs were hematological toxicities; common non-hematological included diarrhea and hypertension. No TLS events (laboratory or clinical) were observed. There were 13 serious AEs in 10 (33.3%) pts, 8 (26.7%) due to study treatment. No deaths were reported. Of all 30 pts, 25 received VEN, with 5 still completing the BR only portion of Schedule B. Dose interruptions were seen in 13 pts mainly due to neutropenia for both VEN and BR; 8 pts had a VEN dose reduction. Early drug discontinuations (any reason): VEN, 2pts (gastroenteritis norovirus, progressive disease); BR together, 3 pts; B, 7 pts (commonly for neutropenia or physician decision); R, 1 pt. Across cohorts, 17/20 R/R CLL pts had response assessments; 100% responded, with 3 CRi. Response evaluation for 1L pts is early and evaluation across all cohorts and patients is ongoing. Full MRD data will be presented at the meeting, but early analysis shows pts exhibiting MRD negativity in peripheral blood, many as early as Cycle 4. Conclusion These early results report the first study evaluating the VEN+BR combination in pts with CLL. Daily VEN 400 mg can be safely combined with BR in patients with R/R CLL using both administration schedules (VEN or BR first), with 400 mg also established as safe for 1L pts with CLL under Schedule A. No TLS was observed with either administration schedule, despite many pts at medium (53%) or high (33%) TLS risk. VEN+BR is, as expected, associated with frequent hematologic toxicity, which appears manageable in most pts being treated, although 10 pts discontinued either B or BR prior to completing 6 cycles of administration. Early response and MRD data are promising. Disclosures Salles: Celgene Corporation; Roche: Speakers Bureau; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Boyd:Genentech, Inc.: Research Funding; Celgene: Speakers Bureau; US Oncology: Research Funding. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Wendtner:Roche: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Hallek:Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding. Eichhorst:AbbVie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Kozloff:Genentech: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; AbbVie: Consultancy. Cartron:Gilead: Honoraria; GSK: Honoraria; Celgene: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Li:Genentech, Inc.: Employment. Hilger:Genentech, Inc.: Employment. Mobasher:Genentech, Inc.: Employment. Stilgenbauer:Roche: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.829.829

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1859-1859

Abstract: Introduction Anti-apoptotic protein BCL2 is overexpressed in hematologic malignancies such as CLL. BCL2 inhibitor VEN has shown profound efficacy when combined with B and anti-CD20 antibodies G and R, all of which are established components of CLL therapy. Pre-clinical and early clinical data in R/R CLL suggest addition of VEN to BR or BG may improve efficacy. Here we present data from a Phase Ib study of VEN in combination with BR/BG evaluated for first line (1L) CLL patients (pts). Methods This single-arm, open-label study had dose-finding (3 + 3 design) and subsequent safety-expansion stages. 1L CLL pts with ECOG PS ≤1, adequate marrow and organ function, who were in need of treatment, were first enrolled to BR-VEN, then safety data were reviewed before initiation of the BG-VEN cohort and expansions. In dose finding, 2 dosing schedules were assessed: a) Cycle 1: VEN ramp up introduced before BR/BG or b) Cycle 1: BR/BG loading dose introduced before VEN ramp up, with 1 schedule to be chosen for expansion. Pts were to receive 6 (28-day) cycles of BR/BG-VEN followed by 6 mo of VEN single agent for an overall treatment duration of 1 yr. VEN single agent could be extended upon request of the treating physician if pts were bone marrow (BM) minimal residual disease (MRD) positive and/or had partial response. Objectives were maximum tolerated dose of BR/BG-VEN, safety/tolerability of the combinations and efficacy, including undetectable MRD ( 〈 1 CLL cell/104 leukocytes) rate by 5-color flow cytometry. Disease response was assessed by investigators per iwCLL 2008. Pooled data from dose finding and safety expansion for each combination are presented. Results During dose finding, no dose-limiting toxicities were observed; schedule b (BR/BG before VEN) and VEN 400mg were recommended for safety expansion. As of June 1 2018, 50 pts were enrolled overall (baseline characteristics in Table 1): 49 pts received ≥1 dose of any study drug (27 BR-VEN, 22 BG-VEN), and 45 (26 BR-VEN, 19 BG-VEN) were evaluable for efficacy. 41% pts (11/27 BR-VEN, 9/22 BG-VEN) completed 6 combination cycles. Median B cycles: 5 (1-6) in both cohorts. Median VEN duration: 371 days (4-1082) BR-VEN, 336 days (11-543) BG-VEN. 8 pts in each cohort had VEN beyond planned 1 yr (14 still on VEN, 2 stopped as of cut-off date). Median time on study: 26 mo (3-43) BR-VEN and 18 mo (1-33) BG-VEN. VEN dose reductions/interruptions occurred in 82% pts (22/27 BR-VEN, 18/22 BG-VEN). 14 pts (8 BR-VEN, 6 BG-VEN) discontinued VEN due to AEs. All pts experienced ≥1 AE. Most common Gr 3-4 AEs: neutropenia (85% BR-VEN, 55% BG-VEN) and thrombocytopenia (37% BR-VEN, 50% BG-VEN; Table 2). No clinical tumor lysis syndrome (TLS) was observed; laboratory TLS was seen in 1 pt with BG before any VEN was given. 1 fatal AE occurred (hemorrhagic transformation after stroke in BR-VEN cohort, onset on Day 82). Infections (all-Gr/Gr 3-4) were observed in 70/0% with BR-VEN and 73/27% with BG-VEN. All pts responded to treatment; objective rates were consistent among pts with del(17p) and/or TP53 mutation (mut) and IGHV unmut status or number of B cycles received (6 vs 〈 6; Table 3). Half of pts achieved a complete response (CR) with each combination. Undetectable MRD was seen in most pts; full data on peripheral blood and BM MRD will be presented at the meeting. As of the cut-off date, only 1 pt experienced PD (in BR cohort), there was no Richter transformation in either cohort. Estimated 18-mo PFS was 96% with BR-VEN and 100% with BG-VEN. Conclusion VEN 400mg daily combined with BR or BG in 1L CLL treatment was associated with toxicity leading to treatment interruptions and discontinuations; the most frequently reported toxicities were hematologic. However, despite dose modifications, all pts responded to treatment, independently of subgroups. 50% of pts achieved a CR/CRi; higher than previously reported with BG or BR alone (Brown et al. Blood 2015; Michallet et al. Haematologica 2018). Responses were durable and preliminary PFS data are encouraging. Response rates were similar, irrespective of whether pts received planned 6 or fewer cycles of B; the optimal number of B cycles and general benefit of B in combination with R-VEN or G-VEN should be examined further with longer follow-up. No marked differences in quality of clinical responses were observed when VEN was combined with BR or BG. Updated MRD data will provide a better understanding of the efficacy of these combination regimens compared with backbone chemo-free regimens. Disclosures Stilgenbauer: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morschhauser:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees. Wendtner:Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Cartron:Roche: Consultancy, Honoraria; Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Sanofi: Honoraria. Hallek:Abbvie: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Kozloff:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lozanski:Novartis: Research Funding; BI: Research Funding; Stem Line: Research Funding; Beckman: Research Funding; Coulter: Research Funding; Genentech: Research Funding. Jiang:Genentech Inc: Employment, Equity Ownership. Huang:F. Hoffmann La Roche: Employment. Pignataro:Roche Products Limited: Employment. Schary:AbbVie: Employment. Humphrey:Roche Products Limited: Employment. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Salles:Gilead: Honoraria, Other: Advisory Board; Epizyme: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Other: Advisory Board; Merck: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Morphosys: Honoraria; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Abbvie: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Honoraria; Servier: Honoraria, Other: Advisory Board; Servier: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-118362

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7