Kooperativer Bibliotheksverbund

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 1 ( 2018-01-01), p. 189-196

Abstract: Purpose: In 2010, a Children's Oncology Group (COG) phase III randomized trial for patients with high-risk neuroblastoma (ANBL0032) demonstrated improved event-free survival (EFS) and overall survival (OS) following treatment with an immunotherapy regimen of dinutuximab, GM-CSF, IL2, and isotretinoin compared with treatment with isotretinoin alone. Dinutuximab, a chimeric anti-GD2 monoclonal antibody, acts in part via natural killer (NK) cells. Killer immunoglobulin-like receptors (KIR) on NK cells and their interactions with KIR-ligands can influence NK cell function. We investigated whether KIR/KIR-ligand genotypes were associated with EFS or OS in this trial. Experimental Design: We genotyped patients from COG study ANBL0032 and evaluated the effect of KIR/KIR-ligand genotypes on clinical outcomes. Cox regression models and log-rank tests were used to evaluate associations of EFS and OS with KIR/KIR-ligand genotypes. Results: In this trial, patients with the “all KIR-ligands present” genotype as well as patients with inhibitory KIR2DL2 with its ligand (HLA-C1) together with inhibitory KIR3DL1 with its ligand (HLA-Bw4) were associated with improved outcome if they received immunotherapy. In contrast, for patients with the complementary KIR/KIR-ligand genotypes, clinical outcome was not significantly different for patients who received immunotherapy versus those receiving isotretinoin alone. Conclusions: These data show that administration of immunotherapy is associated with improved outcome for neuroblastoma patients with certain KIR/KIR-ligand genotypes, although this was not seen for patients with other KIR/KIR-ligand genotypes. Further investigation of KIR/KIR-ligand genotypes may clarify their role in cancer immunotherapy and may enable KIR/KIR-ligand genotyping to be used prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens. Clin Cancer Res; 24(1); 189–96. ©2017 AACR. See related commentary by Cheung and Hsu, p. 3

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-17-1767

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2018

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detail.hit.zdb_id: 2036787-9

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. LB-048-LB-048

Abstract: Introduction: High-risk neuroblastoma (NBL) patients (pts) enrolled in a COG Phase 3 clinical trial (ANBL0032) were randomized to isotretinoin (RA) alone or Immunotherapy: dinutuximab (anti-GD2 mAb) + IL2 + GMCSF + RA (Yu et al., NEJM, 2010). Dinutuximab acts via antibody-dependent cell-mediated cytotoxicity by innate immune cells, including NK cells. NK cells express Killer Immunoglobulin-like Receptors (KIRs); most of the inhibitory KIRs have KIR-ligands that belong to the HLA class I family. Specifically, KIR2DL1 is a receptor for HLA-C2, KIR2DL2 and KIR2DL3 are receptors for HLA-C1, and KIR3DL1 is a receptor for HLA-Bw4. Some prior studies of anti-GD2 mAb immunotherapies have shown associations with outcome based on the genotypes of these inhibitory KIR/KIR ligand relationships. We investigated whether certain KIR/KIR-ligand genotypes were associated with event-free survival (EFS) and overall survival (OS) in this trial. Methods: Of the 226 pts randomized, 174 pts had DNA allowing evaluation of genotype correlations with outcome (RA: n=86; Immunotherapy: n=88; & gt;5yr follow-up if no event). We looked for associations of inhibitory KIRs with their respective KIR-ligands and clinical outcome. Log-rank tests and Cox proportional hazards regression models were used to compare EFS/OS by genotype group; adjustment was made for non-proportional hazards as needed using time-dependent covariates. Results: We found that certain, hypothesis-identified, inhibitory KIR/KIR-ligand combinations were associated with improved clinical outcome. Namely, pts that were both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+ had improved EFS and OS if treated with Immunotherapy (n=23) vs. RA (n=26) (5-yr EFS: 61% vs. 27%, p=0.02; 5-yr OS: 91% vs. 34%, p=0.007). Conversely, for pts that were not both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+, we found insufficient evidence to support an improvement in EFS or OS with Immunotherapy (n=65) vs. RA (n=60) (5-yr EFS: 57% vs. 53%, p=0.76; 5-yr OS: 68% vs. 68%, p=0.66). Conclusions: Our data suggest that KIR/KIR-ligand genotype may be predictive of benefit from Immunotherapy. The impact of immunotherapy appears different for pts that were both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+ vs. those that were not both KIR2DL2+/HLA-C1+ and KIR3DL1+/HLA-Bw4+. Validation of these KIR/KIR-ligand associations in similarly treated high-risk NBL patients would be required prior to proposing their prospective use in the aid of clinical treatment decisions. Further investigation of KIR/KIR-ligand genotypes may also clarify their role and the role of NK cells in the activity of this form of cancer immunotherapy. Citation Format: Amy K. Erbe, Wei Wang, Lakeesha Carmichael, KyungMann Kim, Patrick K. Reville, Wendy B. London, Jacquelyn A. Hank, Mitchell B. Diccianni, Arlene Naranjo, Michael Hogarty, Julie R. Park, Alice L. Yu, Paul M. Sondel. Impact of KIR/KIR ligand genotype for neuroblastoma patients in a Phase 3 COG immunotherapy trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-048. doi:10.1158/1538-7445.AM2017-LB-048

Type of Medium: Online Resource

ISSN: 0008-5472 , 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2017-LB-048

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2017

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detail.hit.zdb_id: 1432-1

detail.hit.zdb_id: 410466-3

In: Nature Communications, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2024-02-28)

Abstract: Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.

Type of Medium: Online Resource

ISSN: 2041-1723

URL: Article

DOI: 10.1038/s41467-024-45916-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2024

detail.hit.zdb_id: 2553671-0

In: Frontiers in Immunology, Frontiers Media SA, Vol. 8 ( 2017-06-12)

Type of Medium: Online Resource

ISSN: 1664-3224

URL: Article

DOI: 10.3389/fimmu.2017.00675

Language: Unknown

Publisher: Frontiers Media SA

Publication Date: 2017

detail.hit.zdb_id: 2606827-8

In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 8, No. 11 ( 2015-11-01), p. 1036-1044

Abstract: We hypothesized that soy phytochemicals may have immunomodulatory properties that may affect prostate carcinogenesis and progression. A randomized, phase II trial was conducted in 32 patients with prostate cancer with asymptomatic biochemical recurrence but no measurable disease on standard staging studies. Patients were randomized to two slices of soy bread (34 mg isoflavones/slice) or soy bread containing almond powder daily as a source of β-glucosidase. Flow cytometry and bioplex assays were used to measure cytokines or immune cell phenotype in blood at baseline (day 0) and following intervention (day 56). Adequate blood samples were available at enrollment and day 56 and evaluated. Multiple plasma cytokines and chemokines were significantly decreased on day 56 versus baseline. Subgroup analysis indicated reduced TH1 (P = 0.028) and myeloid-derived suppressor cell (MDSC)-associated cytokines (P = 0.035). TH2 and TH17 cytokines were not significantly altered. Phenotypic analysis revealed no change in CD8+ or CD4+ T cells but showed increased CD56+ natural killer (NK) cells (P = 0.038). The percentage of cells with a T regulatory cell phenotype (CD4+CD25+FoxP3+) was significantly decreased after 56 days of soy bread (P = 0.0136). Significantly decreased monocytic (CD33+HLADRnegCD14+) MDSC were observed in patients consuming soy bread (P = 0.0056). These data suggest that soy bread modulates systemic soluble and cellular biomarkers consistent with limiting inflammation and suppression of MDSCs. Additional studies to elucidate impact on the carcinogenic process or as a complement to immune-based therapy are required. Cancer Prev Res; 8(11); 1036–44. ©2015 AACR.

Type of Medium: Online Resource

ISSN: 1940-6207 , 1940-6215

URL: Article

DOI: 10.1158/1940-6207.CAPR-14-0464

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2015

detail.hit.zdb_id: 2422346-3

In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 7, No. 1 ( 2019-12)

Type of Medium: Online Resource

ISSN: 2051-1426

URL: Article

DOI: 10.1186/s40425-019-0538-8

Language: English

Publisher: BMJ

Publication Date: 2019

detail.hit.zdb_id: 2719863-7

In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 11, No. 7 ( 2023-07-05), p. 1011-1028

Abstract: Comprehensive investigation of CD8+ T cells in acute myeloid leukemia (AML) is essential for developing immunotherapeutic strategies beyond immune checkpoint blockade. Herein, we performed single-cell RNA profiling of CD8+ T cells from 3 healthy bone marrow donors and 23 newly diagnosed (NewlyDx) and 8 relapsed/refractory (RelRef) patients with AML. Cells coexpressing canonical exhaustion markers formed a cluster constituting & lt;1% of all CD8+ T cells. We identified two effector CD8+ T-cell subsets characterized by distinct cytokine and metabolic profiles that were differentially enriched in NewlyDx and RelRef patients. We refined a 25-gene CD8-derived signature correlating with therapy resistance, including genes associated with activation, chemoresistance, and terminal differentiation. Pseudotemporal trajectory analysis supported enrichment of a terminally differentiated state in CD8+ T cells with high CD8-derived signature expression at relapse or refractory disease. Higher expression of the 25-gene CD8 AML signature correlated with poorer outcomes in previously untreated patients with AML, suggesting that the bona fide state of CD8+ T cells and their degree of differentiation are clinically relevant. Immune clonotype tracking revealed more phenotypic transitions in CD8 clonotypes in NewlyDx than in RelRef patients. Furthermore, CD8+ T cells from RelRef patients had a higher degree of clonal hyperexpansion associated with terminal differentiation and higher CD8-derived signature expression. Clonotype-derived antigen prediction revealed that most previously unreported clonotypes were patient-specific, suggesting significant heterogeneity in AML immunogenicity. Thus, immunologic reconstitution in AML is likely to be most successful at earlier disease stages when CD8+ T cells are less differentiated and have greater capacity for clonotype transitions.

Type of Medium: Online Resource

ISSN: 2326-6066 , 2326-6074

URL: Article

DOI: 10.1158/2326-6066.CIR-22-0961

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2023

detail.hit.zdb_id: 2732517-9

In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5788-5788

Abstract: Introduction: The discovery of immune checkpoint inhibitors has revolutionized metastatic renal cell carcinoma (RCC) treatment. However, in patients with RCC brain metastases, response rates are low and survival outcomes poor. To understand the tumor microenvironmental differences between primary kidney tumors, extracranial metastases, and brain metastases, we developed a detailed single-cell atlas of RCC brain metastases along with their matched extracranial and primary tumors. Methods: We performed single-nucleus RNA-seq on 27 samples (nearly 200,000 cells) from RCC patients; samples included 14 brain metastases, 8 matched primary kidney tumors, and 5 matched extracranial metastases. We performed multiplex IHC to validate selected transcriptomic findings. We used Nanostring CosMx 960-plex RNA spatial molecular imaging technique on selected samples to validate cellular interactions in a spatial context. Results: We established a multi-tissue single-cell atlas of RCC brain metastases by identifying 9 major and 37 minor malignant, immune, and stromal cell clusters. Brain metastases had higher neuronal and glial cells interacting with immune and tumor cells. Brain metastasis tumor cells were also transcriptomically reprogrammed to adapt to the brain microenvironment through enrichment of MYC targets, MTORC1 signaling, epithelial-mesenchymal transition, fatty-acid metabolism, oxidative phosphorylation, and reactive oxygen species pathways. Moreover, cell-to-cell communication and downstream target gene expression analyses showed that brain metastasis tumor cells expressed ligands and receptors that induce tumor cell proliferation in both autocrine and paracrine fashions. Among T-cell populations, we found fewer proliferating cytotoxic T lymphocytes in the brain than in other sites. Moreover, T cells in brain metastases expressed higher levels of several targetable inhibitory checkpoints than did extracranial metastases. In addition, we found that naïve/memory T cells in brain metastases were a favorable prognostic marker for overall survival after craniotomy. Our characterization of myeloid cell populations across the 3 disease sites found fewer dendritic cells and monocytes in the brain compared to other sites. Macrophages in brain metastases more highly expressed an M2 immunosuppressive gene signature than did those in primary RCC tumors. Conclusion: Our findings from the largest single-cell atlas of RCC brain metastases with matched primary and extracranial metastases suggest several unique targetable, immunosuppressive biological mechanisms in the brain microenvironment. These results provide a foundation for a deeper understanding of RCC brain metastasis biology and can serve as a resource for the scientific community to further explore therapeutically targetable tumor and immune-related mechanisms. Citation Format: Elshad Hasanov, Truong Nguyen Anh Lam, Jerome Lin, Patrick K. Reville, Merve Hasanov, Anna K. Casasent, David Shih, Sahin Hanalioglu, Mehmet Asim Bilen, Omar Alhalabi, Berrin Babaoglu, Baylar Baylarov, Adeboye O. Osunkoya, Lisa M. Norberg, Joy Gumin, Tuan M. Tran, Jianzhuo Li, Anh G. Hoang, Haidee D. Chancoco, Brittany C. Parker Kerrigan, Erika J. Thompson, Betty YS Kim, Dima Suki, Melike Mut, Figen Soylemezoglu, Giannicola Genovese, Kadir C. Akdemir, Hussain A. Tawbi, Nizar M. Tannir, Florencia McAllister, Michael A. Davies, Padmanee Sharma, Jason Huse, Frederick Lang, Nicholas Navin, Eric Jonasch. Single-cell and spatial transcriptomic mapping of human renal cell carcinoma brain metastases uncovers actionable immune-resistance targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5788.

Type of Medium: Online Resource

ISSN: 1538-7445

URL: Article

DOI: 10.1158/1538-7445.AM2023-5788

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2023

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detail.hit.zdb_id: 410466-3

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 7-9

Abstract: Background Addition of the BCL2 inhibitor venetoclax to lower intensity therapy improved survival (OS) for older and unfit patients with newly diagnosed AML. We have previously reported the safety and efficacy of the nucleoside analogue cladribine combined with high dose ara-C and idarubicin (ida) as an intensive induction regimen (CLIA) in patients with newly diagnosed AML. Here, we report the results of the combination of venetoclax with the CLIA regimen for younger, fit patients with newly diagnosed AML. Methods Patients & lt; 65 years of age with newly diagnosed AML or high-risk MDS were enrolled (NCT02115295). Induction was cladribine 5 mg/m2 IV on D1-5, ara-C 1.5 g/m2 IV on D1-5, and idarubicin 10 mg/m2 IV on D1-3; venetoclax was given at an effective dose of 400mg PO on D2-8 without ramp up with every cycle. Consolidation consisted of 3d of CLIA (2d of ida). AML patients with FLT3-ITD or FLT3 point mutations could receive midostaurin on D6-19 or gilteritinib on D1-14 for induction, and continuously thereafter. Venetoclax dose modifications for CYP3A4 inhibitors were made. All patients underwent baseline next generation sequencing and MRD testing by multiparameter flow cytometry at the time of response. Results A total of 31 patients have been enrolled. The median age was 48 years (range, 18-64). Baseline characteristics are shown in Table 1. Median follow up is 8.8 months. All patients were evaluable for response, with 28 of 31 (90%) achieving a remission, including 23 (74%) complete remission (CR) and 5 (16%) CR with incomplete count recovery (CRi) (Table 1). Of the 2 patients that did not respond, one was ELN adverse risk with TP53 mutation and complex karyotype, the other was ELN favorable risk with a t(8;21) translocation and mutations in IDH1 and JAK2. At time of initial response assessment 19 of 30 (63%) had undetectable MRD, with another 4 patients (77%) becoming MRD negative overall. Median cycles until response was 1 (range: 1 - 2), and patients have received a median of 2 cycles (range: 1 - 5). Median time to absolute neutrophil count ≥ 1000/µL was 32 days (range: 18 - 49) and platelet count ≥ 50k and 100k/µL were 29 days (range: 17 - 61) and 32 days, respectively after induction. 8 patients received FLT3 inhibition (FLT3i) in addition to CLIA and venetoclax, 7 (88%) with gilteritinib and 1 (12%) with midostaurin. Within this subset, there were 6/8 (75%) CR and 1 CR (12%) (Table 2). Median overall survival (OS) for those receiving FLT3i is not yet reached (95% CI: 0.79 - NE months). Median duration of response for the entire cohort is not reached. At 6 and 12 months 87% of responders had an ongoing response (SE=9%). 18 of 28 (64%) of responders received an allogeneic stem cell transplant. Median OS has not been reached, with 6- and 12-month rates of OS 93% (SE=5%) and 81% (SE=9%), respectively (Figure 1). Median OS in all ELN risk categories has not yet been reached, with 6 month OS of 91% (SE=9%), 100% (SE=NA), and 83% (SE=15%) in favorable, intermediate, and adverse risk groups, respectively (Figure 2). Median event free survival (EFS) has not been reached, with 6- and 12-month rates of EFS are 90% (SE=5%) and 79% (SE=9%), respectively. Overall the regimen was well tolerated, with an acceptable toxicity profile. Tumor lysis syndrome was not seen. The most common Grade & gt;/= 3 adverse events were neutropenic fever, pneumonia, nausea, and liver transaminitis. There was one induction death in the FLT3i cohort and none with CLIA + venetoclax. Conclusion Venetoclax added to CLIA was safe and highly effective in newly diagnosed pts with AML and high risk MDS, including patients with FLT3-mutated AML and adverse risk by ELN or IPSS-R. The addition of FLT3i may be associated with delayed count recovery. CLIA plus venetoclax provided high rates of durable MRD negative remissions and encouraging event-free and overall survival across prognostic subgroups. Disclosures Kantarjian: BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Delta Fly: Honoraria; Ascentage: Research Funding; Janssen: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Oxford Biomedical: Honoraria. Borthakur:Abbvie: Research Funding; BioLine Rx: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Jannsen: Research Funding; GSK: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Argenx: Consultancy; AstraZeneca: Research Funding; Cyclacel: Research Funding; PTC Therapeutics: Consultancy; PTC Therapeutics: Research Funding; Novartis: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; Incyte: Research Funding; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding. Yilmaz:Daicho Sankyo: Research Funding; Pint Pharma: Honoraria; Pfizer: Research Funding. DiNardo:ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; MedImmune: Honoraria; Syros: Honoraria; Novartis: Consultancy. Andreeff:Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jain:Aprea Therapeutics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Alvarado:Daiichi-Sankyo: Research Funding; BerGenBio ASA: Research Funding; Tolero Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; FibroGen: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Research Funding. Bose:Constellation Pharmaceuticals: Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Astellas Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Promedior, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kartos Therapeutics: Honoraria, Research Funding. Garcia-Manero:Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Amphivena Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Onconova: Research Funding; Novartis: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Konopleva:Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Ablynx: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; Amgen: Consultancy; Agios: Research Funding; AstraZeneca: Research Funding; Eli Lilly: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Kisoji: Consultancy; AbbVie: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Forty-Seven: Consultancy, Research Funding. Ravandi:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Kadia:Amgen: Research Funding; Cellenkos: Research Funding; Cyclacel: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Pulmotec: Research Funding; Incyte: Research Funding; Pfizer: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-141075

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 367-367

Abstract: Background The combination of venetoclax and 5-azacytidine (5-AZA) for older and unfit patients with newly diagnosed AML has led to significant improvements in remission rates and survival compared to 5-AZA alone. We previously reported encouraging results with a low-intensity backbone of CLAD/LDAC alternating with a hypomethylating agent (HMA) for older patients with AML observing better outcomes than historical experience with HMA alone. We hypothesized that the addition of venetoclax to the CLAD/LDAC alternating with HMA backbone may further improve outcomes for an expanded cohort of older patients with newly diagnosed AML. Methods This is a phase II study investigating the combination of venetoclax with CLAD/LDAC alternating with AZA in older (age ≥ 60y) or unfit patients with newly diagnosed AML (excluding APL, CBF). The primary objective was composite complete response rate (CRc; CR+CRi); secondary endpoints were overall survival (OS), disease-free survival (DFS), overall response rate (ORR), and toxicity. Induction was cladribine 5 mg/m 2 IV over 30 minutes on D1-5 and araC 20mg SQ BID on D1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m 2 IV on D1-3 and araC 20 mg SQ BID on D1-10 alternating with 2 cycles of AZA 75 mg/m 2 on D1-7, for up to 18 cycles. Venetoclax 400 mg was added on days 1-21 of each cycle with dose adjustments for concomitant CYP3A inhibitors. One cycle was 4 weeks and up to 2 cycles of induction were allowed. Results A total of 60 patients were treated on study with a median age was 68 years (IQR 64 - 73, range: 57 - 84); 22 (37%) patients were ≥ 70 yrs and 1 pt & lt; 60 yrs who was unfit for intensive chemotherapy was enrolled. 14 (23%) patients had secondary AML (sAML). 36 (60%) had diploid cytogenetics with 12 (20%) patients having adverse cytogenetics at enrollment. By European Leukemia Network (ELN) risk, 23%, 33%, and 43% were favorable, intermediate, and adverse risk, respectively. The most commonly mutated genes were NPM1 in 21 patients (33%), DNMT3A in 20 (32%), TET2 in 18 (30%), SRSF2 in 15 (25%), NRAS in 12 (20%), IDH2 in 11 (18%), RUNX1 in 11 (18%), and ASXL1 in 9 (15%). TP53 was mutated in 4 (7%) patients. Baseline characteristics are summarized in table 1. Among 60 evaluable patients the CRc rate was 93%. Best response was CR in 48 (80%), CRi in 8 (13%), no response in 3 (5%), and death in 1 (2%) patient. Responses are summarized in Figure A. In responding patients with a bone marrow sample evaluable for assessment of measurable residual disease (MRD), 43/51 (84%) were negative for MRD at response assessment. Among patients with sAML, with adverse karyotype, or ELN adverse risk the CR/CRi rate was 86% (64%/21%), 83% (58%/25%), and 96% (81%/15%) respectively. 19 (34%) responders received a subsequent allogeneic stem cell transplantation. Early mortality was low with one patient (2%) dying within 4 weeks and four patients (7%) dying with in 8 weeks. Responses are summarized in table 2. The most frequent grade 3/4 non-heme adverse events were febrile neutropenia (n=10), pneumonia (n=5), atrial fibrillation (n=2), and allergic reaction (n=2). One patient developed grade 4 tumor lysis syndrome. With a median follow up of 20.4 months, the median duration of response (DOR) is not reached (95% CI: 18 - NE months). Estimated 12- and 24-month DOR are 69.2% (95% CI: 57.5 - 83.1%) and 60.5% (95% CI: 47.7 - 76.8%), respectively. Median OS is not yet reached (95% CI: 21 - NE months). Estimated 12- and 24-month OS are 71.5% (95% CI: 60.5 - 84.5%) and 60.4% (95% CI: 47.7 - 76.6%), respectively (figure B). The estimated 12-month OS for patients aged & lt;70 years and ≥70 years was 75% and 73%, respectively. Median DFS is not yet reached (95% CI: 18.0 - NE months). Estimated 12- and 24-month DFS are 69.2% (95% CI: 57.5 - 83.1%) and 60.5% (95% CI: 47.7 - 76.6%), respectively (figure C). Conclusion CLAD/LDAC plus venetoclax alternating with AZA plus venetoclax is an effective, lower-intensity regimen that is well tolerated among older patients (≥ 60 years) with newly diagnosed AML, producing high response rates with durable MRD negative remissions. The rates of overall and disease-free survival are encouraging in this cohort of older AML patients with comparable efficacy in patients ≥70 as in patients & lt;70 years old. Further study of this non-anthracycline containing backbone in younger patients unfit for intensive chemotherapy, as well as comparisons to standard frontline therapies are warranted. Figure 1 Figure 1. Disclosures Kantarjian: AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria; Ascentage: Research Funding; BMS: Research Funding; Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Astellas Health: Honoraria; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Precision Biosciences: Honoraria; NOVA Research: Honoraria. Borthakur: Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pemmaraju: Affymetrix: Consultancy, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Sager Strong Foundation: Other; LFB Biotechnologies: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; Aptitude Health: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; CareDx, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Plexxicon: Other, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Roche Diagnostics: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. DiNardo: Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Daver: Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Hanmi: Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Short: Novartis: Honoraria; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; Amgen: Consultancy, Honoraria. Jain: Incyte: Research Funding; Genentech: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; Janssen: Honoraria; Servier: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; Aprea Therapeutics: Research Funding; TG Therapeutics: Honoraria; Precision Biosciences: Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Ferrajoli: AstraZeneca: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board ; BeiGene: Other: Advisory Board, Research Funding. Takahashi: Novartis: Consultancy; Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Andreeff: Senti-Bio: Consultancy; Karyopharm: Research Funding; ONO Pharmaceuticals: Research Funding; Aptose: Consultancy; Medicxi: Consultancy; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Breast Cancer Research Foundation: Research Funding; Amgen: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy; AstraZeneca: Research Funding; Oxford Biomedica UK: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy. Konopleva: AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Cellectis: Other: grant support; AstraZeneca: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Ascentage: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Agios: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights. Ravandi: AstraZeneca: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Agios: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Astex: Honoraria, Research Funding; Taiho: Honoraria, Research Funding. Kadia: Liberum: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Genfleet: Other; AstraZeneca: Other; Sanofi-Aventis: Consultancy; Ascentage: Other; Astellas: Other; Cellonkos: Other; Pulmotech: Other; Pfizer: Consultancy, Other; Amgen: Other: Grant/research support; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-147360

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7