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In: Leukemia Research, Elsevier BV, Vol. 61 ( 2017-10), p. 25-32

Type of Medium: Online Resource

ISSN: 0145-2126

URL: Article

DOI: 10.1016/j.leukres.2017.08.009

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 2008028-1

In: Transplantation and Cellular Therapy, Elsevier BV, Vol. 27, No. 11 ( 2021-11), p. 885-907

Type of Medium: Online Resource

ISSN: 2666-6367

URL: Article

DOI: 10.1016/j.jtct.2021.08.016

Language: English

Publisher: Elsevier BV

Publication Date: 2021

detail.hit.zdb_id: 3056525-X

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 14 ( 2021-05-10), p. 1584-1594

Abstract: Approximately 20% of patients with TP53-mutant myelodysplastic syndromes (MDS) achieve complete remission (CR) with hypomethylating agents. Eprenetapopt (APR-246) is a novel, first-in-class, small molecule that restores wild-type p53 functions in TP53-mutant cells. METHODS This was a phase Ib/II study to determine the safety, recommended phase II dose, and efficacy of eprenetapopt administered in combination with azacitidine in patients with TP53-mutant MDS or acute myeloid leukemia (AML) with 20%-30% marrow blasts (ClinicalTrials.gov identifier: NCT03072043 ). RESULTS Fifty-five patients (40 MDS, 11 AML, and four MDS/myeloproliferative neoplasms) with at least one TP53 mutation were treated. The overall response rate was 71% with 44% achieving CR. Of patients with MDS, 73% (n = 29) responded with 50% (n = 20) achieving CR and 58% (23/40) a cytogenetic response. The overall response rate and CR rate for patients with AML was 64% (n = 7) and 36% (n = 4), respectively. Patients with only TP53 mutations by next-generation sequencing had higher rates of CR (69% v 25%; P = .006). Responding patients had significant reductions in TP53 variant allele frequency and p53 expression by immunohistochemistry, with 21 (38%) achieving complete molecular remission (variant allele frequency 〈 5%). Median overall survival was 10.8 months with significant improvement in responding versus nonresponding patients by landmark analysis (14.6 v 7.5 months; P = .0005). Overall, 19/55 (35%) patients underwent allogeneic hematopoietic stem-cell transplant, with a median overall survival of 14.7 months. Adverse events were similar to those reported for azacitidine or eprenetapopt monotherapy, with the most common grade ≥ 3 adverse events being febrile neutropenia (33%), leukopenia (29%), and neutropenia (29%). CONCLUSION Combination treatment with eprenetapopt and azacitidine is well-tolerated yielding high rates of clinical response and molecular remissions in patients with TP53-mutant MDS and oligoblastic AML.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.20.02341

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2021

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 246-246

Abstract: Introduction:  TP53 gene mutations (m TP53), found in up to 20% of MDS or AML pts and 30-40% of therapy-related (TR) MDS/AML cases, represent a distinct molecular cohort with poor outcomes. Hypomethylating agents (HMA) are the frontline standard of care, with CR rates of ~20% and median OS of & lt; 12 months. APR-246 is a novel, first-in-class small molecule that reactivates the mutant p53 protein and targets cellular redox balance, ultimately inducing apoptosis and ferroptosis in m TP53 cancer cells. We previously reported the Phase 2 results of 2 parallel trials of APR-246+AZA (Sallman et al and Cluzeau et al., JCO 2021). We now report analyses of the combined Phase 2 cohorts and long-term follow-up. Methods: This is a multicenter, international collaboration of the US MDS clinical research consortium and the GFM of HMA-naïve m TP53 higher-risk MDS, MDS/MPN and oligoblastic AML (≤ 30% blasts) pts (NCT03072043/NCT03588078). Pts received APR-246 4500mg IV (days 1-4) + AZA 75 mg/m 2 SC/IV x 7 days (days 4-10 or 4-5 and 8-12) in 28-day cycles. Primary objective was CR rate by International Working Group (IWG) 2006 criteria. Secondary objectives included ORR, OS, outcome following allogeneic hematopoietic stem cell transplant (allo-HSCT), with serial high depth next generation sequencing (NGS, 0.1% cutoff) for evaluation of measurable residual disease (MRD). Results: As of July 15, 2021, 100 pts had been enrolled with a median age of 68 years (range, 34-87; 47% male). By WHO, 74 pts had MDS, 22 AML-MRC and 4 CMML/MDS-MPN; 83% complex karyotype (CK) and 88% were CK and/or biallelic for TP53 mutations; 92% had a TP53 missense mutation in the DNA binding domain. In 63 pts, TP53 was the only mutation detected (i.e. isolated m TP53). Median time on treatment was 6 cycles (1-25+) with 5 pts ongoing and 23 pts who proceeded to allo-HSCT. Non-hematologic treatment (Tx)-related adverse events (AEs) in ≥20% of pts included nausea/vomiting (58%), ataxia (26%), and dizziness (23%). Neurologic AEs were reversible in 100% of cases. Febrile neutropenia occurred in 37% of pts. Thirty and 60-day mortality was 1% (n=1) and 7% (n=7), respectively. Dose reductions of APR-246 and AZA occurred in 16% and 1% of pts, respectively, with only 1 treatment discontinuation due to a treatment-related AE. By intention-to-treat (ITT) analysis, ORR by IWG was 69% with 43 CR, 1 PR, 10 marrow CR (mCR)+HI, 9 HI alone, and 6 with mCR. Of non-responders, 6 had stable disease and 7 pts had progressive disease. The median duration of CR/PR was 10.6 months (95% CI 8.8-12.3, 23+ months ongoing). CR/PR rate for MDS was 49% (36/74), 36% for AML (8/22) and 0% for MDS/MPN (0/4) with an ORR rate of 70%/64%/75%, respectively. Isolated m TP53 was predictive for a higher CR rate (52% vs 30%; P=.04). Patients who had biallelic TP53 or CK had a significantly higher CR rate vs pts without (49% vs 8%; P=0.01). On serial TP53 NGS using a VAF cutoff of 5%, 40 pts achieved NGS negativity with 6 pts MRD negative (VAF & lt; 0.1%). Of NGS negative pts (TP53 VAF & lt;5%), best response was CR/PR in 78% (n=31), mCR+HI in 15% (n=6), mCR in 5% (n=2) and HI in 3% (n=1). The median # of cycles in NGS negative and positive pts was 10 and 4, respectively (P & lt;0.0001). All MRD negative pts received at least 5 cycles of therapy (5-15). At data-cutoff by ITT analysis with a median follow up of 27.8 months, median OS was 11.8 months (95% CI 9.4-14.3). Pts undergoing allo-HSCT had a median OS of 16.1 months (95% CI 14-18.1). Impact of response and NGS clearance was evaluated by landmark analysis at 6 months. Pts achieving CR/PR or NGS negativity had improved OS (15.8 vs 10.1 months; P=0.002; Fig 1A). Additionally, pts who became MRD negative had a 2-year OS of 50% vs 23% (P=0.21). Although allo-HSCT was not predictive of OS in the overall cohort by landmark analysis (14.7 vs 14.4 months; P=0.15; Fig 1B), significant OS improvement was noted in allo-HSCT pts based on CR/PR or NGS negativity (P=0.002; Fig 1C). Notably, pts who achieved CR/PR/NGS negativity and were bridged to allo-HSCT had a median OS that was not reached (95% CI 10.4-NR) vs 9.1 months (95% CI 7.4-NR) in allo-HSCT pts who did not achieve this response (P=0.01). Conclusions: In this international, combined analysis of P2 APR-246+AZA pts, the combination was well-tolerated with high response rates in m TP53 MDS/AML. Quality of response and NGS negativity strongly predicted OS, particularly in the setting of allo-HSCT, validating NGS clearance as a critical biomarker of allo-HSCT outcomes in m TP53 pts. Figure 1 Figure 1. Disclosures Sallman: Intellia: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Komrokji: BMS: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau; Novartis: Honoraria; Geron: Honoraria; Acceleron: Honoraria; Agios: Honoraria, Speakers Bureau. DeZern: Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: 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. Sebert: BMS: Consultancy; Abbvie: Consultancy. Steensma: Novartis: Current Employment. Roboz: Astellas: Consultancy; Otsuka: Consultancy; Blueprint Medicines: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Glaxo SmithKline: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Helsinn: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Jasper Therapeutics: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Janssen: Research Funding; AstraZeneca: Consultancy; Jazz: Consultancy; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Mesoblast: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Astex: Consultancy; Actinium: Consultancy; Roche/Genentech: Consultancy. Sekeres: BMS: 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. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuykendall: Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; Prelude: Research Funding; PharmaEssentia: Honoraria; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher: Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Raffoux: ASTELLAS: Consultancy; ABBVIE: Consultancy; PFIZER: Consultancy; CELGENE/BMS: Consultancy. Padron: Incyte: Research Funding; BMS: Research Funding; Blueprint: Honoraria; Kura: Research Funding; Taiho: Honoraria; Stemline: Honoraria. Attar: Aprea Therapeutics: Current Employment, Current equity holder in publicly-traded company. Kantarjian: Amgen: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astellas Health: Honoraria; Jazz: Research Funding; Aptitude Health: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Taiho Pharmaceutical Canada: Honoraria. List: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Aileron Therapeutics: Consultancy; CTI Biosciences: Consultancy; Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company. Ades: Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Honoraria; Novartis: Honoraria; JAZZ: Honoraria. Lancet: BerGenBio: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Agios: Consultancy; AbbVie: Consultancy. Fenaux: Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-153286

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 15 ( 2018-08-01), p. 3519-3527

Abstract: Purpose: After failure of hypomethylating agents (HMA), patients with myelodysplastic syndromes (MDS) have dismal survival and no approved treatment options. Patients and Methods: We conducted a phase 1b investigator-initiated trial of ipilimumab in patients with higher risk MDS who have failed HMAs. Patients received monotherapy at two dose levels (DL; 3 and 10 mg/kg) with an induction followed by a maintenance phase. Toxicities and responses were evaluated with CTCAE.4 and IWG-2006 criteria, respectively. We also performed immunologic assays and T-cell receptor sequencing on serial samples. Results: Twenty-nine patients from 7 centers were enrolled. In the initial DL1 (3 mg), 3 of 6 patients experienced grade 2–4 immune-related adverse events (IRAE) that were reversible with drug discontinuation and/or systemic steroids. In DL2, 4 of 5 patients experienced grade 2 or higher IRAE; thus, DL1 (3 mg/kg) was expanded with no grade 2–4 IRAEs reported in 18 additional patients. Best responses included marrow complete response (mCR) in one patient (3.4%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 7 patients (24% of entire cohort and 29% of those treated with 3 mg/kg dose), including 3 patients with more than a year of SD. Five patients underwent allografting without excessive toxicity. Median survival for the group was 294 days (95% CI, 240–671+). Patients who achieved PSD or mCR had significantly higher frequency of T cells expressing ICOS (inducible T-cell co-stimulator). Conclusions: Our findings suggest that ipilimumab dosed at 3 mg/kg in patients with MDS after HMA failure is safe but has limited efficacy as a monotherapy. Increased frequency of ICOS-expressing T cells might predict clinical benefit. Clin Cancer Res; 24(15); 3519–27. ©2018 AACR.

Type of Medium: Online Resource

ISSN: 1078-0432 , 1557-3265

URL: Article

DOI: 10.1158/1078-0432.CCR-17-3763

Language: English

Publisher: American Association for Cancer Research (AACR)

Publication Date: 2018

detail.hit.zdb_id: 1225457-5

detail.hit.zdb_id: 2036787-9

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3091-3091

Abstract: Introduction: TP53 mutant (mTP53) MDS and AML, accounting for 5-10% of de novo MDS and 25-30% of therapy related MDS (t-MDS), represent a distinct molecular cohort with inferior outcomes. Hypomethylating agents (HMA) are preferred treatments for patients (pts) with these mutations, although with CR rates of only 20-30% and median OS of 6-12 months. APR-246 is a novel, first-in-class small molecule that selectively induces apoptosis in mTP53 cancer cells through mutant p53 protein re-activation by restoring the wild-type conformation, with single agent activity in mTP53 AML. We report the planned, completed Phase 1b results of APR-246+ azacitidine (AZA) in mTP53 MDS/AML. Methods: This is a multicenter Phase 1b/2 trial of APR-246+AZA in HMA naïve mTP53 MDS and oligoblastic AML (≤ 30% blasts) pts ≥ 18 years of age. Pts received APR-246 in a 3+3 dose escalation design (50, 75, 100 mg/kg lean body weight (equivalent to 4500mg fixed dose based on PK studies)) IV daily over 4 days in a lead-in phase (days -14 to -10) followed by the same dose of APR-246 (days 1-4) + AZA 75 mg/m2 SC/IV over 7 days (days 4-10 or 4-5 and 8-12) in 28 day cycles. The primary objective was to define safety and the recommended Phase 2 dose (RP2D), with AEs graded by CTCAE v4.03 and DLT assessment over 6 weeks. Secondary objectives included response by IWG 2006 criteria as well as serial next generation sequencing (NGS) and p53 IHC for evaluation of clonal suppression and remission depth as predictors of outcomes. For minimal residual disease (MRD) analysis, a custom target-capture NGS assay was developed using unique molecular Identifiers for error correction with a limit of detection of 0.1% with results validated by pt specific digital droplet PCR (ddPCR). Nanostring nCounter RNA expression analysis was conducted on a panel of 770 genes after the lead-in phase to assess transcriptional effects induced by APR-246. Results: As of July 30, 2018, 12 pts (42% male; median age 66 years (39-73)) were enrolled. Three pts had AML-MRC and 9 had MDS; all pts had poor risk cytogenetics (17% poor, 83% very poor) and higher risk disease by IPSS-R (25% high, 75% very high). T-MDS occurred in 5 pts (42%) and 7 pts (58%) were transfusion-dependent at baseline. Median BM blasts were 9% (4-30). Eleven of 12 pts (92%) had a TP53 missense mutation in the DNA binding domain with multiple mutations in 4/12 pts (33%). For 9/12 pts (75%), TP53 was the sole mutation. Median time on study is 176 days (41-298) with 7 pts ongoing. Treatment (Tx) related AEs during the lead-in phase (all G1) included nausea (n=5), neuropathy (n=5), decreased appetite (n=2), and dizziness (n=2) which were all transient. Tx related AEs occurring in 〉 1 pt in the combination phase included nausea/vomiting (n=6), dizziness (n=3), headache (n=3), neuropathy (n=3), fall (n=2), pruritus (n=2), thrombocytopenia (n=6), neutropenia (n=5), and leukopenia (n=4); all G1/G2 except cytopenias (G3/G4). No DLTs have occurred to date. Eleven of twelve pts were response evaluable with 1 pt discontinuing tx prior to 1st disease assessment (Fig 1A). ORR by IWG was 100% (11/11) with 9 CR (82%) and 2 marrow CR (mCR; 18%). Median time to first response was 70 days (4-91) and one CR patient achieved mCR and partial cytogenetic response after APR-246 lead-in prior to combination therapy. All CR pts had high p53 positivity by IHC at baseline (25-80%) which normalized on serial assessment with the 2mCR pts having 〈 5% p53+ at baseline. Serial NGS with a variant allele frequency (VAF) cutoff of 5% was negative in 73% of patients (8/11). In NGS negative pts, MRD analysis, validated by ddPCR, was performed with a median VAF of 0.3% (0.1%-3.1%) at best molecular response. Enriched pathway analysis via Reactome following APR-246 lead-in phase showed transcriptional activation of p53 targets (FDR = 9.16E-09), including pathways involved in cell cycle arrest, apoptosis, DNA repair, and regulation of TP53 activity. At a median follow up of 7 months, the median OS or PFS has not been reached. In comparison to a internal historical cohort of 51 mTP53 MDS/AML treated with AZA alone, APR-246+AZA had a trend for improved OS (NR vs 7.6months; HR 0.30, P=0.07; Fig 1B). Conclusions: APR-246+AZA combination is well tolerated in mTP53 MDS/AML. Responses have been achieved in all evaluable pts (82% CR) accompanied by deep molecular and durable remissions. The RP2D of APR-246 is a fixed dose of 4500mg days 1-4 in combination with AZA and phase 2 accrual has begun. Disclosures Sallman: Celgene: Research Funding, Speakers Bureau. Sweet:Agios: Consultancy; Phizer: Consultancy; Agios: Consultancy; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; Jazz: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; BMS: Honoraria; Phizer: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy; Jazz: Speakers Bureau; Astellas: Consultancy. Cluzeau:Celgene: Consultancy, 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; Pfizer: Speakers Bureau; Sanofi: Speakers Bureau; Menarini: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Roboz:Orsenix: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Eisai: Consultancy; Sandoz: Consultancy; Jazz Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Celltrion: Consultancy; Argenx: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy; Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Roche/Genentech: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; AbbVie: Consultancy; Janssen Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Cellectis: Research Funding. Bhagat:Genoptix: Employment. Tell:Aprea Therapeutics: Employment. Fenaux:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Roche: Honoraria. List:Celgene: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-119990

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. 134, No. Supplement_1 ( 2019-11-13), p. 676-676

Abstract: Introduction: TP53 gene mutations (mTP53), found in up to 20% of MDS or AML pts and 30-40% of therapy-related (TR) MDS/AML cases, represent a distinct molecular cohort with poor outcomes. Hypomethylating agents (HMA) are the standard of care with CR rates of ~20% and median OS of 7-8 months. APR-246 is a novel, first-in-class small molecule that selectively induces apoptosis in mTP53 cancer cells via thermodynamic stabilization of the p53 protein and shifting equilibrium toward the wild-type conformation. We previously reported the Phase 1b results of APR-246+AZA with no DLTs, transcriptional activation of p53 targets and high response rates, identifying a Phase 2 (P2) dose of 4500mg days 1-4 (Sallman et al., ASH 2018). We report herein the planned, completed phase 2 results. Methods: This is a multicenter Phase 1b/2 trial of APR-246+AZA in HMA-naïve mTP53 higher risk MDS, MDS/MPN and oligoblastic AML (≤ 30% blasts) pts (NCT03072043). P2 pts received APR-246 4500mg IV (days 1-4) + AZA 75 mg/m2 SC/IV x 7 days (days 4-10 or 4-5 and 8-12) in 28 day cycles. Primary objective was CR rate by International Working Group (IWG) 2006 criteria. Secondary objectives included ORR, OS, outcome following allogeneic hematopoietic stem cell transplant (allo-HSCT), and both next generation sequencing (NGS) and p53 immunohistochemistry (IHC) to monitor clonal suppression and remission depth as prognostic covariates. For minimal residual disease (MRD) analysis, a custom target-capture NGS assay was developed using unique molecular Identifiers for error correction with a 0.1% limit of detection. Results: As of July 15, 2019, 55 pts were enrolled (6 P1; 49 P2) with a median age 66 years (34-85; 47% male). By WHO, 40 pts had MDS, 11 AML-MRC and 4 CMML/MDS-MPN; 85% had complex cytogenetics and 33% TR-MDS/AML. All pts had higher risk disease by IPSS-R (7% Intermediate, 24% High, 69% Very High). Fifty pts (91%) had a TP53 missense mutation in the DNA binding domain with multiple mutations in 18 (33%), and median variant allele frequency (VAF) of 25%. In 34 pts (62%), TP53 was the sole mutation. Median time on treatment is 154 days (11-392) with 8 pts ongoing. Eighteen pts (33%; 40% of evaluable pts) discontinued study treatment to proceed to allo-HSCT. Treatment (Tx)-related AEs in ≥ 20% of pts included nausea/vomiting (58%), dizziness (31%), constipation (24%), neuropathy (22%), leukopenia (22%) and thrombocytopenia (20%; all G1/G2 except cytopenias (G3/G4). Tx-related febrile neutropenia and anemia occurred in 9% and 5% of pts with no other G3/G4 event in & gt;1 pt. Thirty and 60 day mortality was 2% (n=1) and 6% (n=3), respectively. At data cutoff, 45pts were response evaluable with a median follow up of 10.5 months (Fig 1A). ORR by IWG was 87% (39/45) with 24 CR (53%), 8 marrow CR (mCR)+HI (18%), 3 HI alone (7%), and 4 with mCR (9%). Of 6 non-responders, 4 had stable disease and 2 pts had progressive disease. Median time to response was 2.1 months (0.1-5.4) and median duration of response of 6.5 months. CR rate for MDS was 61% (20/33), 50% for AML (4/8) and 0% for MDS/MPN (0/4) with an 88% ORR rate for MDS/AML and 75% for MDS/MPN. An isolated mTP53 was predictive for a higher CR rate (69% vs 25%; P=.006) with a trend for higher ORR (93% vs 75%; P=.17). Additionally, pts with & gt;10% p53 IHC+ BM-MNC was a covariate associated with higher CR rate (66% vs 13%; P=.01). Complete and partial cytogenetic response occurred in 41% (n=18) and 18% (n=8) of pts, respectively. On serial TP53 NGS using a VAF cutoff of 5%, 39% (n=21) of patients achieved NGS negativity, which was associated with improved OS (12.8 vs 9.2 months; P=.02). In NGS- pts, the median MRD VAF at maximum clearance was 0.63% (0.0%-5%) with 5 pts (11%) MRD negative. By intention-to-treat analysis, median OS was 11.6 months (95% CI 9.2-14) with significantly longer OS in responding pts (12.8 vs 3.9 months; P & lt;.0001). Pts undergoing allo-HSCT had improved median OS (16.1 [95% CI 11.6-NE] vs 9.2 [95% CI 6.3-13.7] months), with a 1-year OS of 66% vs 29% in pts who were not transplanted (P=.002; Fig 1B). All NGS- pts prior to allo-HSCT remain alive at date cutoff. Conclusions: APR-246+AZA is a well-tolerated combination with high response rates in mTP53 MDS/AML. Response durations are promising accompanied by a high fraction of cytogenetic and deep molecular remissions leading to encouraging outcomes post-HSCT. These data support the ongoing, randomized phase 3 study of APR-246+AZA versus AZA alone in mTP53 MDS (NCT03745716). Disclosures Sallman: Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. DeZern:Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Steensma:Stemline: Consultancy; Pfizer: Consultancy; Aprea: Research Funding; H3 Biosciences: Other: Research funding to institution, not investigator.; Astex: Consultancy; Arrowhead: Equity Ownership; Onconova: Consultancy; Summer Road: Consultancy. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: 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; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: 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; Celltrion: 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; Eisai: 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; Jazz: 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; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Cluzeau:Jazz Pharma: Consultancy; Abbvie: Consultancy; Menarini: Consultancy. Sweet:Incyte: Research Funding; Celgene: Speakers Bureau; Pfizer: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Stemline: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Korbel:Aprea Therapeutics: Employment. Attar:Aprea Therapeutics: Employment. Kantarjian:Astex: Research Funding; Amgen: Honoraria, Research Funding; Ariad: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Immunogen: Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Cyclacel: Research Funding. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding. Fenaux:Aprea: Research Funding; Astex: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Jazz: Honoraria, Research Funding. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Komrokji:JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy; DSI: Consultancy; pfizer: Consultancy; celgene: Consultancy; JAZZ: Speakers Bureau; Agios: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-131055

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. 135, No. 22 ( 2020-05-28), p. 1946-1956

Abstract: Short telomeres have been linked to cancer risk, yet other evidence supports them being tumor suppressive. Here, we report cancer outcomes in individuals with germline mutations in telomerase and other telomere-maintenance genes. Among 180 individuals evaluated in a hospital-based setting, 12.8% had cancer. Solid tumors were rare (2.8%); nearly all were young male DKC1 mutation carriers, and they were generally resectable with good short-term outcomes. Myelodysplastic syndrome (MDS) was most common, followed by acute myeloid leukemia (AML); they accounted for 75% of cancers. Age over 50 years was the biggest risk factor, and MDS/AML usually manifested with marrow hypoplasia and monosomy 7, but the somatic mutation landscape was indistinct from unselected patients. One- and 2-year survival were 61% and 39%, respectively, and two-thirds of MDS/AML patients died of pulmonary fibrosis and/or hepatopulmonary syndrome. In one-half of the cases, MDS/AML patients showed a recurrent peripheral blood pattern of acquired, granulocyte-specific telomere shortening. This attrition was absent in age-matched mutation carriers who did not have MDS/AML. We tested whether adult short telomere patients without MDS/AML also had evidence of clonal hematopoiesis of indeterminate potential–related mutations and found that 30% were affected. These patients also primarily suffered morbidity from pulmonary fibrosis during follow-up. Our data show that the Mendelian short telomere syndromes are associated with a relatively narrow cancer spectrum, primarily MDS and AML. They suggest that short telomere length is sufficient to drive premature age-related clonal hematopoiesis in these inherited disorders.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2019003264

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: npj Precision Oncology, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2021-05-14)

Abstract: Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), classified by a translocation between chromosomes 15 and 17 [t(15;17)], that is considered a true oncologic emergency though appropriate therapy is considered curative. Therapy is often initiated on clinical suspicion, informed by both clinical presentation as well as direct visualization of the peripheral smear. We hypothesized that genomic imprinting of morphologic features learned by deep learning pattern recognition would have greater discriminatory power and consistency compared to humans, thereby facilitating identification of t(15;17) positive APL. By applying both cell-level and patient-level classification linked to t(15;17) PML/RARA ground-truth, we demonstrate that deep learning is capable of distinguishing APL in both discovery and prospective independent cohort of patients. Furthermore, we extract learned information from the trained network to identify previously undescribed morphological features of APL. The deep learning method we describe herein potentially allows a rapid, explainable, and accurate physician-aid for diagnosing APL at the time of presentation in any resource-poor or -rich medical setting given the universally available peripheral smear.

Type of Medium: Online Resource

ISSN: 2397-768X

URL: Article

DOI: 10.1038/s41698-021-00179-y

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2891458-2

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 10-12

Abstract: Acute Promyelocytic Leukemia (APL) is a subtype of Acute Myeloid Leukemia (AML), classified by a translocation between chromosomes 15 and 17 [t(15;17)], that is notably distinguished clinically by a rapidly progressive and fatal course. Due to the acute nature of its presentation, prompt and accurate diagnosis is required to initiate appropriate therapy that can be curative. However, the gold standard genetic tests can take days to confirm a diagnosis and thus therapy is often initiated on high clinical suspicion based on both clinical presentation as well as direct visualization of the peripheral smear. While there are described cellular morphological features that distinguish APL, there is still considerable difficulty in diagnosing APL from direct visualization of a peripheral smear by a hematopathologist. We hypothesized that deep learning pattern recognition would have greater discriminatory power and consistency compared to humans to distinguish t(15;17) translocation positive APL from t(15;17) translocation negative AML. To best tackle the problem of diagnosing APL rapidly from a peripheral smear, study patients with APL and AML were identified via retrospective chart review from a list of confirmed FISH t(15;17)-positive (n = 34) and -negative (n = 72) patients presenting at The Johns Hopkins Hospital (JHH). Additional inclusion criteria included new disease diagnosis, no prior treatment, and availability of peripheral blood smear image uploaded to CellaVision. Patients were separated into a discovery cohort presenting prior to 1/2019 (APL, n = 22; AML, n=60) and a validation cohort presenting on or after 1/2019 (APL, n = 12; AML, n = 12). A multiple-instance deep learning model employing convolutional layers at the per-cell level (Figure 1A) was trained on the discovery cohort and then tested on the independent prospective validation cohort to assess generalizability of the model. When compared to 10 academic clinicians (denoted with red +) who consisted of leukemia-treating hematologists, oncologists, and hematopathologists, the deep learning model was equivalent or outperformed 9/10 readers (Figure 1B) with an AUC of 0.861. We further looked at the performance of using proportion of promyelocytes (per CellaVision classification) as a biomarker of APL which had an AUC of 0.611. Finally, we applied integrated gradients, a method by which to extract per-pixel importance to the classification probability to identify and understand the morphological features the model was learning and using to distinguish APL (Figure 1C). We noted that the appearance of the chromatin in the non-APL leukemias was more dispersed and focused at the edge of the cell whereas in APL, the chromatin was more condensed and focused at the center of the cell. These morphological features, taught to us by the model, have not been previously reported in the literature as being useful for distinguishing APL from non-APL. Our work presents a deep learning model capable of rapid and accurate diagnosis of APL from universally available peripheral smears. In addition, explainable artificial intelligence is provided for biological insights to facilitate clinical management and reveal morphological concepts previously unappreciated in APL. The deep learning framework we have delineated is applicable to any diagnostic pipeline that can leverage a peripheral blood smear, potentially allowing for efficient diagnosis and early treatment of disease. Figure 1. Disclosures Streiff: Bayer: Consultancy, Speakers Bureau; Dispersol: Consultancy; BristolMyersSquibb: Consultancy; Janssen: Consultancy, Research Funding; Pfizer: Consultancy, Speakers Bureau; Portola: Consultancy; Boehringer-Ingelheim: Research Funding; NHLBI: Research Funding; PCORI: Research Funding; NovoNordisk: Research Funding; Sanofi: Research Funding. Moliterno:Pharmessentia: Consultancy; MPNRF: Research Funding. DeZern:MEI: Consultancy; Abbvie: Consultancy; Astex: Research Funding; Celgene: Consultancy, Honoraria. Levis:Astellas: Honoraria, Research Funding; Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-135836

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7