Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1812-1812

Abstract: BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-111264

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. 4254-4254

Abstract: Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of individuals with myelodysplastic syndrome (MDS) and have been associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, potent, targeted inhibitor of the mutant isocitrate dehydrogenase 1 enzyme (mIDH1) and is approved in the US for the treatment of newly diagnosed AML with a susceptible IDH1 mutation in patients ≥75 years of age or who have comorbidities that preclude the use of intensive induction chemotherapy, and in adult patients with relapsed or refractory (R/R) AML. The first-in-human, phase 1 dose escalation and expansion study of ivosidenib (NCT02074839) enrolled adults with mIDH1 advanced hematologic malignancies, including R/R MDS, and the study is ongoing. In the initial phase of the study (DiNardo et al. N Engl J Med 2018), the 12 patients with R/R MDS received 500 mg ivosidenib once daily and were characterized as follows: 75% were male, median age was 72.5 years (range 52-78), and 42% were ≥75 years of age; median number of prior therapies was 1 (range 1-3). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n=4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n=3 each, 25.0%). No AEs led to permanent discontinuation of treatment. Response was assessed according to International Working Group 2006 criteria for MDS. According to investigators, five of 12 patients achieved complete remission (CR) (41.7%; 95% CI 15.2%, 72.3%); median duration of CR was not estimable for these patients (95% CI 2.8 months, not estimable). Nine of 12 patients were transfusion independent for at least 56 days during study treatment. Mutation clearance was observed in one of the 5 CR patients. Here we report the design of a new sub-study of this trial, which is being undertaken to further assess the safety, tolerability, and clinical activity of treatment with ivosidenib in patients with R/R MDS. Methods: This sub-study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Adults with R/R MDS with an IDH1 mutation will be enrolled in the MDS sub-study. These individuals must have R/R disease after treatment with standard agents indicated for MDS. Eligible patients must have a platelet count of ≥20,000/μL, and adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN]; aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤3.0 × ULN) and renal function (serum creatinine ≤2.0 × ULN or creatinine clearance 〉 40 mL/min). Additional key inclusion criteria are bone marrow blasts 〉 5% and/or transfusion dependence. Ivosidenib is to be administered at a dose of 500 mg once daily orally on Days 1 to 28 of 28-day cycles. The addition of the MDS sub-study to this phase 1 clinical study in patients with hematological malignancies will provide additional insights into the use of ivosidenib for the treatment of mIDH1 R/R MDS. Disclosures Foran: Agios: Honoraria, Research Funding. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; celgene: Consultancy, Honoraria; syros: Honoraria. Watts:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. De Botton:Daiichi Sankyo: Consultancy; Astellas: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Syros: Consultancy; Forma: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Research Funding. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Stein:Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. Patel:France Foundation: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria. Tallman:UpToDate: Patents & Royalties; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Tetraphase: 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, Research Funding; Biosight: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees. Choe:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Oluyadi:Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership. Attar:Aprea Therapeutics: Employment; Agios: Employment, Equity Ownership. Kantarjian:Astex: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding. OffLabel Disclosure: Ivosidenib (AG-120) is an IDH1 inhibitor indicated for the treatment of AML with a susceptible IDH1 mutation as detected by an FDA-approved test in: 1) adult patients with newly-diagnosed AML who are more than 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy and 2) adult patients with relapsed or refractory AML. It is being evaluated in clinical trials for mutant IDH1 advanced hematologic malignancies.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123946

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. 7 ( 2020-02-13), p. 463-471

Abstract: Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI] , 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2019002140

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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. 3975-3975

Abstract: Background: The incorporation of intensive chemotherapy, hematopoietic stem cell transplantation (HSCT), targeted therapies including rituximab and tyrosine kinase inhibitors contributes substantial improvement in the outcome of patients with ALL over decades. VAD was changed to hyper-CVAD in 1992; rituximab was added to hyper-CVAD for CD20 positive ALL in 1999/2000; inotuzumab ozogamicin in combination with low-intensity chemotherapy was offered to elderly patients starting in 2011. The aim of this study is to describe the outcome of patients with ALL over decades by age groups. Methods: From 1980 to 2016, patients with newly diagnosed ALL at our institution were analyzed. Burkitt leukemia was excluded from our analysis. Patients were divided into age groups as follows: age 15-39, age 40-60, and age 〉 60. Patients were subsequently divided into diagnostic year cohorts by decade: 1980-1989, 1990-1999, 2000-2009, and 2010-2016. Overall survival was defined as time interval from diagnosis to the date of death regardless of any cause. Kaplan-Meier method with a log-rank test was used for survival comparison between cohorts. Stepwise multivariate analysis with Cox proportional hazards model was used to evaluate the impact of diagnosis year on OS. P-values were two-sided, and a p-value less than 0.05 was considered statistically significant. Results: Overall, 972 patients were identified and analyzed in our study. Median age at diagnosis was 39.5 years (range, 16-92) with a median follow-up of 10.4 years (range, 0.0-31.3). Patients were divided into 486 patients (50%) in the age 15-39 category, 301 patients (31%) in the age 40-60 category, and 185 patients (19%) in the age over 60 category. Baseline patient characteristics are summarized in Table 1. Overall, the median OS durations were 4.5 years, 2.8 years, and 1.3 years in age 15-39, age 40-60, and age 〉 60, respectively (p 〈 0.001; p 〈 0.001). Of the 486 patients in age 15-39, the improvement in OS was observed from 1980-1989 to 1990-1999 (p 〈 0.001); of the 301 patients in age 40-60, from 1980-1989 to 1990-1999, and from 1990-1999 to 2000-2009 (p=0.042; p=0.003); of the 185 patients in age 〉 60, from 2000-2009 to 2010-2016 (p=0.039). Stepwise multivariate analysis identified leukocytosis, thrombocytopenia, hypoalbuminemia, elderly age, poor performance status, lack of complete response, and diagnostic year as adverse prognostic factors for OS. Each year since 1980 had an impact on OS with hazard ratio of 0.961 (95% confidence interval, 0.951-0.971; p 〈 0.001). Conclusion: Patients with ALL have significant improvement in OS throughout all ages over decades. However, the decade time points of improvement in OS were different between age cohorts. Different treatment strategy and clinical trial designs by each age group are needed for further improvement in patient's outcome. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Pemmaraju:incyte: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; cellectis: Consultancy, Research Funding; affymetrix: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding. Jain:Genentech: Research Funding; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Servier: Consultancy, Honoraria; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Andreeff:Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3975.3975

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. 122, No. 21 ( 2013-11-15), p. 1544-1544

Abstract: Introduction New, refined prognostic scoring systems have been established for MDS. Most scores assess prognosis at time of diagnosis assuming stable prediction over time. Earlier studies have shown moderate loss of prognostic power over time in scores using clinical parameters whereas cytogenetic scores maintained prognostic power, scores including comorbidity had shown gain of prognostic power (Pfeilstöcker et al, 2012). The aim of this multicenter retrospective study was to assess the relative stability of the newly developed scoring systems over time, to compare and explain observed time-related losses of prognostic power, and to discuss their clinical implications. Methods This study is based on 7212 untreated (no disease modifying treatment) MDS patients from multiple institutional databases of the IWG-PM, which generated the IPSS-R (Greenberg et al, 2012). Patient characteristics were well comparable with other populations: median age 71 years, male gender 60 %, median overall survival 3.8 years (range 3.7-4.0), median time to AML transformation not reached with 25% of patients transforming to AML after 6.8 years. Patients were diagnosed and classified by FAB and WHO; cytogenetics were classified by original IPSS subtypes and by the recently refined proposal integrated into the IPSS-R (Schanz et al, 2012). The following scores were analysed for their stability over time: IPSS, IPSS-R, WPSS variants, cytogenetic scores, age, performance status and other differentiating features of the IPSS-R. Time variations were described by the Cox-zph-test, and by applying Dxy, a measure of concordance, for censored data at separate observation periods. Results In line with previous observations, loss of prognostic power occurred over time after diagnosis in all scoring systems. While for the entire population the risk between adjacent IPSS-R risk categories differs by ∼80%, for patients observed at least 1 year the increase is ∼66%, and for those observed 4 years it is only ∼25%. The IPSS-R and particularly its age-including version (the IPSS-RA) retained the highest prognostic values compared to all other scoring systems at all time points. Dxy for IPSS-R: at diagnosis 0.43, 1 year 0.35, 2 years 0.27, 4 years 0.14. Including age, as in the IPSS-RA, was associated with less loss of prognostic power over time: Dxy at diagnosis 0.46, 1 year 0.38, 2 years 0.31, 4 years 0.22. For the IPSS and WPSS (available for the latter in only 33% cases), these values were: 0.37, 0.30, 0.22, 0.11 and 0.44, 0.36, 0.29, 0.18 respectively. Considering risk categories, the risk remained fairly constant over time for the lower risk categories in every analyzed scoring system, while the risks in the higher risk categories were especially high in the second half of the first year after diagnosis, diminishing thereafter, thus reducing the prognostic value of these categories over time. To determine whether statistical weights optimized for each time period would alter these results, time-specific weights were applied, which did not demonstrate substantially different prognostic values from the basic model analysis. Particularly good retention of prognostic power was found in the lower risk categories over time. The lesser retention of prognostic power in the higher risk categories appeared related to loss of a larger portion of these patients over time due to their deaths or being censored by their beginning treatment. For the IPSS-R intermediate risk category patients, the prognosis for survival approached the “high” category ∼3 years after diagnosis, while it remained intermediate regarding their risk of AML transformation. Conclusions These data demonstrate that a degree of attrition of prognostic value occurred over time from diagnosis for all of the assessed MDS prognostic scoring systems. The IPSS-R, particularly the age-inclusive IPSS-RA, best retained such prognostic capability over time for the untreated patients analyzed. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.1544.1544

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2592-2592

Abstract: Abstract 2592 Background: The phenomenon of EMD in pts with AML has been previously noted. However, little is known about the cytogenetic and molecular characterization of these pts in the modern era of AML prognostic cytogenetic and molecular markers. Methods: We conducted a retrospective review of 2,181 consecutive pts with AML who underwent induction chemotherapy and were treated at our institution from 2000–2011. All pts included in this analysis had histologically-proven EMD-AML. Chi-squared test was used to assess complete response (CR) probability and Kaplan-Meier method was used to assess CR duration and overall survival (OS) outcomes. Results: Overall, 1,120 pts underwent biopsies/tissue sampling during the study period to evaluate for EMD-AML. 244 pts (11% of total group, 22% of those biopsied) were diagnosed (dx) with histologically proven EMD. 47 pts (2% of total group, 4% of pts biopsied, 19% of EMD pts) had EMD-AML at multiple sites. Median age of AML dx was 57 years (range 14–82 years). 135 pts were male (55%). Baseline CBC parameters at AML dx: WBC 9.5 (0–433), platelets 53 (0–581), Hb 8.7 (0–15.6). Median blasts at baseline AML dx: Peripheral 22% (0–99%) and bone marrow 56% (0–98%). EMD occurred at all phases of AML therapy course, with majority of EMD dx occurring at or after time of relapse (n=112, 46%), followed by concomitant at AML dx (28%), during induction therapy (15%) and prior to AML dx (11%). EMD sites were found throughout all major organ systems (Table 1). The specific sites most commonly affected by EMD included skin (n=84), CSF (n=76), pleural fluid (n=41), ascitic fluid (n=7), abdominal wall soft tissue (n=6), pelvic/inguinal lymph node (n=6), stomach (n=5), liver (n=5), cervical/neck lymph node (n=5), and bone (n=5). Cytogenetic abnormalities and molecular mutations were frequent features of EMD pts (Table 2, Table 3). Pts with EMD (n=156, 64%) were more likely to achieve CR than pts without EMD (n=1079, 56%, p=0.01). For those pts with EMD, CR duration was 59.0 months (95% CI 54.8–63.2 months), which was longer than for pts without EMD (CR duration, 43.5 months, 95% CI 40.7–46.4 months, p 〈 0.0001). Overall survival (OS) of EMD pts (30.9 months, 95% CI 25.3–36.6 months) was significantly less than OS of non-EMD pts (43.5 months, 95% CI 40.7–46.4 months, p=0.04). Conclusion: Incidence of EMD in AML pts is common (11%) and occurs at all phases of disease course. Almost every organ system/tissue demonstrates involvement with EMD AML. Cytogenetic and molecular abnormalities are commonly associated with EMD AML pts, with FLT3 mutation being the most common molecular abnormality in this cohort (30% of evaluable pts) and deletion of chromosome 7 being most common chromosomal abnormality (14% of pts). While pts with EMD-AML had significantly longer CR duration, interestingly these pts were noted to have significantly shorter OS in this analysis, suggesting the unique biologic and clinical features of this subset of AML pts. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.2592.2592

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4326-4326

Abstract: Abstract 4326 Background: Extramedullary (EM) disease is a well-known manifestation of acute myeloid leukemia (AML). Despite its recognized incidence, little is known about organ-specific EM-AML, including genitourinary (GU) AML. The purpose of this study is to identify the patients (pts) who develop GU-AML and to characterize the clinicopathologic, cytogenetic, and molecular features of this population. Methods: A database of 2,181 consecutive patients who were diagnosed with AML and underwent induction therapy from 2000 to 2011 at M.D. Anderson Cancer Center was reviewed retrospectively. All pts with histologically proven EM-AML were included in this series. Clinicopathologic, cytogenetic, and molecular data were examined and statistically analyzed. Results: A total of 1,120 pts underwent at least one EM biopsy and 244 were diagnosed with EM-AML. Of these, 9 pts (6 females) demonstrated GU-AML (0.4% of total population, 3.7% of EM-AML pts). Furthermore, 3 GU-AML pts demonstrated additional EM-AML in non-GU sites. At AML dx, GU-AML pts demonstrated median bone marrow blasts of 35% (range 1–69%) and median peripheral blood blasts of 1% (range 0–46%). CBC included median WBC of 3.5 K/uL (range 1.6–21.0 K/uL), median Hgb level of 9.4 g/dL (range 8.0–14.3 g/dL), and median platelet count of 118 K/uL (range 28–206 K/uL). Median age of AML dx in GU-AML pts was 45 years (range 28–69 years) and was significantly younger than the median age of AML dx in all other non-GU pts (60 years, range 12–89 years, p=0.025, Student's t-test). A total of 78% of GU-AML dx were made before or at AML presentation and 89% of GU-AML dx were made within 3 months of AML presentation. A total of 67% of GU-AML pts demonstrated cytogenetic abnormalities. Cytogenetic features included inversion 16 (inv (16), 33%), trisomy 8 (33%), diploid (33%), trisomy 22 (22%) and complex (22%). For all pts with GU-AML, no molecular mutations were present in RAS (0/9), FLT3 (0/7), NPM1 (0/2) or JAK2 (0/2). CR was achieved by 78% of pts with GU-AML. The pts who did not achieve CR expired early in induction therapy (within 29 days) due to sepsis. Of the GU-AML pts with CR, CR duration was 50.7 months (95% CI 15.2–86.2 months). CR duration of GU-AML pts was significantly longer than that of EM-AML pts with no GU sites (18.0 months, 95% CI 14.1–22.0 months, p=0.03, Kaplan-Meier method). Overall survival (OS) for all GU-AML pts was 41.6 months (95% CI 12.7–70.5 months) and was statistically equal to OS of pts without GU-AML and to OS of EM-AML pts with no GU sites. Conclusion: GU-AML is a rare but noteworthy manifestation of AML that tends to be diagnosed before or at AML presentation. Pts with GU-AML developed AML at a significantly younger age by 15 years than pts without GU-AML (p=0.025). Most GU-AML pts demonstrated cytogenetic abnormalities but none demonstrated molecular mutations. The presence of GU-AML, rather than EM-AML in other sites, may contribute to extended duration of CR (p=0.03). However, despite this finding and other advantages such as majority achievement of CR and young age of AML dx, there was no statistical advantage in OS in pts with GU-AML compared to those pts without GU-AML or to pts with EM-AML in non-GU sites. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.4326.4326

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

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. 645-645

Abstract: Background: Acute myeloid leukemia (AML) remains a therapeutic challenge in elderly or unfit patients (pts) and high-risk subgroups. DEC10-VEN has shown high efficacy in these pts. However, outcomes in specific mutational subgroups are unknown. Here we present the results in mutational subgroups and resistance patterns in pts treated with DEC10-VEN (NCT03404193). Methods: This single-institution phase II study enrolled pts with newly diagnosed (ND) AML ( & gt;60 years) ineligible for intensive chemotherapy, relapsed or refractory (R/R) AML, and secondary AML (sAML) with or without prior therapy. DEC was given 20 mg/m2 IV daily on day 1-10 until CR/CRi, followed by 5-day cycles. VEN was given for 21-28 days in cycle 1 and day 1-21 or shorter duration thereafter. BCR-ABL1 and FLT3 inhibitors (FLT3i) were allowed as appropriate. Amplicon-based next-generation sequencing targeting the entire coding regions of 81 myeloid genes was performed on screening bone marrow aspirate with a MiSeq platform. The analytical sensitivity was established at 5% mutant reads in a background of wild type reads. Previously described somatic mutations registered in COSMIC were considered as potential driver mutations. Results: High response rates were noted across mutational subgroups of both previously untreated and previously treated AML (Table 1 and 2). The median follow-up for the entire cohort was 8.1 months (mo). In previously untreated AML (ND AML and untreated sAML, n=49), the CR/CRi rate in NPM1mut pts was 100% (n=13), in RUNX1mut pts was 100% (n=8), in IDH1/2mut pts was 92% (n=12), in TP53mut pts was 85% (n=13), and in N/KRASmut pts was 77% (n=13, Table 1). The median overall survival (OS) among previously untreated NPM1mut pts was not reached (NR), for RUNX1mut pts was NR, for IDH1/2mut pts was 12.4 mo, for TP53mut pts was 5.8 mo, and for N/KRASmut was 12.4 mo. The median DOR for NPM1mut pts was 8.5 mo, for RUNX1mut pts was NR, for IDH1/2mut pts was NR, for TP53mut pts was 5.7 mo, and for N/KRASmut pts was 6.7 mo (Table 1). The one pt with NPM1mut who relapsed had co-occurring ASXL1mut and NRASmut at screening. In previously treated AML (treated sAML and R/R AML, n=52), the CR/CRi rate in NPM1mut pts was 60% (n=10), in IDH1/2mut pts was 50% (n=8), and in TP53mut pts was 21% (n=14, Table 2). The median OS for NPM1mut pts was NR, for IDH1/2mut pts was 7.8 mo, and for TP53mut pts was 4.5 mo. The median DOR for NPM1mut pts was NR, for IDH1/2mut pts was NR, and for TP53mut pts was 3.2 mo (Table 2). The only grade 4 TLS event occurred in a pt with NPM1mut and IDH2mut and baseline WBC of 28x109/L. 2 other pts with high % of PB blasts and FLT3mut experienced grade 3 TLS. Among 15 pts with FLT3-ITD/TKD, 8 pts received sorafenib, 5 pts received midostaurin, and 2 pts did not receive FLT3i (1 insurance non-approval and 1 very low ITD ratio). Among ND FLT3mut AML pts (n=7), the CR/CRi rate was 100% (n=5) in pts receiving FLT3i with negative MRD by flow cytometry (FCM) in 80% pts, with median OS of 8.8 mo and median DOR not reached (Table 1). Of the 2 FLT3-ITD pts not receiving FLT3i, 1 pt with FLT3-ITD of 0.47 did not respond, and 1 pt with low FLT3-ITD of 0.02 achieved CR MRD-. Among previously treated FLT3mut pts (n=8), all received FLT3i with a CR/CRi rate of 38% (n=5) and negative MRD by FCM in 75% pts tested (3/4). The median OS was 6.4 mo and the median DOR was 6.6 mo (Table 2). 2 pts had received prior FLT3i, 1 pt achieved morphologic leukemia-free state (MLFS), and the other pt did not respond. 1 pt with new t(9;22) identified at 4th relapse achieved a MLFS after 1 cycle with addition of ponatinib and transitioned to allogeneic transplant. Overall, pts with durable CR/CRi/MLFS sustained without relapse till data cut-off, had significantly higher proportion of mutations in NPM1 and DNA methylation pathways (DNMT3A, TET2, IDH1/2) compared to pts refractory to, or relapsing after DEC10-VEN (Table 3, Fig. 1). Pts with relapsed or refractory disease to DEC10-VEN had significantly higher frequency of N/KRASmut, ASXL1mut, and TP53mut compared to pts with durable CR/CRi/MLFS (Table 3, Fig. 1). TP53mut associated with worse OS on multivariable analysis (HR 2.9, 95% CI 1.4-5.7, p=0.003). Conclusion: DEC10-VEN is an effective regimen for AML. Addition of FLT3i to DEC10-VEN was safe and may improve upon responses in FLT3mut pts. Mutations in NPM1 and DNA methylation pathways were associated with more durable responses while mutations in ASXL1, RAS and TP53 were associated with refractory disease or relapse. Disclosures Maiti: Celgene: Other: research funding. Cortes:BiolineRx: Consultancy; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria. Pemmaraju:samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding. Daver:Servier: Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Jazz: Consultancy; NOHLA: Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Servier: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Glycomimetics: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy; NOHLA: Research Funding; Celgene: Consultancy; Otsuka: Consultancy; Glycomimetics: Research Funding; Novartis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Pfizer: Consultancy, Research Funding. Ravandi:Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. 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. Borthakur:Cyclacel: Research Funding; AbbVie: Research Funding; Eli Lilly and Co.: Research Funding; Xbiotech USA: Research Funding; Merck: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Janssen: Research Funding; NKarta: Consultancy; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Incyte: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics, Inc.: Research Funding; GSK: Research Funding; BMS: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Novartis: Research Funding; Eisai: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding. Short:Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:AbbVie: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi:Symbio Pharmaceuticals: Consultancy. Jain:Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: 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; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Andreeff:NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Bose:CTI BioPharma: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Cyclacel LTD: Research Funding; BMS: Consultancy, Research Funding. Thompson:AbbVie: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Zhang:The University of Texas M.D.Anderson Cancer Center: Employment. Kantarjian:Daiichi-Sankyo: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding. DiNardo:agios: Consultancy, Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria. OffLabel Disclosure: FLT3 inhibitors, used in combination with decitabine and venetoclax

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-128547

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 42-43

Abstract: Introduction: Outcome of patients (pts) with CD20-positive B-cell acute lymphoblastic leukemia (B-ALL) has significantly improved with hyper-CVAD (HCVAD) in combination with rituximab with 3-year OS 65% (Thomas et al Blood 2009). Ofatumumab is an anti-CD20 monoclonal antibody with higher capacity of promoting complement-dependent cytotoxicity compared to rituximab. The aim of this study is to compare the outcome of pts with CD20-positive B-ALL who received HCVAD plus ofatumumab (HCVAD-O) or HCVAD plus rituximab (HCVAD-R) therapy. Methods: We reviewed 69 adult pts with newly diagnosed, Philadelphia chromosome (Ph)-negative, CD20-positive B-ALL who were treated with HCVAD-O at our institution between 8/2011 and 5/2017. HCVAD therapy consisted of 4 alternating cycles of hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, plus high-dose methotrexate (MTX) / cytarabine (AraC) with 8 intrathecal injections of MTX/AraC. Ofatumumab was administered at 300mg IV as first dose, and 2000mg IV subsequently. The maintenance phase consisted of 30 cycles of 6-MP, MTX, vincristine, and prednisone (POMP) with 4 intensification courses (high-dose MTX plus L-asparaginase and HCVAD+O) on courses 6-7 and 18-19. Overall survival (OS) was calculated from the start date of treatment to the date of death, or last follow-up. We performed a comparison of survival between pts treated with HCVAD-O and a cohort of 153 historical-control pts treated with HCVAD with or without rituximab between 11/2002 and 7/2012. Historical-control pts were treated with HCVAD alone (N=58) if CD20 expression was 1-19% or HCVAD-R (N=95) if CD20 expression was ≥20%. To adjust for baseline differences of pts characteristics between the cohorts, we performed inverse probability of treatment weighing (IPTW) using propensity scores calculated from pts baseline characteristics. Covariates for the calculation of propensity scores included age, performance status, white blood cell count at diagnosis, the positivity of CD20 expression and adverse-risk cytogenetics (KMT2A-rearrangement, complex karyotype or low-hypodiploidy / near triploidy). Results: The median follow-up for HCVAD-O cohort and historical-control cohort was 44 months (95% CI: 41-53) and 133 months (95% CI: 115-141), respectively. There was no difference in baseline characteristics between HCVAD-O cohort and historical-control cohort (Table 1). The 5-year OS rates were 65% and 51% in HCVAD-O cohort and historical-control cohort, respectively. With the IPTW analysis, the HCVAD-O regimen was associated with better outcome compared with the historical HCVAD/HCVAD-R regimen (HR, 0.74; 95% CI, 0.55-0.99, p = 0.047) (Figure 1). The treatment effect was similar regardless of the level of CD20 positivity, although not statistically significant among each subgroup (CD20 ≥20%, HR 0.73, 95% CI, 0.52-1.04, p = 0.09; CD20 1-19%, HR, 0.68; 95% CI, 0.39-1.20, p = 0.18). Conclusions: The combination of HCVAD plus ofatumumab is highly effective and seems to have offered better outcome than did HCVAD plus rituximab therapy in pts with Ph-negative CD20-positive B-ALL. Additional novel monoclonal/bispecific antibody constructs targeting CD19 and CD22 are expected to further improve the outcome. Disclosures Sasaki: Otsuka: Honoraria; Daiichi Sankyo: Consultancy; Pfizer Japan: Consultancy; Novartis: Consultancy, Research Funding. Konopleva:F. Hoffmann La-Roche: 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; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; Forty-Seven: Consultancy, Research Funding; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Agios: Research Funding; Ablynx: Research Funding; Cellectis: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Calithera: Research Funding. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; Astellas: Research Funding; AstraZeneca: Consultancy. Jain:Pfizer: Research Funding; Cellectis: Research Funding; Aprea Therapeutics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: 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; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Adaptive Biotechnologies: 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; BMS: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Fate Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ravandi:Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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. Kadia:Genentech: Honoraria, Research Funding; Cyclacel: Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; Novartis: Honoraria; Celgene: Research Funding; JAZZ: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Cellenkos: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Research Funding. Alvarado:FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. DiNardo:Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Calithera: Research Funding; ImmuneOnc: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Jazz: Honoraria. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Pemmaraju:MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; LFB Biotechnologies: Honoraria; Daiichi Sankyo: Research Funding; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Novartis: Honoraria, Research Funding; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Celgene: Honoraria; DAVA Oncology: Honoraria; Roche Diagnostics: Honoraria; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Merck: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; ItalPharma: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; CTI Biopharma Corp: Research Funding; Sierra Oncology: Consultancy, Research Funding; Promedior: Research Funding; Blueprint Medicines Corp: Research Funding; Protagonist Therapeutics: Research Funding; Celgene: Consultancy, Research Funding. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Omeros: Consultancy; Takeda: Patents & Royalties; Cytonus: Consultancy. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Kebriaei:Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Amgen: Other: Research Support; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Jazz: Consultancy. O'Brien:Kite, Regeneron, Acerta: Research Funding; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy. Kantarjian:Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Ariad: Research Funding; Novartis: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Astex: Research Funding; Pfizer: Honoraria, Research Funding. Jabbour:Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-142121

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

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. 906-906

Abstract: Background: Preclinically blocking PD-1/PD-L1 pathways enhanced anti-leukemic responses. PD-1 positive CD8 T-cells were increased in the bone marrow (BM) of pts with AML (Daver et al, ASH 2016). Azacitidine up-regulates PD-1 and interferon-gamma signaling (Yang et al., Leukemia 2013). Methods: Pts were eligible for the AZA+Nivo (cohort 1) if they had relapsed/refractory AML (R/R AML), ECOG ≤ 2, and adequate organ function. The recommended phase 2 dose was established as AZA 75mg/m2 Days 1-7 with Nivo 3mg/kg Day 1 and 14. Courses were repeated approximately every 4-5 weeks indefinitely. 70 R/R AML pts have been treated; cohort 1 is closed. A subsequent cohort of AZA+Nivo+Ipi in R/R AML was opened (cohort 2), with the same eligibility criteria as cohort 1 except that enrollment was restricted to pts with salvage 1 and 2 AML. Ipi 1mg/kg Q6 weeks was added to the established AZA+Nivo schedule. This dosing was based on lung and melanoma dosing for Ipi + Nivo. Responses in both cohorts included best response within 3 months of therapy initiation. Results: Cohort 1: 70 R/R AML pts with median (med) age 70 years (range, 22-90), secondary AML (44%), poor risk cytogenetics (34%), med salvage 2 (range, 1-7) were enrolled. The ORR was 33% including 15 CR/CRi (22%) (4 CR, 11 CRi), 1 PR, and 7 HI maintained on study 〉 6 months (10%) without allogeneic stem cell transplant. Additionally, 6 pts (9%) remained on study with stable disease (SD) 〉 6 months. The remaining 41 pts (58%) had no response. 8-week (wk) mortality was 10%. Patients who achieved a CR/CRi/PR/HI/SD (n=29; 42%) had significantly improved overall survival (OS) compared with NRs (n=41; 58%) (16.1 versus 4.1 months; p 〈 0·001). By univariate analysis (UVA) improved ORR was seen in pts with pretherapy BM blast 〈 20%, circulating WBC 〈 /=10,000/mL, ASXL1 mutation, and no prior HMA-based therapy (Table 1). By UVA improved OS was seen in pts who achieved any response or SD (CR/CRi/PR/HI/SD), were salvage 1 status, and had ASXL1 mutation. The med OS with Aza+Nivo compared favorably to historical med OS with AZA-based protocols in salvage 1 or 2 pts at MDACC (6.0 versus 4.7 months; p=0.03)(Fig 1), with the most prominent improvement seen in salvage 1 pts (11.1 versus 4.1 months; P 〈 0.001). Grade 3/4 immune related adverse events (irAEs) were observed in 8 (11%) pts, including pneumonitis (n=3), colitis (n=2), and nephritis, skin rash, and hypophysitis (1 each). The majority (12 of 16; 75%) of these occurred in the first 8 wks after nivo initiation. These responded rapidly to steroids when initiated early. Flow-cytometry (MFC) was performed on pre- and post-therapy BMAs, after 2 doses (end of cycle 1 or EOC1) and 4 doses (EOC2) of nivol in 19 of 23 responders (R) (CR/CRi/PR/HI) (83%) and 28 of 41 NRs (68%). 36 parameter CyTOF was performed at same time-points in 5R and 5NRs. On pretherapy BMAs, R had a higher frequency of CD3+ (p=0.04) and CD8+ cells (p=0.09) on MFC (Fig 2A). CD3+ in the pretherapy BMA with a cut-off of 13.2%, had a sensitivity of 74% and a specificity of 65% for predicting response. The CD3+ was 〉 13.2% in 26 of 47 pts (55%) who had an evaluable pretherapy BMA. Immunohistochemistry confirmed that CD3+ cells were increased in pretherapy BMs in R. PhenoGraph clustering of all CD3-gated cells revealed 24 meta-clusters (Fig 2B). The frequency of an effector CD8+ T cell cluster (C2) expressing CD45RA+PD1loTbethiEomeslo was significantly higher in the pretherapy BMAs of R versus NRs (11.2% versus 2.5%; p=0.002), and was further expanded in R not in NRs in the EOC1, EOC2, and EOC4 BMAs (Fig 2C). Cohort 2: 20 pts with R/R AML, med salvage 2 (range 1-2), med age 68 (range, 25-83), secondary AML (36%), adverse cytogenetics (25%), and common molecular mutations TP53 in 5, RAS in 4, DNMT3A/ASXL1 in 2 pts each, were enrolled. 14 pts enrolled before May 1, 2018 were evaluable for response: 6 CR/CRp/CRi (43%) (including 2 CR, 2CRp, 2CRi), 2 stable disease 〉 6 mths, and 6 no response. The 8-wk mortality was 0. Grade 3/4 irAEs noted in 26% of the pts, most common pneumonitis. Med cycles to response of 2 (1-3). The med OS for all pts was not reached and the projected 1-yr OS in R/R AML was encouraging at 58% (Fig 1). Conclusion: AZA+Nivo was effective in pts with AML in Salvage 1 or those with increased pretherapy CD3+ BM infiltrate by MFC or IHC. BM CD3 and CD8 are simple assays to select pts for future trials of AZA+PD1 inhibitors in AML. AZA+Nivo+Ipi had a encouraging CR/CRp/CRi rate (43%) and med OS (NR) in pts with salvage 1/2 AML and is enrolling. Disclosures Daver: BMS: Research Funding; ImmunoGen: Consultancy; Sunesis: Consultancy; Incyte: Research Funding; Novartis: Consultancy; Karyopharm: Consultancy; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Consultancy; Karyopharm: Research Funding; Pfizer: Research Funding; Kiromic: Research Funding; ARIAD: Research Funding; Otsuka: Consultancy; Sunesis: Research Funding; Incyte: Consultancy; Alexion: Consultancy. Cortes:novartis: Research Funding. Ravandi:Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Jazz: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau. Kadia:Takeda: Consultancy; Abbvie: Consultancy; BMS: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Research Funding; Abbvie: Consultancy; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; abbvie: Research Funding; cellectis: Research Funding. DiNardo:Celgene: Honoraria; Medimmune: Honoraria; Abbvie: Honoraria; Karyopharm: Honoraria; Bayer: Honoraria; Agios: Consultancy. Pemmaraju:daiichi sankyo: Research Funding; SagerStrong Foundation: Research Funding; Affymetrix: Research Funding; novartis: Research Funding; abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; plexxikon: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-120157

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7