scholarly journals Early Intracranial Hemorrhages in Acute Promyelocytic Leukemia: Analysis of Neuroradiological and Clinico-Biological Parameters

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5170-5170
Author(s):  
Carmelo Gurnari ◽  
Francesca Di Giuliano ◽  
Mariadomenica Divona ◽  
Alfonso Piciocchi ◽  
Laura Cicconi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Acute Promyelocytic Leukemia ◽  
Arteriovenous Malformations ◽  
Promyelocytic Leukemia ◽  
Small Sample ◽  
Biological Parameters ◽  
Advisory Committees ◽  
Poor Outcome ◽  
Perilesional Edema ◽  
Swirl Sign

Introduction In the last decades, survival outcomes tremendously improved in acute promyelocytic leukemia (APL) due to all‐trans retinoic acid (ATRA)/anthracycline‐based chemotherapy, and more recently ATRA/arsenic trioxide (ATO) combinations. Despite the excellent results, with response rates exceeding 90%, early death (ED), mainly due to hemorrhagic complications occurring during the first 30 days after diagnosis, remains an unsolved issue. The prevalence of ED is largely underestimated due to discrepancies between data deriving from clinical trials, reporting 3-10% rates, and real-life, where it ranges from 10 to 30% of cases, and still remains the dominant cause of poor outcome. The most common site of bleeding is the brain (65%), particularly in fatal cases. Many theories have been proposed to elucidate the pathophysiology of this complication, considering the coagulopathy of APL and the perturbed homeostasis as primum movens, but no specific neuroradiologic studies have been conducted so far. Moreover, there is no specific predictor for bleeding events in APL, with exception of increased white blood cell counts (WBC). Patient and Methods We retrospectively identified 38 patients with APL (23 males and 15 females with a median age of 51.83 years, range 11-82), consecutively diagnosed at our Institution between 2004 and 2019, and treated with standard ATRA-based induction (Table 1). Occurrence of ED and ICH was then correlated with clinico-biological parameters, selecting for commonly reported variables predictors of these complications. In addition, CT scans of the 5 patients who experienced an intracranial hemorrhage (ICH) were revised by an expert neuroradiologist, looking for radiographic predictors of poor outcome (Al-Mufti et al 2018). Results Approximately 13% (5/38) of our APL patients experienced an ICH during induction therapy, which was fatal in 3 cases, while the overall incidence of ED was about 10% (4/38, including 1 case of death due to a differentiation syndrome). Looking at clinico-biological variables, the only predictor of ICH was a lower albumin level at baseline (3.8 vs 4.2 gr/dl; p=0.022), as compared to patients who did not experience ICH. A high Sanz-risk score was present in 2 of 3 pts with a fatal outcome of ICH (67% of cases), together with a shorter activated partial thromboplastin time (aPTT, 0.75 vs 0.86 ratio)(Table 1). Looking at neuroradiological findings (Figure 1) the three fatal cases showed a wider ICH volume, with perilesional edema and, interestingly, a positive "swirl" sign, which is defined as a marker of ongoing extravasation of blood within a hematoma. Both cases with a favourable outcome had a cerebellar involvement, without perilesional edema, and no major involvement of basal ganglia or thalamus. None of the patients had radiological signs of arteriovenous malformations. Conclusions Our data remark the impact of lower albumin levels at baseline and of a high Sanz-risk category on ED in patients with APL. In APL cases with fatal ICH, the thrombo-hemorrhagic imbalance is more profound than in other AMLs and results in a more devastating clinical picture. Taking into account the limitations of the small sample size, we found that a wide hemorrhage volume with perilesional edema, and the presence of the "swirl" sign are characteristic of fatal cases, while arteriovenous malformations did not seem to play a predisposing role. Further studies including large series of patients are warranted to identify the characteristics and the possible strategies to ameliorate the outcome of ICH in APL. Disclosures Venditti: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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.

Aberrant Expression of the MLL5, BAALC, ID1, and WT1 Genes Is Associated with Higher Induction Mortality and Poorer Overall Survival in Acute Promyelocytic Leukemia Patients Treated with ATRA and Anthracycline-Based Chemotherapy: An International Consortium On Acute Promyelocytic Leukemia Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1407-1407
Author(s):  
Antonio R Lucena-Araujo ◽  
Rafael Henriques Jacomo ◽  
Haesook T Kim ◽  
Raul A Melo ◽  
Rosane Bittencourt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Board Of Directors ◽  
Acute Promyelocytic Leukemia ◽  
Outcome Prediction ◽  
Promyelocytic Leukemia ◽  
Advisory Committees ◽  
Aberrant Expression ◽  
Expression Levels ◽  
Gene Expression Levels

Abstract Abstract 1407 Background: Aberrant expression of MLL5, BAALC, ID1, and WT1 genes is frequently associated with inferior outcome in cytogenetically normal acute myeloid leukemia patients (Damm et al. Blood 2011; 117(17):4561–8). The expression levels of these genes vary in patients with acute promyelocytic leukemia (APL), but the clinical significance of these findings remains unclear. Objective: (1) to determine if the gene expression levels of MLL5, BAALC, ID1, and WT1 are associated with clinical outcome of APL patients treated with ATRA and anthracycline-based chemotherapy, (2) to generate an integrative score (IS) based on these potential prognostic factors and clinical parameters and (3) to use this score for outcome prediction in APL. Design and Methods: One hundred and fifty APL patients (age, 15–73y) from seven different Brazilian institutions and treated according to the IC-APL protocol were included. The treatment schedule was identical to the PETHEMA-LPA 2005, except for the replacement of idarubicin by daunorubicin; ATRA treatment was initiated immediately in all cases in which the diagnosis of APL was suspected based on morphology. Gene expression profile was analyzed by Real-time PCR. Integer weights for the IS were derived from Cox proportional hazard model, using overall survival (OS) as outcome parameter. Hazard ratios (HR) for OS were calculated for each variable separately (Table 1). Variables with P<0.05 in univariate analyses were included in the model. Variables considered for the model inclusion consisted in 2 clinical (WBC counts, albumin levels) and 5 molecular markers (FLT3-ITD status and gene expression levels of MLL5, BAALC, ID1, and WT1). Other candidates, such as age, platelet count, gender, ECOG performance status, PML breakpoint and FAB subtype were not significant and not included in the score. The HR were converted to integer weights according to the following: variables with HR < 1 were excluded from analyses; variables with HR 3 1 and < 1.5 were assigned a weight of 1; variables with HR 3 1.5 and < 2.5 were assigned a weight of 2; variables with HR 3 2.5 were assigned a weight of 3. The final score was the sum of these integer weights. Based on maximally selected rank statistics, the scores were grouped into 3 risk-groups: 0–5 (low-IS), 6–9 (intermediate-IS), and > 9 (high-IS). Results: The integrative weights of variables analyzed are summarized in Table 1. The IS was modeled in 137 patients (median score: 6; range, 1–17). According to PETHEMA-GIMEMA relapse risk criteria, 22%, 23% and 70% of patients assigned in the low-IS (n=46), intermediate-IS (n=57) and high-IS (n=34) groups were deemed high-risk of relapse (P<0.001). Overall, 118 (86%) patients achieved CR; the remaining 19 patients (14%) experienced early death due to hemorrhage (n=12), therapy-related infection (n=6) and differentiation syndrome (n=1). Induction mortality was significantly higher in the high-IS group (low: 2%; intermediate: 15%; high: 26%) (P=0.001). CR was achieved in the low-, intermediate-, and high-IS group in 98%, 84%, and 73% of the patients, respectively (P=0.007). With a follow-up of 24 months among survivors, patients assigned in the high-IS group had a lower 2-y OS rate (63%) compared with those in the intermediate- (80%) and low-IS groups (97%; P<0.001). Eight relapses were recorded. The IS was not predictive of relapses (P=0.351). Conclusions: Our results suggest that MLL5, BAALC, ID1, and WT1 expression levels are associated with clinical outcome and that the IS may become a useful tool for outcome prediction in APL. Disclosures: Lo-Coco: Cephalon: Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Löwenberg:Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Treatment of Elderly Patients with Acute Promyelocytic Leukemia: A Real Life Experience of the "Rete Ematologica Lombarda"

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3862-3862
Author(s):  
Valentina Mancini ◽  
Erika Borlenghi ◽  
Livia Leuzzi ◽  
Claudia Basilico ◽  
Massimo Bernardi ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Acute Promyelocytic Leukemia ◽  
Prognostic Score ◽  
Significant Proportion ◽  
Safety Data ◽  
Real Life ◽  
Promyelocytic Leukemia ◽  
Treatment Schedule ◽  
Advisory Committees ◽  
Adequate Treatment

Background Acute promyelocytic leukemia (APL) in the elderly has a favourable outcome in a significant proportion of patients (pts). Elderly and frail pts are usually treated with attenuated treatment schedules, mostly "according to medical judgment". The combination of all-trans retinoic (ATRA) and anthracycline-based chemotherapy (CT) has been the mainstay of treatment for many years. Alternative approaches, such as arsenic trioxide (ATO) and gentuzumab ozogamicin (GO) have recently been tested with success in this setting, even though no large series of elderly pts treated with CT-free first-line treatment have been published yet. Moreover, neither a "standard of care approach" nor a specific prognostic score system have been developed to guide physician in choosing the most adequate treatment schedule in this setting. Objective Aim of the present preliminary survey was to assess genetic and clinical features of APL in pts over 60 yrs. This cut off reflects the definition of "elderly patient" in most Italian APL GIMEMA trials. Moreover, both the real life outcome and safety data after either conventional anthracycline-based CT or alternative CT-free approaches were analysed. OS, response rate to either regimens and adverse event occurrence were collected. Methods This retrospective multicenter REL (Rete Ematologica Lombarda) survey, enrolled a total of 101 consecutive APL pts aged ≥60, treated between 2000-2018. Demographics, clinical data and therapy outcome data were recorded in a dedicated patient's report form. Statistical analysis was performed using the Kaplan Maier method, Log-rank test and Cox regression. Results For analysis, pts were grouped into different categories according to age and fitness. Tables 1 and 2 summarise clinical charcteristics and treatment administered. Performance status (PS) and number of comorbidities increase with age. Twentynine of 102 (28,4%) and 9/102 (8,8%) pts had a history of or subsequently developed a solid tumor respectively. High frequency of additive cytogenetic abnormalities was observed as well. CT+ATRA was preferentially administered, mostly with attenuated intensity, to younger pts with better PS, while ATO+ATRA was preferred in pts with reduced cardiac function and ATRA monotherapy was reserved to frail or over 80 yrs old pts. Rates of differentiation syndrome or infections or cardiac events were similar in the different treatment groups. Overall, complete remission (CR) rate after induction therapy was 94.16% [CI95%: 87,5%-97,8% ]. At a median follow-up of 40 mos (range 0-199), the overall relapse rate was 24%. Median time to relapse was 7 mos in 1/8 (12,5%) ATRA monotherapy treated pts and 13 mos (range 5-66) in the 23/68 (33,8%) pts receiving CT+ATRA. No relapse occurred among the 22 pts treated with ATO+ATRA (p 0.005). OS and EFS were significantly associated with pts' age (HR 9% and 7.6%; p<0.001); 35/101 (34,6%) deaths were observed, due to early deaths/toxicity (9/35; 25,7%), relapse or progressive disease (9/35; 25,7%), concurrent neoplasia (10/35; 28,5%), other cause (6/35; 17,1%). Deaths in ATO+ ATRA group occurred after CR, because of neoplasia. Both EFS (median 34 months , range 0.03-199) and OS were significantly higher in the ATO-based therapy group (p<0.0001). (Fig. 1-2) Conclusion This survey confirms that elderly and frail APL pts may benefit from ATO-based regimens. Reduced-dose antracycline-based CT, appears to be less effective, with high rate of relapse in elderly pts. Scoring systems and prospective data are needed in order to better define treatment strategies aiming to further improve outcome in this challenging but growing population. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria.

Impact of Additional Cytogenetic Abnormalities and Complex Karyotype on Event-Free Survival in Acute Promyelocytic Leukemia: Analysis from a Single Academic Center Plus the APML4 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-35
Author(s):  
Zachary D. Epstein-Peterson ◽  
Sridevi Rajeeve ◽  
Andriy Derkach ◽  
Jae H. Park ◽  
Eytan M. Stein ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Acute Promyelocytic Leukemia ◽  
Research Funding ◽  
Promyelocytic Leukemia ◽  
Complex Karyotype ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Cytogenetic Abnormalities

Background: Current risk stratification for patients with acute promyelocytic leukemia (APL) is based solely on the presenting white blood cell count. There are conflicting data concerning the prognostic relevance of additional cytogenetic abnormalities (ACA) beyond t(15;17) and whether the presence of such abnormalities might influence treatment decisions for patients with APL. This is especially unclear among patients receiving ATO given that many existing data are from patients treated prior to incorporation of ATO into treatment paradigms. We sought to determine the prognostic importance of ACA and complex karyotype (CK) in influencing event-free survival in patients with APL. Methods: We analyzed patients with APL evaluated at our center since 2005 and patients treated in the Australasian Leukaemia and Lymphoma Group APML4 study (frontline ATRA + ATO + idarubicin,Lancet Haematology2015). We included all patients with baseline karyotype and those without karyotype but with FISH at diagnosis revealing ACA. Chart review extracted patient, disease, and clinical data. Only patients who commenced induction therapy with an ATO-based regimen were included in this analysis to ensure uniformity of the study population and applicability of results to contemporary clinical practice in APL. We also included patients deceased early in the disease course (&lt;1 month). We excluded patients with absent follow-up information given our interest in relapse and patients who relapsed prior to transferring care to our center. We defined CK as the presence of &gt;1 ACA beyond t(15;17). Coagulopathy was defined as either APTT/mean laboratory normal APTT &gt;1.5, INR &gt;1.5 (PT/mean laboratory normal PT &gt;1.5 when INR and ISI unavailable), or fibrinogen &lt;100 mg/dL. We defined events as either relapse or death. Associations between time-to event outcomes and patient and disease characteristics were assessed were calculated using univariate Cox proportional hazards models in each study separately. Fixed-effect meta analyses was used to combine estimates from both studies. Results: A total of 168 patients were included (N = 49 MSKCC, 109 APML4); 6 patients were removed from the MSKCC cohort due to relapse prior to initial visit and one from APML4 due to lack of follow-up information (Table 1). The mean age at diagnosis was 47 years in the MSKCC cohort and 43 years in the APML4. Median follow-up among survivors was 36 months (MSKCC, range 2-144) and 54 months (APML4, range 28-96); overall survival is displayed in Figure 1. Forty-nine (31%) patients' disease harbored ACA (most commonly trisomy 8 in 25 patients), and 17 CK (12% MSKCC, 10% APML4, denominator excludes one patient with single ACA by FISH). The event-free survival did not differ between ACA+ and ACA- (Table 2), but patients with +CK harbored inferior EFS (9/139 events non-CK vs. 4/17 events CK). No other clinical parameters that we queried correlated with EFS. Conclusions: In a large cohort pooled from a single-center experience and a cooperative prospective trial, the presence of an ACA beyond t(15;17) did not influence EFS in patients with APL. However, our data suggested that CK influences EFS. Further studies could collect data from other cooperative trials and/or single institutions to garner adequate power to better address the question of CK influencing EFS and confirm these preliminary findings. If a convincing signal emerges, treatment paradigms could be altered in the context of a prospective study (for example, intensifying or prolonging treatment) towards overcoming this adverse effect. Disclosures Park: Minverva:Consultancy;Kite:Consultancy, Research Funding;Amgen:Consultancy, Research Funding;Intellia:Consultancy;Artiva:Membership on an entity's Board of Directors or advisory committees;AstraZeneca:Consultancy;Incyte:Consultancy, Research Funding;GSK:Consultancy;Juno Therapeutics:Research Funding;Autolus:Consultancy, Research Funding;Genentech/Roche:Research Funding;Fate Therapeutics:Research Funding;Servier:Consultancy, Research Funding;Takeda:Consultancy, Research Funding;Novartis:Consultancy;Allogene:Consultancy.Stein:Biotheryx:Consultancy;Bayer:Research Funding;Genentech:Consultancy, Membership on an entity's Board of Directors or advisory committees;Syndax:Consultancy, Research Funding;Seattle Genetics:Consultancy;Abbvie:Consultancy;Amgen:Consultancy;Celgene Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Agios Pharmaceuticals:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astellas Pharmaceuticals: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, Research Funding;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;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.Tallman:Bioline rx:Membership on an entity's Board of Directors or advisory committees;Amgen:Research Funding;Rafael:Research Funding;Orsenix:Research Funding;ADC Therapeutics:Research Funding;BioSight:Membership on an entity's Board of Directors or advisory committees, Research Funding;Glycomimetics:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;UpToDate:Patents & Royalties;KAHR:Membership on an entity's Board of Directors or advisory committees;Rigel:Membership on an entity's Board of Directors or advisory committees;Delta Fly Pharma:Membership on an entity's Board of Directors or advisory committees;Oncolyze:Membership on an entity's Board of Directors or advisory committees;Jazz Pharma:Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Membership on an entity's Board of Directors or advisory committees;Cellerant:Research Funding;Abbvie:Research Funding.

scholarly journals Practice Patterns and Real-Life Outcomes for Patients with Acute Promyelocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-22
Author(s):  
Jan Philipp Bewersdorf ◽  
Stephanie Prozora ◽  
Rong Wang ◽  
Nikolai A. Podoltsev ◽  
Rory M. Shallis ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Mortality Rate ◽  
Board Of Directors ◽  
Acute Promyelocytic Leukemia ◽  
Research Funding ◽  
Primary Outcome ◽  
Promyelocytic Leukemia ◽  
Early Mortality ◽  
Hospital Death ◽  
Advisory Committees

Background: Despite a potential for cure, a large proportion of patients with acute promyelocytic leukemia (APL) succumb early to hemorrhagic and thrombotic complications. Prompt initiation of all-trans retinoic acid (ATRA) has been associated with improved outcomes. However, little is known about the patterns of care and clinical outcomes of patients with APL in the United States (US) outside of the controlled trial setting. Method s : We identified APL patients (pts) included in the Vizient Clinical Database/Resource Manager (CDB/RM™), which includes patient demographics, hospital characteristics, charge-level medication usage, procedures and mortality data from over 100 academic health centers and affiliated hospitals. Initial inpatient encounters of adult APL pts (≥18 years) during 2014-2015 (most recent years available) were identified by ICD-10 code (C92.40; C92.42) or ICD-9 codes for acute myeloid leukemia (AML; 250.00, 205.02) plus receipt of ATRA for ≥3 days as monotherapy, or in combination with arsenic trioxide (ATO) or an anthracycline. The 3-day minimum ATRA requirement is intended to exclude AML patients who may have therapy initiated while awaiting diagnostic confirmation. Pts were excluded if information on discharge disposition or medication administration were missing or if patients had an ICD-9/10 code consistent with relapsed AML/APL. Primary outcome was a composite of in-hospital death or discharge to hospice. Pearson's Chi-square test was used to compare categorical variables in bivariate analysis. Multivariable logistic regression was used to examine associations between patient, hospital, and treatment characteristics with the primary outcome. We lacked information on laboratory test results needed to assess the impact of treatment on clinical outcomes. Results: We identified 486 pts treated at 76 hospitals. Patient demographic, treatment and hospital characteristics are shown in Table 1. Median length of stay was 30 days (interquartile range [IQR]: 22-36 days). Pts received a median of 26 days of ATRA (IQR: 12-34 days). The majority of pts was treated with ATRA + ATO (240 pts; 49.4%) or ATRA + anthracycline (146 pts; 30.0%), which are the standard of care for lower- and higher-risk APL, respectively. Forty-two pts (9.3%) received ATRA monotherapy and 58 (11.9%) were treated with ATRA + ATO + anthracycline. Forty-eight pts (9.9%) required endotracheal intubation. Overall, 54 (11.1%) pts experienced our composite adverse outcome of in-hospital death or transfer to hospice (45 pts [9.3%] died in the hospital; 9 pts [1.9%] were discharged to hospice). Among 45 pts who died in the hospital, median time to death was 17 days (IQR: 5-24 days) with 31.1% of deaths occurring during the first 7 days of hospitalization. Half of the pts (n=18; 50%) who died in the ATRA monotherapy group died within 5 days of admission. In bivariate analyses, age ≥66 years (22.9% vs. 7.9%; p&lt;0.001), endotracheal intubation (64.6% vs. 5.3%; p&lt;0.001), and ATRA monotherapy (42.9% vs. 8.1%; p&lt;0.001) were associated with an increased risk of poor outcome (i.e. inpatient death or discharge to hospice). Similar results were obtained from the multivariable logistic regression model (Table 2). Discussion: A substantial proportion (11%) of adults treated for APL in this large inpatient dataset died or were discharged to hospice. This likely underestimates the full mortality rate of APL, because our APL case definition excluded pts who received &lt;3 days of ATRA therapy, which may have been due to early mortality. Age≥66 years, receipt of ATRA monotherapy or ATRA + anthracycline was associated with higher odds of adverse outcomes. The higher mortality with ATRA + anthracycline compared to ATRA + ATO is likely due to an inherently higher disease risk, but the database lacked laboratory results (e.g. white blood cell count) needed to confirm that hypothesis. Early complications related to coagulopathy or differentiation syndrome that precluded co-administration of ATO or anthracycline could be a potential explanation for the high early mortality rate in pts receiving ATRA monotherapy. Disclosures Wang: Celgene/BMS: Research Funding. Podoltsev:Kartos Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Incyte: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Samus Therapeutics: Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Boehringer Ingelheim: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squib: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Arog Pharmaceuticals: Research Funding; Blueprint Medicines: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding. Huntington:Genentech: Consultancy; DTRM: Research Funding; Astrazeneca: Honoraria; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy; Pharmacyclics: Honoraria; TG Therapeutics: Research Funding. Neparidze:Janssen: Research Funding; GlaxoSmithKline: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Diagnostic committee member ; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Ma:BMS: Consultancy; Celgene/BMS: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Zeidan:Acceleron: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; CCITLA: Other; Leukemia and Lymphoma Society: Other; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Astex: Research Funding; MedImmune/Astrazeneca: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; ADC Therapeutics: Research Funding; Taiho: Consultancy, Honoraria; Aprea: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Davidoff:Celgene: Research Funding; Amgen: Consultancy; AbbVie: Consultancy.

scholarly journals Early Death in Patients with Disseminated Intravascular Coagulation during Induction Therapy for Acute Promyelocytic Leukemia: A Nationwide Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-31
Author(s):  
Kensuke Matsuda ◽  
Taisuke Jo ◽  
Kazuhiro Toyama ◽  
Kumi Nakazaki ◽  
Hideo Yasunaga ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Hospital Mortality ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Promyelocytic Leukemia ◽  
Hospital Death ◽  
Conventional Chemotherapy ◽  
Advisory Committees ◽  
Soluble Thrombomodulin

Background: Real-world data studies showed poorer outcomes in patients with acute promyelocytic leukemia (APL) than randomized controlled trials, because elderly patients were excluded in such trials. Reportedly, the main cause of death was severe bleeding due to disseminated intravascular coagulation (DIC) during induction therapy for APL. The management of DIC was therefore crucially important especially in elderly patients. This study aimed to clarify factors associated with in-hospital death in all patients, and elderly patients with DIC during induction therapy for APL. Study Design and Methods: We retrospectively identified 1,463 patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) between July 2007 and March 2018 from a nationwide inpatient database in Japan. In-hospital death was evaluated with multivariable logistic regression models in all patients, and in ≥60 year-old patients. Anticoagulants included recombinant human soluble thrombomodulin, delteparin (low molecular weight heparin), danaparoid sodium, gabexate mesilate, and nafamostat mesilate which were administered within three days from admission. Patients who died within three days from the admission were excluded from the study to avoid immortal time bias. Results: We identified a total of 1,138 (78%) patients who developed DIC. We excluded 23 patients who died within three days from the admission. The remaining 1,115 patients were analyzed. During hospitalization, 172 (15%) patients died at a median of 13 days (interquartile range: 7-30). Compared with younger patients (20 to 39 years old), elderly patients were significantly associated with higher in-hospital mortality (60 to 79 years old: odds ratio 5.58 [95% confidence interval 3.05-10.22], 80 years or older: 13.51 [6.07-30.08]). Patients who received ATRA monotherapy had significantly higher incidence of in-hospital death (2.48 [1.54-4.01]). Delayed initiation of ATRA was significantly associated with higher mortality (1.60 [1.11-2.30]). A total of 699 patients (63%) received anticoagulant therapies, but none of these were significantly associated with lower mortality. Use of multiple anticoagulants was significantly associated with higher in-hospital mortality (2.47 [1.16-5.26]). Subgroup analyses in patients ≥60 years old were then conducted. During hospitalization, 122 of 416 (29%) patients died at a median of 13 days (interquartile range: 7-29). Both late initiation of conventional chemotherapy and no conventional chemotherapy were significantly associated with higher in-hospital mortality (1.88 [1.01-3.49], 3.25 [1.74-6.06], respectively). Use of recombinant human soluble thrombomodulin and use of multiple anticoagulants were significantly associated with higher mortality (1.91 [1.09-3.35], 2.64 [1.01-6.90], respectively). Conclusions: Elderly patients who developed DIC during induction therapy for APL were significantly associated with higher in-hospital mortality. Immediate initiation of ATRA and early initiation of conventional chemotherapy may have contributed to preferable outcomes. Disclosures Matsuda: Kyowa Kirin: Speakers Bureau. Jo:Tsumura: Other: Belongs to joint program with Tsumura, Research Funding. Toyama:Bristol-Myers Squibb: Speakers Bureau; Eisai: Speakers Bureau; Kyowa Kirin: Speakers Bureau; Celgene: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Chugai Pharmaceutical,: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Otsuka Pharmaceutical: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Kurokawa:Ono: Research Funding, Speakers Bureau; Jansen Pharmaceutical: Speakers Bureau; Teijin: Research Funding; Eisai: Research Funding, Speakers Bureau; Shire Plc: Speakers Bureau; Nippon Shinyaku: Research Funding, Speakers Bureau; MSD: Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Research Funding, Speakers Bureau; Sanwa-Kagaku: Consultancy; Pfizer: Research Funding; Otsuka: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Bioverativ Japan: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau.

Pixantrone Dimaleate (PIX) and Comparators In the Treatment of Relapsed Aggressive Non-Hodgkin Lymphoma (aNHL): An Analysis of Response and Survival by Gender and Age

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4883-4883
Author(s):  
Jack Singer ◽  
Paul Cernohous ◽  
Gabor Jurida ◽  
Lixia Wang ◽  
Christine Kuepfer ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Subgroup Analysis ◽  
Complete Response ◽  
Study Groups ◽  
Small Sample ◽  
Phase 3 ◽  
Advisory Committees ◽  
Cell Therapeutics ◽  
Gender And Age

Abstract Abstract 4883 Introduction: Survival after treatment for aNHL is higher in women than men (Leuk Lymph 48:736-745, 2007) and may be worse in elderly patients. We conducted an exploratory demographic subgroup analysis of a phase 3 study that compared PIX, a novel aza-anthracenedione, to single agents in the treatment of patients with multiply relapsed aNHL. Overall, PIX was efficacious on the basis of primary and secondary endpoints. The results from these exploratory analyses suggest that PIX potentially is most efficacious in women and elderly patients even though there are no significant gender- or age-dependent differences in PIX pharmacokinetics. Patients and Methods: This phase 3, randomized, multicenter, controlled, open-label study enrolled patients who had ≥1 prior anthracycline-containing regimen and failed 2 prior treatment regimens for relapsed aNHL (de novo or transformed). Patients (N=140) were randomized to either PIX 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle, for up to 6 cycles, or to investigator's choice of a single-agent comparator (COMP): vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, or, in the US only, gemcitabine or rituximab. The primary endpoint was the complete response/complete response unconfirmed (CR/CRu) rate in the intent-to-treat population. Other efficacy endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Response was assessed by an independent radiologic panel. Results: A total of 140 patients were randomized (n=70 per group). The results of the analysis of efficacy by gender and age are shown in the table below. There were no important demographic differences between the study groups or between patients in these exploratory analyses. The differences in CR/CRu rate and ORR between the study groups appeared greater in women than in men and also in patients ≥65 years than in younger patients. PFS and OS were significantly better for women in the PIX group than in the COMP group. During the treatment period, neutropenia and leukopenia were the most common (≥10%) grade 3/4 adverse events and were similar by gender and age. Conclusions: In this phase 3 study, an exploratory subgroup analysis suggests that treatment with PIX appears to provide particular benefit in women and elderly patients and was not accompanied by a meaningful increase in toxicities. These results are limited by small sample sizes and would need to be validated with an additional prospective study. Disclosures: Singer: Cell Therapeutics, Inc: Employment, Membership on an entity's Board of Directors or advisory committees; DiaKine Therapeutics, Inc: Membership on an entity's Board of Directors or advisory committees. Cernohous: Cell Therapeutics, Inc: Employment. Jurida: Cell Therapeutics, Inc: Employment. Wang: Cell Therapeutics, Inc: Employment. Kuepfer: Cell Therapeutics, Inc: Consultancy, Equity Ownership. Pettengell: Cell Therapeutics, Inc: Honoraria.

CCND1 and CCND2 Mutations Are Frequent in Adults with Core-Binding Factor Acute Myeloid Leukemia (CBF-AML) with t(8;21)(q22;q22)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2740-2740
Author(s):  
Ann-Kathrin Eisfeld ◽  
Jessica Kohlschmidt ◽  
Sebastian Schwind ◽  
Deedra Nicolet ◽  
James S. Blachly ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Amino Acid ◽  
Board Of Directors ◽  
Sanger Sequencing ◽  
Small Sample ◽  
Wild Type ◽  
Advisory Committees ◽  
Cell Counts ◽  
Recurrent Mutations ◽  
Frequent Mutations

Abstract CBF-AML is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11. The resulting fusion genes require a "second hit" to initiate leukemogenesis. Although compared with other AML subtypes patients with CBF-AML have a relatively favorable prognosis, still almost 40% of CBF-AML patients experience relapses of their disease. Mutation assessment of 84 leukemia- and/or cancer-associated genes using a customized targeted next-generation sequencing (NGS) approach was done on samples from 177 adults with CBF-AML [t(8;21), n=68; inv(16)/t(16;16), n=109]. We identified frequent mutations in the CCND1 and CCND2 genes as novel molecular alterations in AML with t(8;21). They were detected in 10 (15%) patients with t(8;21), making CCND1/2 mutations the third most frequently detected mutations in t(8;21) AML patients. In contrast, we found a single CCND2 mutation in only 1 (0.9%) patient with inv(16), and CCND1/2 mutations in only 11 of 1,426 non-CBF-AML patients (0.77%). Testing for CCND1 and CCND2 mutations using Sanger sequencing in additional 25 CBF-AML patients with t(8;21), for whom NGS analysis was not possible, identified 3 CCND1/2 mutated patients, thereby confirming the CCND1/2 mutation frequency in t(8;21) AML (15% in the NGS set, and 12% in Sanger sequencing set). All CCND2 mutations cluster around the highly conserved amino acid residue threonine 280 (Thr280), and encode a degradation-resistant CCND2 protein. Curiously, de novo germline CCND2 mutations affecting the identical amino acid residues Thr280 or Pro281 have been recently found to cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) type 3, an extremely rare neurodegenerative disorder (Mirzaa et al., Nat Genet. 2014;46:510-5). The variant allele fractions of the detected CCND1/2 mutations were variable, suggesting that these mutations can represent both early and later mutational events. Interestingly, three of the 11 CCND1/2 mutated patients had two different CCND1/2 mutations, suggesting a dependence of their leukemia on this mutational event. The evaluation of mutations in other genes found in CBF-AML patients with CCND1/2 mutations did not reveal any statistically significant co-occurring or mutually exclusive mutations. The most frequent mutation co-occurring with CCND1/2 was ASXL2, detected in 4 of the 10 (40%) cases with t(8;21). Patients with CCND1/2 mutations presented with lower percentages of blood (P=0.02) and bone marrow (P=0.05) blasts than patients without these mutations, but did not differ significantly with regard to other pretreatment characteristics. No differences in the achievement of complete remission, disease-free or overall survival were observed between CCND1/2 mutated and CCND1/2 wild-type patients. Mechanistically, we show that Thr280Ala mutated CCND2 significantly increased cell growth (as assessed by TiterGlo assays and cell counts) in all experimental set-ups. Western blotting revealed an increase of retinoblastoma gene phosphorylation, indicating increased downstream signaling. Moreover, both propidium iodide mediated cell cycle analysis and immunofluorescence staining for phospho-histone H3 indicated an increased mitotic rate and a decreased G1 fraction. In summary, recurrent mutations in CCND1/2 are consistent with the currently known mutational landscape of t(8;21) AML, which is dominated by receptor tyrosine kinase, RAS, and chromatin remodeling gene mutations─all of which can result in targeting of CCND1/2. While CCND1 and CCND2 play a crucial role in the regulation of hematopoietic differentiation and cell proliferation, and their differential activation has been implicated in leukemogenesis, frequent mutations in these genes have not previously been reported in AML. The fact that no outcome difference was seen when comparing CCND1/2-mutated versus wild-type patients may be due to the relatively small sample size, or may possibly reflect the common use of cell cycle affecting high-dose cytarabine-based therapy in CBF-AML patients. Thus, the identification of CCND1/2 mutations as frequent mutational events in t(8;21) AML may provide further justification for cell cycle-directed therapy in this disease. Disclosures Stone: Merck: Consultancy; Karyopharm: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; Juno Therapeutics: Consultancy; ONO: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy; Celator: Consultancy; Agios: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Dicentric t(8;13)(q10;q10) as an additional chromosomal abnormality in a case of acute promyelocytic leukemia with very poor outcome

2009 ◽  
Vol 50 (2) ◽  
pp. 287-289 ◽  
Author(s):  
Luize Otero ◽  
Bruno Terra ◽  
Cláudia Diniz ◽  
Eliana Abdelhay ◽  
Teresa De Souza Fernandez
Keyword(s):  
Acute Promyelocytic Leukemia ◽  
Chromosomal Abnormality ◽  
Promyelocytic Leukemia ◽  
Poor Outcome

scholarly journals Heterozygosity for Loss-of-Function Mutation in SERPINE1 (PAI-1 Gene) Linked with Longer Absolute Telomere Length

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4953-4953
Author(s):  
Sweta Gupta ◽  
Sadiya Khan ◽  
Sanjiv Shah ◽  
Ekaterina Klyachko ◽  
Abigail S Baldridge ◽  
...  
Keyword(s):  
Clinical Research ◽  
Telomere Length ◽  
Board Of Directors ◽  
Cellular Senescence ◽  
Small Sample ◽  
Loss Of Function ◽  
Advisory Committees ◽  
Restriction Fragments ◽  
Research Protocols ◽  
Pai 1

Abstract Introduction: Plasminogen activator inhibitor-1 (PAI-1) is an important component of the senescence-associated secretome that contributes directly to cellular senescence. Telomeres, the nucleotide repeat structures located at the ends of chromosomes, shorten progressively with each round of cellular replication and telomere attrition is associated with cellular senescence. In murine models, genetic or pharmacologic inhibition of PAI-1 results in preservation of telomere length. Identification of a unique Amish kindred that harbors a loss-of-function mutation in SERPINE1 (c.699_700dupTA), which encodes PAI-1, provides a novel opportunity to assess the effects of lifelong PAI-1 deficiency on leukocyte telomere length (LTL) in humans. Methods: We conducted an observational study in the Old Order Amish, a founder population who originally settled in Berne, Indiana characterized by a homogeneous diet and lifestyle, and included participants aged 18 years and older. All study participants were genotyped for the c.699_700dupTA frameshift mutation in SERPINE1. For the primary analysis, we excluded participants who were homozygous for the null SERPINE1 mutation (n=7) due to their young age (18-34 years old) and small sample size. Relative LTL was quantified from peripheral blood using Southern blot of the terminal restriction fragments. We tested the association of SERPINE1 mutation status with LTL, after adjustment for age, sex, and relatedness in SOLAR. Results: A total of 170 participants were enrolled with mean age 46±19 years. Forty-three participants were identified as carriers of the null SERPINE1 mutation with an overall minor (null) allele frequency of 16% in the study population. SERPINE1 carriers had a significantly greater LTL compared with noncarriers, after adjustment for age, sex, and family structure (p=0.039; FIGURE). Every 1-year increase in age of study participant was associated with a 30 base pair decrease in LTL (p<0.0001). Conclusions: Heterozygosity for the null SERPINE1 gene, encoding a senescence-associated protein, PAI-1, is associated with longer LTL in a rare loss-of-function cohort. In addition, LTL is strongly and inversely correlated with chronologic age and supports the hypothesis that PAI-1 may contribute to cellular and organismal aging as reflected by LTL. Figure Mean telomere restriction fragments (kilobase pairs) as a function of age and genotype Figure. Mean telomere restriction fragments (kilobase pairs) as a function of age and genotype Disclosures Shapiro: CSL Behring: Other: Clinical research protocols; Kedrion Biopharma: Consultancy; Daiichi Sankyo: Other: Clinical research protocols; OPKO: Other: Clinical research protocols; National Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Other: Clinical research protocols; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Baxter/Baxalta/Shire: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Biogen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical research protocols; Genentech: Membership on an entity's Board of Directors or advisory committees; American Thrombosis and Hemostasis Network: Other: Medical Director; ProMetic Life Sciences: Consultancy; Bayer healthcare Pharmaceuticals: Other: International network on pediatric hemophilia; Novartis: Other: Clinical research protocols; Selexys: Other: Clinical research protocols; Octopharma: Other: Clinical research protocols.

scholarly journals Predicting Response to Hypomethylating Agents in Patients with Myelodysplastic Syndromes (MDS) Using Artificial Intelligence (AI)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2089-2089
Author(s):  
Nathan Radakovich ◽  
Mikkael A. Sekeres ◽  
Cameron Beau Hilton ◽  
Sudipto Mukherjee ◽  
Jacob Shreve ◽  
...  
Keyword(s):  
Neural Network ◽  
Sample Size ◽  
Board Of Directors ◽  
Research Funding ◽  
Validation Cohort ◽  
Data Monitoring Committee ◽  
Small Sample ◽  
Patient Specific ◽  
Hypomethylating Agents ◽  
Advisory Committees

Introduction While the hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) improve cytopenias and prolong survival in MDS patients (pts), response is not guaranteed. Timely identification of non-responders could prevent prolonged exposure to ineffective therapy, thereby reducing toxicities and costs. Currently no widely accepted clinical or genomic models exist to predict response or resistance to HMAs. We developed a clinical model to predict response or resistance to HMA after 90 days of initiating therapy based on changes in blood counts using time series analysis technology similar to the kind used in Apple's Siri or Google Assistant. In the setting of voice recognition, the sequence and context of words determines the meaning of a sentence; similarly, we hypothesized that the pattern of changes in MDS pts' blood counts would predict response or resistance early during treatment. Methods We screened a cohort of 107 pts with MDS (per 2016 WHO criteria) who received HMAs at our institution between February 2005 and July 2013 and had regular CBCs drawn during treatment. Mutations from a panel of 60 genes commonly mutated in myeloid malignancy were included. Responses were assessed after 6 months of therapy per International Working Group (IWG) 2006 criteria. Pts were divided randomly into training (80%) and validation (20%) cohorts. To address the potential for bias due to a small sample size, an oversampling algorithm was used to cluster similar pts based on their CBC data, Revised International Prognostic Scoring System (IPSS-R) score, and % bone marrow blasts at the time of diagnosis. CBC data from the first 90 days of treatment were fed into deep neural network (recurrent neural network) and decision tree algorithms, which were trained to predict whether pts would achieve a response (defined as complete remission (CR), partial remission (PR), or hematologic Improvement (HI)). Area under the curve (AUC) was used to assess model performance. Important features that impact the algorithm's predictions were extracted and plotted. Results 20747 unique data points were used, including CBC, clinical and genomic data. Among 107 pts, 61 (57.0%) received AZA only, 19 (17.8%) DAC only, 4 (3.7%) received both DAC and AZA, and 23 (21.5%) received HMA with an additional agent. Median age was 69 years (range: 37-100 years), and 27 (26.4%) were female. Forty pts (37.4%) were very low/low risk, 32 (29.9%) intermediate, 19 (17.8%) high, and 16 (14.9%) very high risk per IPSS-R. Responses included 23 (22.5%) CR, 2 (1.9%) marrow CR, 4 (3.9%) PR, and 20 (19.6%) HI. The most commonly mutated genes were ASXL1 (17.6%), TET2 (16.7%), SRSF2 (15.7%), SF3B1 (11.8%), RUNX1 (10.8%), STAG2(10.8%), and DNMT3A (10.8%). The median number of mutations per sample was 1 (range, 0-11), and 40 pts (39.2%) had > 3 mutations per sample. When trained using absolute values and changes in CBC values, the model's AUC was 0.95 in the training cohort and 0.83 in the validation cohort. When the cohort was oversampled to 1000 pts, the validation cohort AUC increased to 0.89. Feature extraction algorithms identified increases in MCV and RDW during weeks 2-8 of treatment, increased proportion of lymphocytes, decreased proportion of monocytes, and increased platelet counts during weeks 6-8 as factors favoring response to HMA. The model provides personalized, patient-specific predictions that correlate with blood counts (Figure 1). Conclusions We describe a machine learning model that monitors changes in blood counts during therapy with HMA to predict response or resistance to HMA in MDS pts. Such a model can be used to develop novel trial designs wherein pts predicted to not respond after 90 days of HMA treatment could be assigned to an investigational agent. Conversely, it would help inform the decision to continue HMA therapy in pts predicted to respond. Increasing sample size with oversampling dramatically increased model accuracy; a larger cohort of pts treated at different institutions is currently under development. Disclosures Sekeres: Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; McGraw Hill Hematology Oncology Board Review: Other: Editor; Bristol-Myers Squibb: Speakers Bureau. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Nazha:Novartis: Speakers Bureau; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; MEI: Other: Data monitoring Committee.

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