bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sorafenib plus 5-azacytidine (AZA) in older untreated FLT3-ITD mutated AML.
Authors: Ohanian Maro , Garcia-Manero Guillermo , Levis Mark J. , Jabbour Elias , Daver Naval Guastad , Borthakur Gautam , Kadia Tapan M. , Brandt Mark , Pierce Sherry , Burger Jan Andreas , Richie Mary Ann , Patel Keyur , Cortes Jorge E. , Kantarjian Hagop M. , Ravandi Farhad 
Published: September 2018

7029 Background: Sorafenib plus 5-azacytidine (AZA) is observed to be safe and effective in relapsed / refractory FLT3-ITD mutated acute myeloid leukemia (AML) patients (pts). Hypothesis: Combining sorafenib with AZA is safe and effective in older untreated FLT3-ITD mutated AML pts. Methods: Eligibility included: untreated FLT3-ITD mutated AML (≥10% mutation burden), age ≥60 yrs, adequate organ function, and ECOG performance status ≤ 2. The regimen was: AZA 75 mg/m2daily x 7 days and sorafenib 400 mg twice daily for 28 days. Results: 26 pts with untreated AML [median age 73 (61-86)] were enrolled: 16 (62%) pts had normal karyotype, 2 (8%) complex karyotype, 4 (15%) other miscellaneous abnormalities, and 4 (15%) with insufficient metaphases. Prior to the initiation of treatment, FLT3-ITD was detected in all pts with a median allelic ratio of 0.3735 (0.009-0.885). The overall response rate (ORR) in 25 evaluable pts was (76%) [7 (28%) with CR, 10 (40%) CRi/CRp, and 2 (8%) PR]. Pts underwent a median of 3 (1-35) treatment cycles. The median number of cycles to response was 2 (1-4), and the median time to achieve response, 1.77 months (mos) (0.689-4.271 mos). The median duration of CR/CRp/CRi is 14.5 mos (1.18—28.74). Three (18%) responding pts (CR, CRp, CRi) have proceeded to allogeneic stem cell transplant. With a median follow-up of 6.8 mos (0.2-18.8), 6 pts are alive, 3 in remission (CR/CRP/CRi). The median overall survival (OS) for the entire group is 8.3 mos; 9.2 mos in 17 responders. Evaluable pts treated with AZA + sorafenib (n = 25) were compared to a matched cohort of historical FLT3-ITD mutated pts > 60 yrs, but treated with hypomethylator-based (HMA) therapy without sorafenib (n = 20); the respective ORR (CR, CRp, CRi, PR) (76% vs. 70%, p = 0.653) and median OS (8.3 and 9.4 mos, p = 0.69) were similar. The remission duration for the responding pts treated with AZA+sorafenib was significantly longer (14.5 mos) than those on other HMA regimens without sorafenib (3.8 mos) (p = 0.01). Adverse events possibly attributable to the regimen included: grade (Gr) 1/2 nausea (n = 3), Gr 1/2 diarrhea (n = 2), Gr 1 dyspnea (n = 1), and Gr 1 breast pain (n = 1). Conclusions: The combination of AZA and Sorafenib is both well tolerated and effective in older untreated FLT3-ITD mutated AML. Clinical trial information: NCT02196857;NCT01254890.
Clinical observations of AML expressing mutant RUNX1 and pre-clinical studies of RUNX1-targeted novel therapy of AML.
Authors: Dinardo Courtney Denton , Mill Christopher P , Fiskus Warren , Saenz Dyana T , Nowak Agnieszka J , Sun Baohua , Patel Keyur , Kadia Tapan M. , Benton Christopher Brent , Takahashi Koichi , Kantarjian Hagop M. , Bhalla Kapil N. 
Published: September 2018

7030 Background: Runt-related transcription factor 1 ( RUNX1) is critically involved in normal and malignant hematopoiesis. Somatic mutations in RUNX1 occur in ~10% of AML, especially in older patients with history of radiation or antecedent hematologic disorder. Presence of mRUNX1 is reported to confer relative resistance to therapy and poorer prognosis in AML, and there are no mRUNX1-targeted or specific therapies available. Methods: We retrospectively analyzed outcomes of 94 mRUNX1 and 444 wild-type RUNX1 AML patients treated at our institution from 9/2013 to 12/2016. We also determined the pre-clinical efficacy of a targeted therapy against cultured and primary AML cells expressing mRUNX1. Results: 67% of mRUNX1 patients were > 65 years of age. Co-occurring mutations with mRUNX1 were ASXL1 (33%), N/KRAS (20%), FLT3 (20%), IDH2 (18%), IDH1 (13%) and TET2 (10%). In patients > 65 years treated with hypomethylating agent-based therapy, the presence or absence of mRUNX1 did not impact response rate (42% vs 46% CR/CRp, p = 0.67), median event-free survival (3.4 vs 4.7 mo, p = 0.82) or overall survival (11.5 vs 9.3 mo, p = 0.97). In mRUNX1 expressing AML OCI-AML5 and MonoMac1 cells, knockdown of RUNX1 by shRNA repressed its targets, e.g., MYC and PU.1, inhibited growth and induced apoptosis. Ex vivo knockdown of RUNX1 abrogated in vivo leukemia initiation by OCI-AML5 cells. After engraftment, inducible shRNA-mediated in vivo knockdown of RUNX1 restored survival of immune-depleted NSG mice engrafted with OCI-AML5 cells. RUNX1 transcription is driven by a super enhancer occupied by the bromodomain extraterminal protein (BETP), BRD4. Accordingly, BRD4 knockdown by shRNA or treatment with the BRD4-inhibitor OTX015 depleted RUNX1 and its targets, and induced apoptosis of AML cells. Treatment of OCI-AML5 cell-engrafted NSG mice with OTX015 (50 mg/Kg/day X 5, for 3 wks) reduced AML burden and improved survival (p < 0.01). Co-treatment with the BETi and BCL2 inhibitor venetoclax or CDK4/6 antagonist palbociclib or decitabine synergistically induced apoptosis of OCI-AML5 and primary AML blasts. Conclusions: These findings highlight a novel, promising, BETP antagonist-based therapy of AML expressing mtRUNX1.
Exposure-adjusted adverse events (AEs) comparing blinatumomab to standard of care (SOC) chemotherapy in patients (pts) with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) from a randomized phase III study.
Authors: Stein Anthony Selwyn , Larson Richard A. , Schuh Andre C. , Stevenson William , Lech-Maranda Ewa , Nie Kun , Zimmerman Zachary Franklin , Kormany William , Topp Max S. 
Published: September 2018

7032 Background: Blinatumomab (blin), a bispecific T-cell engaging antibody construct, has shown improved overall survival vs SOC in pts with r/r ALL in a randomized phase 3 study ( Haematologica 2016;101:S129). To better evaluate safety, we compared AEs of blin vs SOC after adjusting for varying treatment exposure times. Methods: Adults ≥ 18 yrs with r/r ALL (refractory, 1st relapse < 1 yr, ≥ 2 relapses or relapse after transplant) were randomized to receive blin or SOC (1 of 4 predefined regimens). Blin was dosed by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (9 µg/d on d1−7 in cycle 1, then 28 µg/d); up to 4 maintenance cycles (4 wks on/8 wks off) were allowed for ≤ 12 mo. Exposure-adjusted (exp-adj) event rates were calculated as no. of events*100/total exposure time (Table). Results: Median (range) no. of cycles were 1 (1−4) for SOC and 2 (1−9) for blin. The highest exp-adj rates (per 100 pt-yrs) were for pyrexia (507 SOC vs 376 blin), anemia (987 vs 229), thrombocytopenia (750 vs 126) and neutropenia (351 vs 121), all lower in blin. Febrile neutropenia (365 vs 93) and infections (1216 vs 436) were also both lower in blin (p < 0.0001). Exp-adj rates for neurologic events were 743 SOC vs 472 blin, with median time (range) to onset of 7 (1−43) d and 7 (1−190) d, respectively, and gr ≥ 3 cytokine release syndrome (CRS) rates were 0 SOC vs 10 blin. The most frequent AEs in both cycles 1 and 2 were pyrexia, nausea and anemia in both arms; CRS events decreased in the blin arm between cycles 1 and 2 (14% vs 2%). Most fatal AEs were related to infection in both arms. Conclusions: Here blin showed an AE profile consistent with that previously reported for r/r ALL, including similar rates of manageable CRS and neurologic events. Exp-adj AE rates were generally higher in SOC vs blin, including for cytopenias and infections. Clinical trial information: NCT02013167. [Table: see text]
Response and survival rates with frontline hypomethylating agent (HMAs) in favorable risk AML.
Authors: Grunwald Michael Richard , Peters Daniel T. , Robinson Myra M. , Zimmerman Michael Keith Allister , Ai Jing , Knight Thomas Gregory , Lalli Peter N. , Block Jared G. , Smith Elton Travis , Lipford Edward H. , Copelan Edward Alan , Symanowski James Thomas , Gerber Jonathan Michael 
Published: September 2018

7039 Background: HMAs are an accepted frontline therapy for AML patients (pts) who are unfit for intensive induction therapy (IIT), particularly pts with unfavorable cytogenetics and/or p53 mutations. However, little is known about the response of favorable risk AML to HMAs. We previously reported that NPM1 mutated and/or CD34- AML status were predictors of response to HMAs. Here, we evaluated responses to frontline HMAs in AML. Methods: A total of 117 patients with de novo AML diagnosed between 7/2013 and 9/2016 were evaluated based on pt and disease related variables, overall response rate (ORR = CR + CR with incomplete count recovery + hematologic remission (ANC > 1000/µL, Hgb > 10g/dL, Plts > 100,000/µL, & no circulating blasts)), and overall survival (OS). Categorical variables were compared using Fisher’s exact test. Kaplan Meier methods estimated survival outcomes, and log rank tests compared survival between groups. Multivariable analyses were performed using Cox proportional hazards models. Results: 51 pts, considered unfit for IIT, received frontline HMAs. ORR and OS were highest in the ELN favorable risk AML pts (n = 13; ORR = 92%, p = .009; median OS = 17.5 months, p = .022). Among 41 NPM1 mutated pts, 15 received HMAs; and 26 received intensive induction. ORRs were 73% and 84%, respectively (p = .434). No difference was found in OS distributions between the HMA and IIT groups in univariate and multivariate (adjusted for age and FLT3 status) models (p = .329 and .241, respectively). Interestingly, ORR was 100% among 9 HMA-treated pts with NPM1 mutated, CD34-, FLT3/ITD-, cytogenetically normal AML. Conclusions: HMA therapy is highly effective frontline treatment in favorable risk AML pts considered unfit for IIT. Survival results with HMAs in NPM1 mutated AML are comparable to those of fitter pts treated with IIT. In selected favorable risk pts considered unfit for standard induction, HMAs can be a successful bridge to potentially curative therapy, including more intensive therapy or transplant. Cytogenetically normal AML with an isolated NPM1 mutation and CD34- status appears to be exceptionally responsive to frontline treatment with HMAs. Prospective validation of these findings is necessary.
Emotion and Symptom-focused Engagement (EASE): A randomized pilot trial of an integrated psychosocial and palliative care intervention for individuals with acute leukemia (AL).
Authors: Rodin Gary , Malfitano Carmine , Rydall Anne , Lo Christopher , Schimmer Aaron David , Marmar Charles , Zimmermann Camilla 
Published: September 2018

7041 Background: Individuals diagnosed with AL may experience severe physical and psychological distress due to the illness and its treatment, the threat of relapse and treatment failure, and a high risk of mortality. To alleviate psychological and physical distress in this population, we developed a novel, 8-week, manualized intervention called EASE. This includes: 1) EASE-psy- a tailored psychotherapeutic component to reduce psychological distress; and 2) EASE-phys-symptom screening, with moderate to severe physical symptoms triggering early palliative care. Methods: To assess the feasibility and preliminary efficacy of EASE, patients were recruited within 2 weeks of admission to a comprehensive cancer center and randomized to receive either EASE or usual care (UC). Physical and psychological symptoms were assessed at baseline, 4, 8 (primary endpoint), and 12 weeks. Intervention patients received 6-10 psychotherapy sessions over 8 weeks, weekly assessment of physical symptoms, and consultation and follow-up by palliative care, when needed. One-way ANOVA was performed to assess mean change scores over time between groups. Results: Forty-two patients were randomized to EASE (n = 22) or UC (n = 20). Predefined feasibility outcomes were all met: > 86% (19/22) of EASE participants (goal > 64%) completed > 50% of proposed EASE-psy sessions; 64% (14/22) completed symptom screenings (goal > 50%); and 100% of those with moderate to severe symptoms had > 1 meeting with the EASE-phys team (goal 100%). There were statistically significant findings favoring EASE vs. UC for satisfaction with care at 8 and 12 weeks (Δ: -3.12 vs 7.39, p < 0.04; -6.1910 vs 0.0125 p < 0.03). There were trends favoring EASE vs. UC for traumatic stress symptoms, depressive symptoms, quality of life, attachment security, and number, severity, and distress related to physical symptoms at 4, 8, and 12 weeks. Conclusions: Although not powered for statistical significance, this randomized pilot trial of EASE for AL showed promising reductions in psychological and physical distress and supports the feasibility and need for a larger randomized controlled trial. Clinical trial information: NCT02353559.
Unsupervised hierarchical clustering of surface antigen expression to identify normal karyotype AML patients with distinct disease characteristics and poor outcome.
Authors: Jentzsch Madlen , Bill Marius , Schuhmann Luba , Grimm Juliane , Schulz Julia , Schubert Karoline , Knyrim Maria , Schmalbrock Laura , Beinicke Stefanie , Häntschel Janine , Pönisch Wolfram , Vucinic Vladan , Franke Georg-Nikolaus , Behre Gerhard , Niederwieser Dietger , Schwind Sebastian 
Published: September 2018

7042 Background: Surface antigen expression evaluation is part of the standard work-up at acute myeloid leukemia (AML) diagnosis. The biological & prognostic implications of surface antigen expression patterns in normal karyotype (NK) AML patients (pts) remain unknown. Methods: The diagnostic antigen expression patterns of mononuclear cells in bone marrow (BM) of 111 NK-AML pts were assessed using a standard flow cytometric panel. At diagnosis common AML gene mutations (mut) & expression levels were analyzed. Pts received stem cell transplantation (SCT, 98% allogeneic, 2% autologous; median age 63 years [y, range 26-74y]) after induction therapy at our institution. Median follow up was 3.3y. With R’s gplot package unsupervised hierarchical clustering of surface antigens was performed & revealed 4 distinct clusters. Results: Pts in cluster 1 (n = 36) had higher expression of immature, in cluster 2 (n = 31) of thrombocytic/T-cell/erythroid, in cluster 3 (n = 24) of monocytic & in cluster 4 (n = 20) of myeloid surface antigens. All 4 clusters associated with distinct clinical & molecular features. At diagnosis, compared to all others, pts in cluster 1 had a higher CD34+/CD38- cell burden ( P< .001), higher blood blasts ( P< .03) & BM blasts ( P< .06) by trend. They had less NPM1 mut ( P< .001) & DNMT3A mut ( P= .02), were more likely to be EVI1 positive ( P= .03) & had higher EZH2 ( P= .02), RUNX1 ( P= .009), BAALC ( P< .001), ERG ( P= .02) & MN1 ( P< .001) expression. Compared to all others, pts in cluster 1 had a higher cumulative incidence of relapse (CIR, P= .002, at 1y 41% vs 15%) & shorter event-free survival (EFS, P= .02, at 1y 50% vs 69%). In multivariate analysis, cluster 1 pts had a significantly higher CIR (Hazard Ratio [HR] 5.4, P= .01) after adjustment for FLT3-ITD & shorter EFS (HR 2.1, P= .02) after adjustment for FLT3-ITD, age & disease status at SCT. Conclusions: Pts in cluster 1 had high expression of immature surface antigens (eg CD34, CD117, CD13), genes involved in stem cell renewal & worse outcome. Our data indicate a relationship between easily accessible surface antigen expression patterns at diagnosis, molecular disease features & aggressiveness of the NK-AML phenotype.
The effect of donor source on outcomes after second allogeneic hematopoietic cell transplantation for relapsed leukemia.
Authors: Huselton Eric , Slade Michael , Abboud Camille N. , Cashen Amanda F. , DiPersio John F. , Ghobadi Armin , Pusic Iskra , Romee Rizwan , Uy Geoffrey L. , Vij Ravi , Westervelt Peter , Schroeder Mark A. 
Published: September 2018

7044 Background: There is no standard treatment for patients with leukemia who relapse after allogeneic stem cell transplant (HCT). A second HCT (HCT2) may be the only possibly curable option; however, this is performed in few patients. We hypothesized that patient and transplant characteristics, such as donor source will affect outcomes. Methods: We retrospectively evaluated adult patients who received a HCT2 for relapsed leukemia or MDS at a single institution between 2000-2016. 85 patients underwent a HCT2 with an unmanipulated graft from a matched related (MRD, n = 21), matched unrelated (MUD, n = 40), or haploidentical (haplo, n = 24) donor, preceded by either a reduced intensity (RIC) or myeloablative conditioning (MAC) regimen. Results: The median age at HCT2 was 50 yrs and the median time between transplants was 448 days. Patients had relapsed AML (n = 62), ALL (n = 12), and MDS (n = 10). The median length of follow up for survivors was 22.3 months (range 3.9-131) with 20 patients alive in June 2016. 65 patients died; 32 from relapse, 21 from infection, 7 from GvHD, and 5 from organ failure. 1-year OS from HCT2 was 38.6%. For patients with MRD, MUD, haplo donors, 1 year OS was 52.3%, 33.3%, and 34.6% (p = 0.72). 1-year DFS in the entire cohort, MRD, MUD, and haplo groups was 26.4%, 14.3%, 34.8%, and 25.3% (p = 0.45). 1-year TRM was 36.2% and not different across these groups (p = 0.80). Univariate analyses of OS, DFS, and TRM based on patient, disease, and transplant characteristics showed an association with RIC and worse OS and DFS (HR 2.0, 95% CI 1.2-3.3; and HR 1.9, 1.2-3.1). Having > 1 year between transplants was associated with lower TRM (HR 0.38, 0.19-0.77). Traditional risk factors like age, presence of active disease at HCT2, shorter time between transplants, and using the same donor from the first HCT were not otherwise significantly associated with OS, DFS, or TRM. Conclusions: Outcomes after HCT2 did not differ based on donor source. MAC is associated with better OS relative to RIC (1yr OS 51% vs 23%, p < 0.01), DFS (1yr DFS 37% vs 12%, p < 0.01), with similar TRM (1yr TRM 30% vs 47%, p = 0.12). Based on these data, serious consideration is necessary before using RIC regimens for HCT2 in patients with relapsed leukemia.
Impact of dose reductions on 5-year efficacy in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP) from DASISION.
Authors: Cortes Jorge E. , Hochhaus Andreas , Kantarjian Hagop M. , Guilhot François , Kota Vamsi K. , Hughes Timothy P. , Shelat Suresh , Li Li , Jabbour Elias 
Published: September 2018

7051 Background: Dasatinib (DAS) dose modifications generally mitigate adverse events (AEs) without affecting efficacy for responding patients (pts). A 2-year retrospective analysis of DASISION showed that rates of cytogenetic and molecular responses remained higher for pts given DAS vs imatinib (IM), even when daily doses were modified (Jabbour ASH 2011). Efficacy was not compromised due to dose reductions to manage DAS-related AEs. Here, we report results from a 5-year analysis evaluating the impact of dose reductions on efficacy in pts from DASISION. Methods: In DASISION (NCT00481247), pts with treatment-naïve CML-CP were randomized to receive either DAS (100 mg once/day; N = 259) or IM (400 mg once/day; N = 260). Up to 2 dose reductions were permitted for AEs (DAS: 80 mg, then 50 mg; IM: 300 mg, then 200 mg). Efficacy in all pts was evaluated retrospectively by 5 years. Results: Molecular response rates remained higher for DAS than IM, independent of dose reductions, and were comparable in pts with and without dose modifications in each arm (table). Overall, 95 (37%) DAS- and 44 (17%) IM-treated pts had dose reductions at any time due to AEs. Median average daily dose was 83 mg DAS and 328 mg IM for pts with reductions for any cause and 82 mg DAS for pts with reductions due to pleural effusion. The most common AEs resulting in dose reduction were hematological toxicity for IM (9%) and pleural effusion for DAS (12%). Conclusions: A 5-year retrospective analysis of DASISION showed molecular responses remained higher for DAS vs IM when daily doses were modified due to AEs. Dose reductions for any cause, including pleural effusion, did not affect efficacy (MMR rates were not reduced). In this analysis, for pts who experienced AEs, DAS dose reductions to 80 mg or 50 mg were safe and effective treatment options. Clinical trial information: NCT00481247. [Table: see text]
Hypomethylating agent (HMA) therapy use and survival in older patients with higher risk myelodysplastic syndromes (HR-MDS) in the United States (USA): A large population-based study.
Authors: Zeidan Amer M , Hu Xin , Long Jessica B. , Wang Rong , Huntington Scott F. , Podoltsev Nikolai Alexandrovich , Giri Smith , Stahl Maximilian , Gore Steven , Ma Xiaomei , Davidoff Amy J. 
Published: September 2018

7057 Background: The HMA azacitidine improved overall survival (OS) compared to conventional care in patients with HR-MDS in the landmark randomized clinical trial AZA-001 by a median of 9.5 months compared to conventional care regimens. However recent registry data from USA (Zeidan et al, 2016) and Spain (Bernal et al, 2015) did not show substantial population-level gains in OS. We used HMA market entry in the US (2004-06) as a natural experiment to assess the effect of HMA on OS. Methods: We conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results-Medicare data.Individuals were included if they were 66 years or older in age, had refractory anemia with excess blasts (RAEB, considered to have HR-MDS), and were diagnosed in 2001-11.We performed 2-stage residual inclusion instrumental variable (IV) analysis, using diagnosis year as the IV. Residuals from the first stage model were added to the second stage regression to control for effects of unobserved factors between HMA treatment and OS. We also adjusted for demographic characteristics, comorbidity, disability status and transfusion receipt. Results: Among 2,581 patients with RAEB, the median OS from diagnosis was 9 months, and 35.8% received HMAs. In the first stage model, diagnosis year was a strong predictor of HMA (2001-06 vs. 2011, Odds Ratio = 0.004-0.56, P-value < .01). In IV analysis, patients who received HMAs showed no gain in OS (Hazard Ratio (HR) = 0.93, 95% Confidence Interval (CI) = 0.76-1.14), while there was a strongly protective effect of unobservable characteristics on OS (HR = 0.58, 95% CI = 0.47-0.73). Conclusions: In our US population-based analysis,HMA use was not associated with survival prolongation in older adults with HR-MDS. It is unclear if this is related to suboptimal use of HMAs (alternate schedules, doses, number of cycles), use of decitabine (which did not show survival benefit in randomized studies), or the unselected nature (compared to strict eligibility in clinical trials) of patients receiving HMAs at the community level. Better understanding of these issues is vital for optimal HMA patient selection and administration.