bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of pevonedistat (P) + azacitidine (A) versus A in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB AML) (NCT02610777).
Authors: Ades Lionel , Watts Justin M. , Radinoff Atanas , Arnan Montserrat , Cerrano Marco , Font Lopez Patricia , Zeidner Joshua F. , Diez-Campelo Maria , Graux Carlos , Liesveld Jane , Selleslag Dominik , Tzvetkov Nikolay , Fram Robert J. , Zhao Dan , Faller Douglas V. , Sekeres Mikkael A. 
Published: May 2020

7506 Background: P, the first and only small-molecule inhibitor of the NEDD8-activating enzyme, disrupts proteasomal degradation of select proteins and has shown promising clinical activity and good tolerability in combination with A in AML. Methods: 120 pts with higher-risk (Revised International Prognostic Scoring System risk > 3) MDS/CMML or LB AML naïve to hypomethylating agents were randomized 1:1 to receive P 20 mg/m2 intravenously (IV) on days (d) 1, 3, 5 + A 75 mg/m2 (IV/subcutaneously) on d 1–5, 8, 9 (n = 58), or A alone (n = 62), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. The primary endpoint was overall survival (OS), although the study was underpowered for OS. Results: Baseline characteristics were generally balanced between arms. Pts received a median of 13.0 vs 8.5 cycles of P+A vs A. Median OS in the intent-to-treat (ITT) population with P+A vs A (n = 120) was 21.8 vs 19.0 mos (hazard ratio [HR] 0.80; 95% CI 0.51–1.26; P = .334; median follow-up 21.4 vs 19.0 mos). Subanalyses showed median OS with P+A vs A in higher-risk MDS (n = 67) of 23.9 vs 19.1 mos (HR 0.70; 95% CI 0.39–1.27; P = .240) and in LB AML (n = 36) of 23.6 vs 16.0 mos; HR 0.49; 95% CI 0.22–1.11; P = .081). Event-free survival (EFS – time from randomization to death/transformation to AML) with P+A vs A trended longer in the ITT population (median 21.0 vs 16.6 mos; HR 0.65; 95% CI 0.41–1.02; P = .060) and was significantly longer in higher-risk MDS (median 20.2 vs 14.8 mos; HR 0.54; 95% CI 0.29–1.00; P = .045). In response-evaluable pts, overall response rate was 71% (n = 39/55; 46% complete remission [CR] + CR with incomplete blood count recovery [CRi], 5% partial response [PR], 20% hematologic improvement [HI]) with P+A vs 60% (n = 32/53; 38% CR+CRi, 8% PR, 15% HI) with A. In higher-risk MDS, CR rate was 52% vs 27% ( P = .050) with P+A vs A. Median A dose intensity was 97% vs 98% with P+A vs A. Rates of grade ≥3 adverse events were 90% vs 87% with P+A vs A; the most common were 31% vs 27% neutropenia, 26% vs 29% febrile neutropenia, 19% vs 27% anemia, and 19% vs 23% thrombocytopenia. On-study deaths occurred in 9% of P+A pts and 16% of A pts. Conclusions: P+A had a comparable safety profile to A alone, did not increase myelosuppression, and maintained A dose intensity. Although not statistically significant, P+A increased OS, EFS, and response rates vs A, particularly in pts with higher-risk MDS. Further evaluation of P+A vs A is ongoing in a randomized phase. Clinical trial information: NCT02610777 .
Inotuzumab ozogamicin (INO) plus bosutinib (BOS) in R/R PH+ ALL or CML in lymphoid blast phase (CML LBP).
Authors: Jain Nitin , Maiti Abhishek , Ravandi Farhad , Konopleva Marina , Alvarado Yesid , Kadia Tapan M. , Short Nicholas James , Borthakur Gautam , Naqvi Kiran , Pemmaraju Naveen , Dinardo Courtney Denton , Daver Naval Guastad , Yilmaz Musa , Patel Keyur P. , Linderman Debra B , Garris Rebecca , Jabbour Elias , Cortes Jorge E. , Kantarjian Hagop M. 
Published: May 2020

7512 Background: Pts with R/R Ph+ ALL and CML LBP have poor outcomes. INO is an anti-CD22 antibody drug conjugate approved for R/R ALL. BOS is a 2nd generation BCR-ABL TKI approved for CML. Methods: This was a phase I/II study of INO + BOS for R/R Ph+ ALL and CML LBP. Primary objective was to determine safety and the maximum tolerated dose (MTD) of the combination. Secondary objective was to assess efficacy. Pts with T315I mutation were excluded. Pts needed to have adequate organ function (Cr ≤2 gm/dL, total bilirubin ≤2 mg/dL, ALT & AST ≤3xULN). BOS was dosed once daily starting on cycle 1 day 1, and 3 dose levels were evaluated (300, 400, 500 mg) in a standard 3+3 design. INO was given IV weekly during cycle 1 (0.8 mg/m2 day 1; 0.5 mg/m2 day 8; 0.5 mg/m2 day 15). In responding pts, INO was subsequently administered at 1 mg/m2 once every 4 weeks for a total of 6 cycles. Results: Between June 2015 and December 2019 we enrolled 18 R/R pts (16 Ph+ ALL, 2 CML LBP). The median age was 62 yrs (range 19-74), median no. of prior therapies was 1 (range 1-5) and 9 pts had ABL kinase domain mutations at screening. There were no early deaths (<30 days). 3 pts were treated at BOS dose level 1; 6 pts at dose level 2; 9 pts at dose level 3. 1 pt had a DLT at dose level 2 - G3 skin rash, and 2 pts had a DLT at dose level 3 - both G3 skin rash. First 3 pts at dose level 3 did not receive ≥80% BOS doses during cycle 1 due to issues unrelated to adverse events (AE). As 2/6 DLT evaluable pts at dose level 3 had DLTs thus exceeding the MTD, the dose level 2 was identified as the MTD. Most frequent AE were diarrhea in 50%, rash in 50%, and nausea in 39%. Grade 3 AEs were rash (3), reversible ALT elevation (1) and hyponatremia (1). No pts had veno-occlusive disease. Pts have received a median of 3 cycles (range 1-8) with a median of 1 cycle to response (range 1-2). Responses are shown in Table. Median time to response was 1 months (mo, range 0.8-2.1), median time to negative MRD by flow cytometry (FCM) was 6.9 mo (range 3.4-18) and median time to complete molecular response (CMR) was 9.1 mo (range 3.4-18). After a median follow-up of 32 mo, the median overall survival was 15.4 mo and median event-free survival censored at stem-cell transplantation (SCT) was 6.1 mo. 6 pts underwent SCT, 8 pts relapsed, 10 pts are alive and 2 pts continue therapy. Conclusions: INO + BOS was well tolerated and showed promising activity in R/R Ph+ ALL and CML LBP. Clinical trial information: NCT02311998 . [Table: see text]
Long-term survivors and gilteritinib safety beyond one year in FLT3-mutated R/R AML: ADMIRAL trial follow-up.
Authors: Perl Alexander E. , Martinelli Giovanni , Neubauer Andreas , Berman Ellin , Baer Maria R. , Larson Richard A. , Fathi Amir Tahmasb , Yokoyama Hisayuki , Hosono Naoko , Hasabou Nahla , Lu Qiaoyang , Bahceci Erkut 
Published: May 2020

7514 Background: The phase 3 ADMIRAL trial showed that gilteritinib was superior to salvage chemotherapy (SC; median overall survival [OS]: 9.3 vs 5.6 mo, respectively) in FLT3mut+ R/R AML patients (pts; Perl, et al. N Engl J Med. 2019). This follow up (FU) of the ADMIRAL trial assessed long-term (LT) survivors and gilteritinib safety beyond 1 year. Methods: A data cut was performed 1 year after the primary analysis. Response outcomes in LT survivors (OS ≥18 mo) in the gilteritinib arm, and safety during and after 12 mo of gilteritinib therapy were assessed. Results: At 1 year after the primary analysis, median FU for OS was 29.2 mo. Median OS remained longer with gilteritinib (9.3 mo) than with SC (5.6 mo; HR=0.679 [95% CI: 0.527, 0.875], nominal P=0.0026); 18-mo OS rates were 27% and 15%, respectively (Table). Of 49 censored pts in the gilteritinib arm, 20 continued treatment; 13 of these 20 pts underwent transplantation (HSCT) and received gilteritinib post-HSCT. Median gilteritinib exposure was 4.1 mo (IQR, 2.1-8.2) and median average dose was 120 mg/day (range, 43.8-192.3); 12% (n=30/246) of pts had ≥18 mo and 7% (n=17/246) had ≥24 mo of drug exposure. A total of 63 gilteritinib-treated pts had OS ≥18 mo (median exposure, 17.6 mo [IQR, 3.1-25.7 mo]). A high proportion of these LT survivors achieved remission pre-HSCT (Table); median durations of complete remission (CR) or CR with partial hematologic recovery (CRh) have not been reached. After a median of 3.5 mo, 35 of 63 (56%) LT survivors underwent HSCT; 25 of these 35 pts (71%) received post-HSCT gilteritinib therapy. Of 28 pts who did not undergo HSCT, 15 (54%) received gilteritinib for ≥18 mo. Most common grade ≥3 adverse events (AEs) during the first 12 mo of gilteritinib therapy were febrile neutropenia (45%), anemia (40%), and thrombocytopenia (23%); rates of these grade ≥3 AEs decreased to 8%, 10%, and 0, respectively, after 12 mo of treatment. Most common fatal AEs during the first 12 mo of gilteritinib therapy were AML (11%), infections (11%), and cardiac disorders (3%); after 12 mo of treatment, rates of these fatal AEs were 6%, 8%, and 2%, respectively. Conclusions: Results from this ADMIRAL trial FU suggest LT survival in pts receiving gilteritinib is related to ongoing remission, subsequent HSCT, or post-HSCT gilteritinib therapy. The safety profile of gilteritinib beyond 1 year was stable. Clinical trial information: NCT02421939 . [Table: see text]
Clonal hematopoiesis in the bone marrow and blood of healthy volunteers.
Authors: Hirsch Pierre , Ravalet Noémie , Guermouche Helene , Gallay Nathalie , Gyan Emmanuel , Delhommeau François , Herault Olivier 
Published: May 2020

7517 Background: Clonal hematopoiesis of indeterminate potential (CHIP) has been described in blood samples from large series of patients. Its prevalence and consequences remain questioned because sequencing methods vary and because most studies were performed in cohorts of individuals suffering from non-hematological diseases (solid cancers, diabetes, cardiovascular or psychiatric diseases). CHIP has been described as a risk factor for blood cancer. However, the diagnosis of most blood cancers relies on morphologic and genetic examination of the bone marrow, and clonal hematopoiesis has never been evaluated in bone marrow samples from healthy individuals. Hence, it is not clear whether the current definition of CHIP is clinically relevant. To address this issue, we studied clonal hematopoiesis in paired peripheral blood and bone marrow samples from an unprecedented cohort of rigorously selected healthy volunteers. Methods: Here, we investigated the frequency of clonal hematopoiesis in 82 paired bone marrow and blood samples from carefully selected healthy adult volunteers (HEALTHOX clinical trial, ClinicalTrials.gov Identifier: NCT02789839). This study was approved by the ethics committees (CPP Tours and AFSSAPS identifier ID-RCB: 2011-A00262-39; CPP Ile-de-France III: 2753). Forty-one genes known to be mutated in myeloid malignancies were sequenced with a 1% threshold of detection. All variants were checked using IGV software v2.3. Statistical analyses were performed using Mann-Whitney, chi-squared, Fisher’s exact, Wilcoxon matched-pairs tests or Spearman correlation using GraphPad Prism 6. Results: In bone marrow samples, clones were found in almost 40 % of healthy volunteers over 50 years-old (yo). The most frequent mutations were found in DNMT3A (48%) and TET2 (28%) and the other mutations were found in ASXL1 (8%), JAK2 (8%), RAD21 (4%) and SRSF2 (4%) with one individual carrying three variants. Blood parameters and bone marrow smears were normal with the exception of two individuals with mild macrocytosis or thrombocytosis. Clonal hematopoiesis cases differed from others by age (62.8 vs. 38.6 years, P < .0001) and platelet count (294 vs. 241 G/L, P < .0208). Conclusions: These results confirm that clonal hematopoiesis is a very common condition in healthy adults over 50 years old. Consequently, the detection of driver myeloid mutations should be interpreted with caution in the absence of cytologic abnormalities in the blood and/or in the bone marrow.
A fork in the road: A mixed methods study exploring why older adults with acute myeloid leukemia choose different treatment paths.
Authors: LeBlanc Thomas William , Walter Roland B. , Hernandez Loriana , Morgan Lucy , Bell Timothy , Panter Charlotte , Peloquin Francois , Healy Jasmine , Gater Adam , Welch Verna , Amer Karim , O'Hara Louise , Hohman Ryan , Brown Andrew , Russell Nigel , Merino Diana M. , Horikoshi Neil , Maze Dawn 
Published: May 2020

7520 Background: Current treatment options for acute myeloid leukemia (AML) are diverse, including intensive chemotherapy (IC), low intensity therapy, best supportive care (BSC), and hospice care. Despite continued development of new therapies, recent data suggest that approximately 60% of older US patients remain untreated, but reasons for this are not well understood. By gathering insights from physicians, patients, and their family members, this study aims to better understand the factors that influence treatment decisions for adults with AML. Methods: Physicians in the US (n=4), UK (n=3) and Canada (n=3), and 15 US AML patient-family member dyads took part in one-on-one, 60-minute semi-structured interviews. Each participant rated a series of factors on a scale from 0 (not at all important) to 3 (very important) to determine their importance in treatment decision-making. Among the 15 adults with AML (>65 years, not taking IC) interviewed thus far, 13 had not received any treatment. Additional interviews are scheduled in the UK and Canada with patients having varied treatment experiences (data will be available for presentation). Results: To date, findings highlight the key role perceptions of side effects and patient health play in treatment decision making. A fear of treatment side effects was the primary reason patients (n=9/13) opted not to receive treatment. For the 2/15 study patients who had received treatment, side effects were considered the worst part of their treatment experience. Physicians also stated patients on BSC would be more willing to take low intensity treatments if risks (e.g., side effects) were minimized. Patients (n=11/15), their family members (n=11/15), and physicians (n=10/10) agreed that patients’ health (including age and comorbidities) influenced if treatment was pursued. Additionally, US physicians suggested that some patients have little desire to pursue treatment, with patients’ perception of low intensity therapy having poor efficacy and proximity of care influencing their choice for BSC or hospice care. Further analysis will explore other factors influencing patients’ treatment decisions and differences among patients who receive treatment versus those who do not. Conclusions: The treatment decision-making process for older adults with AML is complex and multifactorial. Understanding factors that influence treatment decisions is important if drug developers and prescribers are to ensure the availability of therapies that better align with individual patients’ needs.
Timing of response to venetoclax combination treatment in older patients with acute myeloid leukemia.
Authors: Jonas Brian Andrew , Dinardo Courtney Denton , Pratz Keith , Wei Andrew , Hong Wan-Jen , Chyla Brenda , Duan Yinghui , Potluri Jalaja , Werner Michael , Pollyea Daniel Aaron 
Published: May 2020

7531 Background: Venetoclax (Ven) has synergistic activity with hypomethylating agents (eg, azacitidine [Aza] or decitabine [Dec]) or low-dose cytarabine (LDAC). These Ven-based combinations have demonstrated rapid median response times. This analysis describes the rapidity and likelihood of response to Ven treatments, and its associated characteristics, in older patients with newly diagnosed acute myeloid leukemia (AML). Methods: Included are data from two open-label trials of Ven, at label recommended doses, in combination with Aza, Dec (NCT02203773; phase 1b), or low-dose cytarabine (NCT02287233; phase 1/2) in newly diagnosed patients with AML. Patients were classified based on CR/CRi timing: within 2 cycles of therapy, after 2 cycles, or never achieving CR/CRi. Within each group, baseline and post-baseline characteristics were evaluated to determine impact on response timing. The percentage of patients in each category and duration of response (DOR) in each category were also evaluated. Results: Data cutoff was August 2018. Of 197 patients, 42% (n = 83) had CR/CRi in ≤2 cycles, 22% (n = 44) had CR/CRi in > 2 cycles, and 36% (n = 70) did not achieve CR/CRi. Median DOR was 21.2 mos. (95% CI 14.1-NR) for ≤2 cycle responders and 8.1 mos. (95% CI 5.3-14.9) for > 2 cycle responders. Baseline characteristics are shown in the Table. Patients with baseline IDH1/2 mutation were more likely to have CR/CRi in ≤2 cycles, while those with secondary AML and no response by the end of cycle 2 were more likely to never achieve CR/CRi. Of the patients who achieved CR/CRi after 2 cycles of therapy, 43% (19/44) achieved MLFS within the first two cycles. Of those who never achieved CR/CRi, 17% (12/70) of patients achieved MLFS within 2 cycles. In depth regression analyses of factors predictive of response, including analysis of biomarkers, will be available upon presentation. Conclusions: Over 1/3rd of patients that achieved CR/CRi on Ven combination therapy within these two studies required more than 2 cycles of treatment. Therefore, prior to discontinuing therapy for nonresponders, it is critical to assess key predictive patient characteristics. Clinical trial information: NCT02203773 and NCT02287233 . [Table: see text]
Outcomes in older patients with high-risk/secondary AML who achieved remission with CPX-351 versus 7+3 but did not undergo transplant: Phase 3 exploratory analysis.
Authors: Lin Tara L. , Ryan Robert J , Faderl Stefan , Ritchie Ellen K. 
Published: May 2020

7537 Background: CPX-351 (Vyxeos; daunorubicin [D] and cytarabine [C] liposome for injection) is approved by the FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In a phase 3 study (NCT01696084) in patients (pts) aged 60-75 y with newly diagnosed high-risk/secondary AML, CPX-351 demonstrated significantly longer overall survival (OS) and higher rates of remission and hematopoietic cell transplant (HCT) vs conventional 7+3, with a comparable safety profile. To better understand the impact of treatment on outcomes in pts who did not undergo HCT, this exploratory analysis evaluated outcomes in the subgroup who achieved complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 vs 7+3 but did not undergo HCT. Methods: Pts were randomized 1:1 to receive ≤2 induction cycles of CPX-351 (100 units/m2 [C 100 mg/m2 + D 44 mg/m2] as a 90-min infusion on Days 1, 3, 5 [2nd induction: Days 1, 3]) or 7+3 (C 100 mg/m2/d continuously for 7 d + D 60 mg/m2 on Days 1-3 [2nd induction: 5+2]). Pts achieving CR or CRi could receive up to 2 consolidation cycles. Pts could receive HCT at the physician’s discretion. Results: CR+CRi was achieved by 73/153 (48%) pts with CPX-351 vs 52/156 (33%) with 7+3; of these pts, 33/73 (45%) vs 28/52 (54%) did not subsequently undergo HCT. The baseline characteristics of these pts were generally balanced between arms; however, the CPX-351 arm had more male pts vs 7+3 (64% vs 43%) and pts with ECOG PS of 1 (82% vs 54%), and fewer pts with antecedent MDS and HMA exposure (21% vs 39%). Median OS was longer with CPX-351 vs 7+3 (14.72 vs 7.59 mo; HR = 0.57 [95% CI: 0.31-1.03]; Table). There was no early mortality by Day 60 in either arm (see Table for additional data). Conclusions: CPX-351 improved median OS vs 7+3 in pts who achieved CR+CRi but did not undergo HCT, suggesting a treatment benefit with CPX-351 even among pts who do not undergo HCT. The CPX-351 safety profile in this subgroup was consistent with the overall study population and known profile of 7+3. Clinical trial information: NCT01696084 . [Table: see text]
Etanercept with extracorporeal photopheresis (ECP) for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation.
Authors: Singh Sunny R K , Malapati Sindhu Janarthanam , Neme Klodiana , Michael Angela , Mikulandric Nancy , Vulaj Vera , Emole Josephine 
Published: May 2020

7543 Background: Acute graft versus host disease (aGVHD) is a well-described complication of allogeneic stem cell transplantation (allo-SCT). Complete response to steroids is achieved in 40-50% of cases, with steroid refractory GVHD requiring second line therapy. Currently, there is no accepted standard of care in this setting. In our study, we assessed the safety and efficacy of etanercept with ECP for steroid refractory aGVHD in a single center tertiary care hospital. Methods: Thirty adult patients who underwent peripheral blood allo-SCT and developed steroid-refractory aGVHD between January 2010 - July 2019 were retrospectively analyzed. Patients were planned to receive etanercept 25 mg subcutaneously twice weekly for at least 4 weeks. Safety was assessed by estimating infection related mortality. For efficacy, we analyzed the change in grade of aGVHD using the Wilcoxon signed-rank test. Results: Median age at the time of allo-SCT was 57.6 years and the most common indication for transplant was Myelodysplastic syndrome. Median time from allo-SCT to steroid initiation was 39.5 days (range 14-183 days). Median time from steroid initiation to etanercept was 6 days, with 7.5 median number of etanercept doses received. A total of 25 patients (83.3%) received ECP. As depicted in the table, there was a significant improvement in severity of aGVHD after etanercept therapy compared to that before its initiation. Overall response rate was 83.3%, while overall mortality was 86.7%. Median overall survival for responders was 306 days (range 59-2005 days) and for non-responders was 181 days (range 89-261 days). Death attributed to infection alone occurred in 28% (n=7), infection along with GVHD in 28% (n=7) and infection with relapsed disease in 1 patient. Active infection within 6 months of transplant occurred in 93.3% patients. Conclusions: The use of Etanercept with ECP resulted in improvement of steroid refractory aGVHD following allo-SCT, with responses noted in the majority of patients. High rates of infection related mortality were also noted and remain a cause of concern. [Table: see text]
Bosutinib (BOS) for chronic phase (CP) chronic myeloid leukemia (CML) after imatinib (IMA) failure: ≥8-y update of a phase I/II study.
Authors: Brümmendorf Tim H. , Cortes Jorge E. , Goh Yeow Tee , Yilmaz Musa , Klisovic Rebecca B. , Purcell Simon , Viqueira Andrea , Leip Eric , Gambacorti-Passerini Carlo 
Published: May 2020

7549 Background: BOS is approved for newly diagnosed CP CML and CML resistant/intolerant to prior therapy. In a phase I/II study, BOS showed durable efficacy and manageable toxicity in patients (pts) with CP CML after IMA failure. We report an ≥8-y update of this phase I/II and ongoing extension study. Methods: Pts with CP CML resistant/intolerant to IMA (CP2L) or IMA + dasatinib and/or nilotinib (CP3L) or with accelerated/blast phase (AP/BP) CML or Philadelphia chromosome+ acute lymphoblastic leukemia with prior tyrosine kinase inhibitor (TKI) therapy (ADV) received BOS starting at 500 mg/d. Results: 54/284 (19%) CP2L pts were still on BOS after ≥9 y and 8/119 (7%) CP3L and 5/167 (3%) ADV pts after ≥8 y; 61 CP2L pts discontinued BOS since y 5 and 21 CP3L and 12 ADV pts since y 4. Overall, the most common reason for discontinuation was disease progression/lack of efficacy in CP2L (27%), CP3L (42%) and ADV (50%) pts; last dose before discontinuation was ≥500 mg/d in 59 (21%), 28 (24%) and 46 (28%) pts, respectively. In CP2L pts, median (range) of follow-up was 54 (1–155) mo, treatment duration 26 (<1–155) mo and dose intensity 438 (87–599) mg/d; responses were durable (Table) and overall survival (OS) at 9 y was 74% vs 84% at 5 y. OS at 8 y was 69% in CP3L, 54% in AP CML and 23% in BP CML pts vs 78%, 59% and 23% at 4 y. 55 CP2L, 29 CP3L and 98 ADV pts died on study (10, 3 and 2 since the 4/5-y reports); 15, 5 and 3 had on-treatment transformations to AP/BP. Most common new treatment-emergent adverse events since y 5 in CP2L pts were pleural effusion (n=13), arthralgia (n=12) and increased blood creatinine (n=11). Conclusions: After ≥8 y, BOS continued to show durable efficacy and no new safety signals in pts with CP CML on long-term treatment, providing further support for BOS use after prior TKIs. Clinical trial information: NCT00261846 and NCT01903733 . [Table: see text]