bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase III study of venetoclax plus low-dose cytarabine in previously untreated older patients with acute myeloid leukemia (VIALE-C): A six-month update.
Authors: Wei Andrew H. , Montesinos Pau , Ivanov Vladimir , Dinardo Courtney Denton , Novak Jan , Laribi Kamel , Kim Inho , Stevens Don A. , Fiedler Walter M. , Pagoni Maria , Samoilova Olga , Wang Jianxiang , Anagnostopoulos Achilles , Bergeron Julie , Hou Jing-Zhou , Yamauchi Takahiro , Jiang Qi , Mendes Wellington , Hayslip John W. , Panayiotidis Panayiotis 
Published: May 2020

7511 Background: VIALE-C was designed to compare the safety and efficacy of the BCL-2 inhibitor venetoclax (VEN) or placebo (PBO) plus low-dose cytarabine (LDAC) in previously untreated patient (pts) with acute myeloid leukemia (AML; ≥75 yr or ≥18 yr with comorbidities precluding intensive chemotherapy). The primary overall survival (OS) analysis showed a clinically meaningful improvement with VEN+LDAC, although the primary endpoint was not met. Herein, we present a 6-mo update after primary analysis, with a focus on OS. Methods: This double-blind, PBO-controlled phase 3 study (NCT03069352) randomized pts 2:1 to VEN (600 mg orally QD, days [d]1–28) with 4-d ramp-up in first cycle or PBO in 28-d cycles, plus LDAC (20 mg/m2 subcutaneously QD, d1–10). The primary endpoint was OS; secondary endpoints included response, transfusion independence (TI; red blood cells [RBC] or platelets), and event-free survival (EFS). OS and EFS were analyzed by the Kaplan-Meier method and compared between arms using the log-rank test stratified by AML status (de novo vs secondary) and age (18 to < 74 vs ≥75). The planned sample size was 210 pts (n = 140, VEN; n = 70, PBO) to detect a hazard ratio (HR) of 0.545 in OS with 2-sided alpha of 5% and power of 90%. Results: As of 15 Aug 2019, 211 pts were randomized (n = 143, VEN; n = 68, PBO); median age: 76 yr in both arms (range: 36–93); secondary AML: 38% (88% post-MDS/CMML); prior hypomethylating agent: 20%. With a median follow-up of 17.5 mo (range: 0.1–23.5), median OS was 8.4 mo vs 4.1 mo in the VEN+LDAC and PBO+LDAC arms (HR 0.70; 95% CI 0.50–0.99; P= .04), representing a 30% reduction in the risk of death. Complete remission (CR)/CRi and CR/CRh (CR with partial hematologic recovery) rates were both 48% for the VEN+LDAC arm, and 13% and 15%, respectively, for PBO+LDAC. RBC/platelets TI rates were 43%/49% vs 19%/32% for VEN+LDAC and PBO+LDAC. Median EFS was 4.9 mo vs 2.1 mo in the VEN+LDAC and PBO+LDAC arms (HR 0.61; 95% CI 0.44–0.84; P= .003). Grade ≥3 adverse events (AEs [ > 30%]; VEN+LDAC/PBO+LDAC) included neutropenia (49%/18%), thrombocytopenia (45%/38%), and febrile neutropenia (32%/29%); serious AEs ( > 10%) were febrile neutropenia (17%/18%) and pneumonia (14%/10%); tumor lysis syndrome occurred in 5.6%/0%. Conclusions: VEN+LDAC demonstrates a clinically meaningful improvement in OS compared with PBO+LDAC, with a tolerable and manageable safety profile. These data support VEN+LDAC as a frontline treatment option for older pts with AML, as well as those considered unfit for intensive chemotherapy. Clinical trial information: NCT03069352 .
Ivosidenib (IVO) prior to hematopoietic cell transplant for patients with IDH1-mutant relapsed or refractory acute myeloid leukemia (R/R AML).
Authors: Dinardo Courtney Denton , Stein Eytan , Pigneux Arnaud , Altman Jessica K. , Collins Robert , Erba Harry Paul , Watts Justin M. , Uy Geoffrey L. , Kapsalis Stephanie M. , Liu Hua , Winkler Thomas , Roboz Gail J. , de Botton Stéphane 
Published: May 2020

7521 Background: Allogeneic hematopoietic cell transplantation (HCT) provides a potentially curative option for patients (pts) with R/R AML. Disease status at the time of transplant is a major determinant of long-term prognosis, with pts typically receiving salvage chemotherapy prior to HCT to induce a remission. However, older and/or heavily pre-treated pts frequently cannot tolerate intensive chemotherapy (IC) or do not obtain adequate disease control to permit an HCT. IVO is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for the treatment of adults with newly diagnosed AML ≥75 y of age or ineligible for IC, and those with R/R AML. We assessed HCT outcomes in pts with m IDH1 R/R AML who proceeded to HCT after treatment with IVO in a phase I study (NCT02074839). Methods: Baseline characteristics, clinical response (including CR, CRi/CRp, MLFS), and overall survival (OS) for the subgroup of pts with m IDH1 R/R AML who received IVO 500 mg QD, responded to treatment and then underwent HCT are reported. m IDH1 variant allele frequency (VAF) from bone marrow mononuclear cells was assessed using BEAMing digital PCR (0.02–0.04% VAF detection limit). Results: Among 179 pts with R/R AML treated with IVO, 18 proceeded to HCT: median age, 61.5 y (range 36–68); 56% male; 16.7% had secondary AML; 27.8% had ≥3 prior regimens; 11.1% had a prior HCT. The median duration of IVO treatment prior to HCT was 3.9 mo (range 2.1–15.2). The last reported response prior to HCT was 50.0% CR. Six- and 12-mo post-HCT survival rates were 77.8% and 50.0%; median relapse-free survival post HCT was 7.3 mo (range 2.6–NE). Median OS from start of IVO was 16.8 mo (95% CI 9.2, NE) for HCT pts vs 9.0 mo (95% CI 7.1, 10.2) in the entire study cohort; median follow-up time, 33.2 mo (range 3.2–41.9). Eight HCT pts were censored for OS: 5 are in remission, 2 relapsed and are in survival follow-up, and 1 was lost to follow-up. Median OS was not estimable (95% CI 9.1, NE) for the 12 HCT pts who achieved CR after IVO therapy and was 20.5 mo (95% CI 16.4, NE) for the 31 CR pts who did not undergo HCT. m IDH1 was undetectable in 1/18 (6%) pts; 4/18 (22%) pts had reduction below 1% VAF in ≥1 at the last assessment prior to HCT. Conclusions: IVO monotherapy is a putative treatment option to induce remissions prior to HCT for m IDH1 R/R AML pts who are not considered candidates for intensive salvage therapy. Post-transplant survival rates are encouraging and warrant further investigation of IVO monotherapy or combination salvage therapies prior to HCT. Clinical trial information: NCT02074839 .
Clinicopathologic and molecular profile of Philadelphia like ALL in Hispanic population of Central Valley California.
Authors: Akabane Hugo , Ali Mir , Abdulhaq Haifaa , Bukari Mohammed SANI 
Published: May 2020

7524 Background: Philadelphia-like Acute B-ALL(PHL) are Ph negative B-ALL(PHN) with molecular signatures that mirrors Ph + B ALL. Studies have shown worse prognosis in this subtype of leukemias, but few have reported outcomes with incorporation of novel agents. Our study seeks to describe clinical and molecular profile of a single center experience. Methods: This is a retrospective study of patients treated for PHL in community referral center in central valley of California from 1/2009 to 12/2019. Of the initial 71 patients, 34 met the inclusion and exclusion criteria. 16 of the 34 patients who had Next Generation Sequencing (NGS) by Foundation Medicine (14) or NeoGenomics (2). Data for 34 PHN and 8 with PHL patients were analyzed. Results: There are no differences in mean ages (36.7 x 36) and gender between the PHN and PHL subgroup. There is over representation of Hispanics in both groups (63% x 65%) with slightly male predominance in PHL group (62%). This ratio is slightly higher than reported by 2010 census of 46%. The BMI 38.4(27.5-48.4) vs. 29.1(26.6-39.1), mean WBC (71 vs. 58), bone marrow CD20+ by flow cytometry (90% vs. 63%) and abnormal cytogenetics (50% vs.15%) are all higher in PHL compared to PHN group. The prevalence rate of PHL signature in 16 tested patients is 8(50%). CRLF2 like subtype accounted for 6/8(75%), with 1 each of ABL-like and JAK-Stat subtype. All patients harbored multiple other mutational abnormalities in addition to those associated with Ph-like genetic signatures (Table). The median number of mutations was 4.55(3-7). The distribution of the 20 other mutation is as shown in table. 6 patients had morphological remission after induction chemotherapy of HyperCVAD (37%) and CALGB 10403 (25%) with measurable MRD in 5 of the patients. 7 patients were exposed to novel therapy; Blinatumomab; 2nd line (6 patients), Cart T cell; 3rd line (2 patients), Inotuzumab; 3rd line (3 patients) and ASCT; (3 Patients post second- or third-line remission). 2 patients died at the time of data cut off, 1 from infection and other from refractory leukemia. Conclusions: Our data shows high incidence of PHL signatures in the cohort. The mutational heterogeneity between and within patients, may represent sub-clonal population vs. passenger and hence poor clinical outcomes. [Table: see text]
STAG2-mutated AML patients: ASXL1 cohesin binding motif status and mutation landscape.
Authors: Scarpa Frank J , Paul Madhuri , Wolfson Wendy A , Weiss Lawrence M. , Funari Vincent Anthony , Blocker Forrest 
Published: May 2020

7538 Background: ASXL1 and the cohesin complex ( STAG2, RAD21, SMC1A, and SMC3) are commonly mutated chromatin regulators with significant clinical implications in AML. The ASXL1-cohesin interactome regulates gene expression through chromatin accessibility via ASXL1’s cohesin binding motif (CBM). ASXL1 variants are most commonly located in the ASXM1 domain and onwards, and characteristically lead to loss of the PHD domain. Gain-of-functions in truncated ASXL1 are suggested to increase catalytic activity of BAP1, which binds the ASXH domain at AA 351, and to gain an interaction with BRD4, which binds somewhere between the ASXN and ASXH domains, to drive H3K4Me3 and H2AK119Ub. Methods: 2463 suspected AML patient bone marrow, peripheral blood, or FFPE tissue samples were evaluated using an all exon amplicon-based 27 gene NGS panel. Patients with a VAF <10% in ASXL1 were excluded to avoid reporting artifacts, particularly in variant c. 1934dup. Statistics were performed using Fisher’s exact test. Results: Mutations in STAG2-mutated patients were enriched for sAML, as evidenced by the higher number of mutations in ASXL1, SRSF2, and BCOR (associated with sAML) compared to NPM1, DNMT3A, and PTPN11 (pAML). STAG2 mutations were found in 173 samples representing 93.5% of cohesin mutations. Of all ASXL1 mutations (VAF 10.1– 54.5%; median 32.2%) 4.0% occurred in the CBM. While 23.5% of samples with mutations outside ASXL1 CBM had concomitant mutations in STAG2, none of the 18 samples with CBM mutations (VAF 11.3 – 51.7%; median 42.5%) had any cohesin gene mutation (P = 0.0174). The proportion of BCOR (27.8% vs 9.2%; P = 0.024) and CEBPA (27.8% vs 8.2%; p = 0.016) mutated patients in the CBM+ group was significantly higher than the CBM- group. JAK2 (16.7% vs 5.4%), KRAS (22.2% vs 13.6%), EZH2 (22.2% vs 13.6%), and RUNX1 (38.9% vs 27.7%) mutations were also higher though not significantly in this group. Mutations throughout all of ASXL1, the 13 amino acids after the CBM, and hotspot variants all had STAG2 mutations at a frequency of 20.9-44.4%, further suggesting mutual exclusivity. Conclusions: STAG2 mutations and mutations in the CBM were mutually exclusive events and harbored different co-mutation frequencies. In compromised ASXL1 CBM cases, BCOR and CEBPA transcriptional regulators are significantly more mutated, but in cases of ASXL1 mutation outside the CBM, cohesin mutations are preferred, suggesting alternative chromatin accessibility mechanisms driving leukemogenesis. This observation has not been previously reported in the literature to our knowledge.
Venetoclax (Ven) added to intensive chemo with cladribine, idarubicin, and AraC (CLIA) achieves high rates of durable complete remission with low rates of measurable residual disease (MRD) in pts with newly diagnosed acute myeloid leukemia (AML).
Authors: Kadia Tapan M. , Garcia-Manero Guillermo , Yilmaz Musa , Dinardo Courtney Denton , Konopleva Marina , Montalban-Bravo Guillermo , Borthakur Gautam , Jabbour Elias , Jain Nitin , Andreeff Michael , Short Nicholas James , Issa Ghayas C. , Ohanian Maro , Bose Prithviraj , Daver Naval Guastad , Wang Sa A , Tidwell Rebecca , Estrov Zeev , Ravandi Farhad , Kantarjian Hagop M. 
Published: May 2020

7539 Background: Ven is a BCL2 inhibitor that is approved in combination with lower intensity therapy for pts with newly diagnosed AML who are ineligible for intensive chemo. We previously reported the safety and efficacy of cladribine and araC with idarubicin in young and fit pts with AML. Here, we studied the combination of ven with the intensive CLIA regimen in newly diagnosed AML. Methods: Pts < 65 yrs with newly diagnosed FLT3-wildtype AML were enrolled. Induction was cladribine 5 mg/m2 IV on D 1-5, followed by ara-C 1.5 g/m2 IV on D 1-5, idarubicin 10 mg/m2 IV D 1-3, and ven at an effective dose of 400mg PO on D2-8. There was no ramp up for ven and dose modifications for CYP3A4 inhibitors were made. Consolidation consisted of up to 5 more cycles of CLIA+Ven. All pts underwent baseline next generation sequencing and MRD testing by multiparameter flow cytometry at the time of response. Results: 18 pts are enrolled, with a median age of 50 yrs (range, 18-64). Baseline pt characteristics are in Table. 16 pts were evaluable for response and 2 are too early. 14 of 16 pts (88%) achieved a remission, including 10 (63%) complete remission (CR) and 4 (25%) CR with incomplete count recovery (CRi). The median time to response was 1 cycle and the median number of cycles given was 2 (1-5). 10 of the 14 responders (71%) had undetectable MRD at the time of remission. Both nonresponding pts had a complex karyotype and 1 had a TP53 mutation. With a median follow up of 4.5 months (0.2 – 11.2), none of the responding pts have relapsed. 8 of the 14 responders (57%) have received allogeneic stem cell transplant. The median survival has not been reached; the 6-month OS and RFS are 90% and 100%, respectively. Treatment was well tolerated, with 0% 4-week mortality. The median days to ANC ≥ 1 and Platelets ≥ 100 were 30 (19-49) and 26 (18-39), respectively. Tumor lysis syndrome was not seen. The most common adverse events were neutropenic fever, pneumonia, nausea, and liver transaminitis. Conclusions: The addition of ven to CLIA was safe and effective in newly diagnosed pts with AML. The combination was not associated with early mortality or prolonged myelosuppression, but did result in high rates of durable MRD negative remissions. Clinical trial information: NCT02115295 . [Table: see text]
Incidence of graft versus host disease in peri transplant hospitalization after clostridium difficile infection.
Authors: Murray Drew Carl Drennan , Kumar Rohit , Bhandari Shruti , Hegazi Mohamed M. 
Published: May 2020

7542 Background: Hyperacute graft versus host disease (GVHD) after allogenic stem cell transplantation (SCT) has adverse outcomes with increased rates of chronic GVHD and relapse. GVHD risks include mismatched related or matched unrelated donors, myeloablative conditioning, heavy pretreatment, and donor-recipient sex mismatch. Clostridium difficile infection (CDI) is a leading cause of diarrhea in immunocompromised patients. Proposed microbiome effect on immunity and GVHD in allogenic SCT recipients prompts concern of microbiome modulation from CDI and antibiotics inciting GVDH. Methods: National Inpatient Sample database 2014 for hospitalizations with allogeneic SCT in patients ≥18yo. Characteristics (age, sex, race, insurance, graft source, hospital type, region, comorbidities) were compared for hospitalizations with and without CDI. Primary outcome was the difference in the incidence of GVHD during the transplant hospitalization between the 2 groups. Other outcomes were mortality, length of stay and hospital charges. Chi-square, t-test, and multivariate logistic regression utilized. Results: Of 6210 patients with allogenic SCT, 745 (12%) had CDI during the transplant hospitalization. In transplanted patients without CDI the average age was 55yo, 43.9% female, 69.5% Caucasian (C), 7.1% African American (AA), 8.6% Hispanic (H), 32.1% had Medicare/Medicaid, 61.8% private insurance, 5.7% uninsured, 44.7% had hypertension, 13.7% had diabetes, graft source was 84.3% PBSC (peripheral blood stem cells), 11.3% bone marrow, and 4.4% cord blood. CDI group the average age was 52.5yo, 45.3% female, 73% C, 4.7% AA, 8.1% H, 25.7% had Medicare/Medicaid, 66.2% private insurance, 8.1% uninsured, 41.9% had hypertension, 10.1% had diabetes, graft source was 83.8% PBSC, 10.8% bone marrow, and 5.4% cord blood. 25.7% of patients with CDI developed GVHD during that hospitalization while 14.2% of patients without CDI developed GVHD during the hospital stay (OR 2.1, p < 0.001 multivariate analysis). GVHD during the hospitalization had no difference in length of stay (p = 0.32), total cost of stay (p = 0.50) or same hospitalization mortality (p = 0.94). Conclusions: Allogeneic SCT patients with CDI develop GVHD on the same hospitalization at significantly higher rates than patients without CDI. This is true after controlling for age, sex, race, insurance, comorbidities, graft source, hospital location, and type of institution. Despite known associations of early evidence of GVHD on relapse, overall mortality was not different between the two groups.
Discontinuation of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia in chronic phase (CML-CP) in US clinical practice after guideline updates.
Authors: Atallah Ehab L. , Sadek Islam , Maegawa Rodrigo O. , Cao Xiting , Latremouille-Viau Dominick , Pivneva Irina , Rossi Carmine , Guerin Annie , Kota Vamsi 
Published: May 2020

7548 Background: NCCN CML practice guidelines were updated in 11/2016 and in 9/2019 to include considerations for discontinuation of TKI therapy in patients (pts) with CML-CP. This study characterized TKI discontinuation practices in the US after these updates and drew parallels with a similar study conducted prior to these guideline updates (Ritchie et al. Leuk Lymphoma. 2019). Methods: Pt charts of adult CML-CP pts with TKI discontinuation (1/2017-12/2018) outside a clinical trial after achieving an adequate response were abstracted (11/2019-12/2019) via an online case report form by US oncologists/hematologists. Physicians’ assessment of adequate response (TKI duration, molecular response [MR], MR duration) and relapse were described. Results: 61 physicians (academic: 43%; community-based practices: 57%) contributed 153 pt charts. Most physicians were from large practices (57%), had > 10 years (y) experience since completing subspecialty training (59%), and treated a median of 30 CML pts in the last 2y; 56% did not have access to precise molecular response monitoring for BCR-ABL of ≥4.5 log when attempting TKI discontinuation. Pts with TKI discontinuation had mean age 56 years, were mostly male (60%), white (69%), and had TKI discontinued in first-line (96%). Most common reasons for TKI discontinuation were pt request (54%) and adverse events (18%), besides achieving an adequate response. Physicians’ assessment of adequate response for TKI discontinuation are reported in the Table. 21% of pts (academic: 12%; community: 30%) relapsed after TKI discontinuation (treatment-free remission [TFR] failure; 66% relapsed within 1y). Conclusions: Although NCCN CML practice guidelines provide guidance for discontinuation of TKI therapy, there remains heterogeneity in US practice and TKI discontinuation is predominantly attempted in first-line (similar to Ritchie et al. 2019). TKI discontinuation is being practiced without adequate sensitive tools mandated by practice guidelines to monitor response. Broader application of practice guidelines for optimal TKI therapy discontinuation in CML-CP pts is needed, particularly in community-based practices, to improve long-term TFR rates. [Table: see text]
An independent review of arterial occlusive events (AOEs) in the ponatinib (PON) phase II PACE trial (NCT01207440) in patients (pts) with Ph+ leukemia.
Authors: Januzzi James L , Garasic Joseph , Kasner Scott , McDonald Vickie , Petrie Mark C , Seltzer Jonathan , Mauro Michael J. , Croce Kevin , Berman Ellin , Deininger Michael W.N. , Hochhaus Andreas , Pinilla-Ibarz Javier , Nicolini Franck E. , Kim Dong-Wook , DeAngelo Daniel J. , Kantarjian Hagop M. , Xu Jing , Srivastava Shouryadeep , Naranjo Daniel , Cortes Jorge E. 
Published: May 2020

7550 Background: The final 5-year analysis of the PACE trial, which evaluated use of PON in pts with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia, identified a 25% incidence of AOEs (Cortes, Blood 2018) from a search utilizing > 400 preferred terms (PTs) defined by MedDRA and related to vascular ischemia or thrombosis. We performed a retrospective review using an independent Endpoint Adjudication Committee (EAC) to better understand clinically relevant AOE rates in PACE. Methods: The EAC consisted of 3 cardiologists, 1 hematologist, and 1 neurologist to review AOEs (identified using > 500 terms) in PACE using American College of Cardiology/American Heart Association (ACC/AHA) definitions for major adverse cardiovascular events (MACE), and to review pt profiles including event, severity, concomitant medication, and hospitalization data. These results were compared with MedDRA PT search results. The EAC was blind to dose, dose modification, and investigator causality opinion. Results: The PACE review included 449 heavily pretreated pts with Ph+ leukemia (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). With median follow-up 37.3 mo in all pts, AOEs were identified by MedDRA PT search in 25% of pts and EAC-verified in 17% (Table). In each category listed in the table, the EAC verification identified fewer AOEs and serious AOEs. Serious AOEs were identified by MedDRA PT search in 20% of pts and EAC-verified in 16%. Events that were not associated with a cardiovascular etiology or failed to meet the MACE definition set forth by the ACC/AHA were determined by the EAC not to be an AOE. Conclusions: The independent EAC review showed a lower rate of clinically relevant AOEs than was reported in PACE, suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with PON. The ongoing PON dose-ranging OPTIC study will further evaluate the PON risk:benefit profile. Clinical trial information: NCT01207440 . [Table: see text]