bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantification of circulating free and circulating tumor DNA in pretreated EGFR mutant NSCLC to inform patient outcomes.
Authors: Pender Alexandra , Hughesman Curtis , Law Elaine , Kristanti Amadea , McNeil Kelly , Tucker Tracy , Bosdet Ian , Young Sean , Laskin Janessa J. , Karsan Aly , Yip Stephen , Ho Cheryl
Published: March 2020

9080

Background: EGFR T790M testing is standard of care for EGFR mutant (EGFRm) NSCLC progressing on 1st/2nd generation TKIs to select patients for osimertinib. Circulating free DNA (cfDNA) levels are measured prior to circulating tumour DNA (ctDNA) testing using droplet digital PCR (ddPCR) to measure activating/resistant EGFR mutations. We reviewed cfDNA levels and ctDNA mutational status to determine the influence on patient outcome. Methods: Following extraction of cfDNA from plasma using the QIAamp Circulating Nucleic Acid Kit, cfDNA levels are measured with a Qubit 2.0 Fluorometer. Custom ddPCR assays were used to test for the appropriate EGFR activating mutation and the EGFR T790M resistance mutation using the Bio-Rad QX200 system. The custom designed ddPCR assays have a limit of detection of < 0.1% variant allele fraction. All patients undergoing ctDNA testing from February-December 2018 were identified. Baseline characteristics and follow up data were collected retrospectively. OS was calculated from date of metastatic diagnosis to death/last follow-up. Results: 142 patients with EGFR mutant adenocarcinoma had EGFR ctDNA testing: results 52% indeterminant, 32% T790M, 16% activating EGFRm only. At the time of testing: median age 66, 64% female, 57% never smokers 53% Asian; systemic treatment (tx) 62% first line only, 25% two lines and 13% ≥ three lines. First TKI therapy: 32% afatanib, 66% gefitinib, 2% erlotinib. Median cfDNA concentration was 5.65 ng/ml (range 0.50-217.72). The 5 yr OS was 72% below cfDNA median and 25% above the median. Tx after ctDNA testing for below and above cfDNA median: 52 vs 33% original TKI, 34 vs 55% osimertinib, 14 vs 12% other systemic tx. Multivariate analysis shows that even accounting for age, sex and ctDNA mutation result, cfDNA concentration remains an independent predictor of outcome (HR 2.36, 95% CI 1.08-5.18, p = 0.032). Conclusions: cfDNA concentration can predict patient outcome in patients with EGFR mutant NSCLC progressing on TKI regardless of ctDNA testing results. Clinicians may consider switching to chemotherapy for patients with high cfDNA and without detectable EGFR T790M ctDNA to avoid missing the window for therapy instead of awaiting repeat EGFR T790M testing
Impact of KRAS allele subtypes and concurrent genomic alterations on clinical outcomes to programmed death 1 axis blockade in non-small cell lung cancer.
Authors: Ricciuti Biagio , Recondo Gonzalo , Umeton Renato , Nishino Mizuki , Sholl Lynette M. , Awad Mark M.
Published: March 2020

9082

Background: Immune checkpoint inhibitors (ICI) treatment can result in durable responses for KRAS-mutant (mut) non-small cell lung cancer (NSCLC). The impact of KRAS allele subtypes and concurrent genomic alterations on ICIs efficacy is unknown. Methods: We collected clinicopathologic and genomic data from patients (pts) with advanced NSCLC treated with programmed death (PD)-1 axis inhibition at the Dana-Farber Cancer Institute. We evaluated outcomes to ICIs according to KRAS mut alleles and concurrent STK11 and KEAP1 mut. Results: Of 617 ICI-treated NSCLCs, 181 (29.3%) had KRAS mut. Median TMB (mTMB) and median PD-L1 tumor proportion score (TPS) were similar between KRAS mut and KRAS wild type (wt) tumors. Among tumors with KRAS codon 12 mut, mTMB was higher in G12V (n = 37, 12.2 mut/Mb) compared to G12C (n = 84, 11.4 mut/Mb), G12D (n = 20, 9.4 mut/Mb) and G12A (n = 13, 10.1 mut/Mb), P = 0.05. Tumors with KRAS transversions (Tv) (n = 156) had higher mTMB compared to those with KRAS transitions (Ti) (n = 25) (10.9 vs 7.6 mut/Mb, P = 0.03). Median PD-L1 TPS was similar across KRAS mut alleles. Pts with KRAS G12V had longer median progression-free survival (mPFS) (5.5 vs 2.7 months, HR:0.62 [95%CI:0.40-0.96], P = 0.03) and overall survival (mOS) (17.5 vs 9.7 months, HR:0.62 [95%CI:0.36-0.99], P = 0.05), compared to non-G12V. Pts with KRAS Tv had longer mPFS and mOS compared to pts with Ti (mPFS: 3.4 vs 2.0 months, HR: 0.58 [95%CI:0.37-0.92], P = 0.02; mOS: 10.9 vs 5.4 months, HR:0.59 [95%CI:0.35-0.99], P = 0.048). Clinicopathologic features and STK11/KEAP1 mut were balanced across all KRAS mut alleles. Among KRAS mut pts, those with KEAP1 (n:52) and STK11 (n:50) concurrent mut had shorter mPFS (KEAP1 mut 1.8 vs. KEAP1 wt 4.1 months, HR: 0.55 [95%CI:0.38-0.80], P = 0.002; STK11 mut 1.8 vs STK11 wt 4.6 months, HR:0.46 [95%CI:0.32-0.67], P < 0.0001) and mOS (KEAP1 mut 4.8 vs KEAP1 wt 15.1 months, HR: 0.51 [95%CI:0.34-0.76], P = 0.001; STK11 mut 4.8 vs STK11 wt 13.6 months, HR:0.51 [95%CI:0.34-0.76], P = 0.001). KEAP1 and STK11 mut did not impact outcome in KRAS wt pts. Conclusions: KRAS allele subtypes and concurrent genomic alterations impact ICI efficacy in NSCLC.
Safety and efficacy of abivertinib (AC0010), a third-generation EGFR tyrosine kinase inhibitor, in Chinese patients with EGFR-T790M positive non-small cell lung cancer (NCSLC).
Authors: Zhou Qing , Wu Lin , Feng Luo , An Tongtong , Cheng Ying , Zhou Jianying , Li Junling , Feng Ji Feng , Zhang Li , Han Baohui , Xu Walson , Zhu Lvyu , Xu Li , Xu Xiao , Luo Feng Roger , Wu Yi-Long
Published: March 2020

9091

Background: Abivertinib (AC0010) is a potent, selective third-generation EGFR tyrosine kinase inhibitor (TKI) that demonstrated clinical efficacy and manageable adverse events (AEs) in the phase 1 portion of the study in Chinese patients with EGFR T790M+ NSCLC. Here we report the results from patients enrolled to the phase 2 portion of the study (NCT02330367). Methods: The study enrolled locally advanced or metastatic NSCLC patients who were ≥ 18 years, progressed with the prior EGFR-TKI therapy, and must have T790M+ in tumor based on the central laboratory test. All patients received the recommended phase 2 doses of 300 mg twice daily [BID]. Results: As of March 5, 2018, 227 patients received treatment, majority of patients had adenocarcinoma (n = 220, 97%) with the median age of 59 years, 65% (n = 148) patients were female, most patients were non-smoker (n = 171, 75%), ECOG performance status of 1 (n = 162, 71%). The median treatment duration was 21 week. The treatment-related adverse events (AEs) were reported for 96.9% (n = 220) patients, mostly of grade 1 or 2 severity. The most common drug-related grade 3/4 AE (≥2%) was ALT increase (7.0%), AST increase (4.8%), diarrhea (4.4%), interstitial lung disease (4.0%), neutrophil count decrease (3.5%), and there was no drug-related grade 5 AEs. Among 209 response evaluable patients, per investigator’s assessment, 90.0% (n = 188) patients had tumor size reduction, the objective response rate (Complete Response + Partial Response [PR]) was 50.2% (n = 105; 95% CI 43.3%, 57.2%); 37.8% (n = 79) had stable disease, and the disease control rate was 88% (95% CI 82.9%, 92.1%). The median duration of response and progression-free survival estimated by Kaplan-Meier was 7.5 months (95% CI 6.0, 9.2) and was 7.5 months (95% CI 6.0, 8.8), respectively. Conclusions: Abivertinib demonstrated the clinical efficacy with manageable side-effects in patients with EGFR T790M+ NSCLC. Therefore, abivertinib could be a suitable treatment for patients with EGFR T790+ disease who have progressed on an EGFR-TKI. Clinical trial information: NCTNCT02330367.
Efficacy and safety of IBI305 compared with bevacizumab in advanced non-squamous NSCLC patients as first-line treatment in a randomized, double-blind, phase III study.
Authors: Zhang Li , Wu Bin , Huang Linian , Shi Meiqi , Liu Yunpeng , Zhao Yanqiu , Wang Lijun , Lu Shun , Chen Gongyan , Li Baolan , Xie Conghua , Fang Jian , Yang Nong , Zhang Yiping , Cui Jiuwei , Song Yong , Zhang Cuiying , Mei Xiaodong , Cao Bangwei , Yang Lan
Published: March 2020

9095

Background: IBI305 is a recombinant humanized anti-VEGF monoclonal antibody, a biosimilar candidate to bevacizumab in analytical and functional comparisons. Pharmacokinetic similarity has been demonstrated in healthy males. Here we present primary efficacy and safety results from a phase 3 comparative study in non-small cell lung cancer (NSCLC). Methods: In this double-blind, active-controlled study, subjects with advanced non-squamous NSCLC on first-line treatment with carboplatin and paclitaxel were randomized (1:1) to IBI305 or bevacizumab (15 mg/kg IV Q3W). After six cycles, patients were on maintenance treatment with IBI305 or bevacizumab (7.5 mg/kg IV Q3W) till progression. Clinical equivalence of the primary endpoint, confirmed objective response rate (ORR) was evaluated by comparing the 2-sided 90% confidence interval (CI) of the risk ratio (RR) between study arms with the prespecified margin (0.75, 1.33). Results: A total of 450 subjects were randomized (IBI305: n = 224; bevacizumab: n = 226). Baseline characteristics were well balanced between treatment arms. ORR evaluated by Independent Radiological Review Committee (IRRC) in full analysis set (FAS) was 44.3% (98/221) for IBI305 and 46.4% (102/220) for bevacizumab; the RR for ORR was 0.95 (90% CI: 0.803, 1.135). Sensitive analysis result on RRs of ORR in Intention to Treat (ITT) population (IBI305: n = 224; bevacizumab: n = 226) and other analysis set were consistent and all within the prespecified equivalence margin. The medium PFS were 8.4 months for IBI305 and 8.3 months for bevacizumab and duration of response (DOR) was also similar in both arms. Treatment-emergent adverse events (TEAEs) were well balanced between treatment arms and consistent with the known adverse event profile of bevacizumab. Patients developing binding antibodies were 0.5% in the IBI305 arm vs 0% in the bevacizumab arm; no subject tested positive for neutralizing antibodies. Conclusions: This is the first released phase 3 clinical study with maintenance treatment for bevacizumab biosimilar in NSCLC patients till now. The comparative study met its predefined primary endpoint that the RR for confirmed ORR was within the prespecified equivalence margin. There was no significant difference between the two arms in safety profile and immunogenicity. Clinical trial information: NCT02954172.
Crizotinib versus pemetrexed-based chemotherapy in patients with advanced ROS1-rearranged non-small cell lung cancer.
Authors: Shen Lan , Lu Shun
Published: March 2020

9101

Background: ROS1 rearrangement is an important therapeutic target that occurs in approximately 1-2% of patients with non-small cell lung cancer (NSCLC). It has been shown that ROS1-rearranged patients could benefit from crizotinib treatment. However, the efficacy of crizotinib as compared with pemetrexed-based chemotherapy in such patients is unknown. Methods: Advanced ROS1-rearranged NSCLC patients receiving crizotinib or pemetrexed-based chemotherapy as first-line treatment in Shanghai Chest Hospital between August 2010 and December 2017 were retrospectively reviewed. Clinical characteristics, treatments and survival outcomes data were abstracted. Results: Of 77 patients included, 30 patients (39.0%) received crizotinib and 47 patients (61.0%) received pemetrexed-based chemotherapy as their first-line treatment. The median follow-up was 26.8 months. The objective response rate was significantly better with crizotinib than with pemetrexed-based therapy (86.7% vs 44.7%, P < 0.001). The disease control rate wasc 96.7% with crizotinib, as compared with 85.1% with pemetrexed-based therapy (P = 0.140). The median progression-free survival was significantly longer with crizotinib versus pemetrexed-based therapy (18.4 months [95% confidence interval [CI]: 6.8-30.0] vs 8.6 months [95% CI:7.1-10.2], P < 0.001). No significant difference in overall survival (OS) was observed between the two groups (Not reach vs 28.1 months [95% CI:18.7-38.5], P = 0.173). Six patients (20%) in the crizotinib group switched to pemetrexed-based therapy in subsequent lines, while twenty-nine patients (61.7%) in the chemotherapy group crossed over to receive crizotinib after progression. There was no significant difference in median OS between patients who received crizotinib first and those who received pemetrexed-based treatment prior to crizotinib (38.6 months [95% CI: 0-81.0] vs 32.7 months [95% CI:14.3-51.1], P = 0.890). Conclusions: Crizotinib is superior to pemetrexed-based chemotherapy as an initial treatment for advanced ROS1-rearranged NSCLC patients. The sequence of crizotinib treatment and pemetrexed-based chemotherapy does not influence OS.
Determinants of early discontinuation of first-line chemotherapy, and associated outcomes among elderly with advanced non-small cell lung cancer.
Authors: Nadpara Pramit
Published: March 2020

9102

Background: Chemotherapy is the primary treatment modality in elderly with Advanced-NSCLC (Adv-NSCLC), with ASCO/NCCN guideline recommending First-Line Chemotherapy (FL-Chemo) for at least 4 months. The objective of this study was to identify the determinants, and outcomes of early discontinuation of FL-Chemo, in a nationwide sample of elderly patients. Methods: We used NCI’s Surveillance, Epidemiology, and End Results registry linked Medicare (SEER-Medicare) 2007-2014 files. We included patients with NSCLC diagnosis in 2007-2013, age ≥65, AJCC Stage IIIB/IV, receiving only FL-Chemo (Identified using HCPCS/CPT codes), and surviving at least 9 months post-diagnosis. We excluded those with non-continuous Medicare enrollment, or HMO enrollment. Patients receiving 1-3 months (vs. 4-7 months) of FL-Chemo were characterized as those experiencing early discontinuation. Patient’s performance status and comorbidity burden were assessed using previously validated algorithms. Survival was calculated from the diagnosis date to the date of death/study end date. Chi-square test, logistic regression, survivor function, proportional hazards regression, and propensity score–adjusted modeling were conducted. Results: We identified 1,029 patients (meeting inclusion and exclusion criteria) with incident Adv-NSCLC during the study years. Of those, 43.2% patients experienced early discontinuation. Adjusted analysis revealed Age as the only significant factor associated with early FL-Chemo discontinuation, with odds increasing with increase in age (p < 0.035). Other patient factors (non-clinical and clinical factors including performance score, comorbidity) were not associated with early discontinuation in any model. Survival outcomes and mortality risk were poor among those experiencing early discontinuation, however the difference was not statistically significant (p < 0.165). Conclusions: A large proportion of elderly with Adv-NSCLC experience early discontinuation of FL-Chemo. Even after controlling for variability in patient performance score and comorbidity burden, Age remained a key factor associated with early discontinuation, raising a cause for concern. Future studies need to explore the impact of Age along with patient reported Quality of Life on early treatment discontinuation.
SM-88 therapy in high risk poor prognosis pancreatic cancer (PDAC).
Authors: Noel Marcus Smith , Wang-Gillam Andrea , Ocean Allyson J. , Chawla Sant P. , Chung Vincent , Del Priore Giuseppe , Picozzi Vincent J.
Published: March 2020

e15714

Background: Refractory PDAC has no established therapy (JCO 37, 2019 supp 4; 226). SM-88 (D,L-alpha-metyrosine) is a novel oral therapy used with low doses of sirolimus, phenytoin and methoxsalen. Previous studies show safety and efficacy in compromised patients (JCO 37, 2019 supp 4; 200. JCO 37, 2019 supp 4; 310). We now report the dose optimization phase (NCT03512756). Methods: Randomized Phase 2 with dose optimization and expansion cohort of PDAC after 1 prior line, ECOG PS ≤2 and radiographic PD. Subjects randomized to 460 or 920 mg/d SM-88; all received phenytoin 50 mg, methoxsalen 10 mg and sirolimus 0.5 mg. Results: As of Jan 2019, 85 subjects consented, 41 ineligible, 38 randomized and 28 evaluable (1 cycle dosed). Average age 66.9 yrs, BMI 24.1, CA-19.9 median 2,562 (1.2 – 700,000), 2 prior lines 50%, 3 prior 14.3%, > 4 prior 21.4%; 85.7% had prior 5FU, 89.3% Gem, 71.4% taxanes, and 71.4% platinums. In both SM-88 doses, toxicity did not increase on treatment. AEs were not increased among high risk groups (age, sex, low BMI, low albumin, high CA-19.9 and prior radiotherapy). AEs increased with more prior lines of therapy, but were not dose dependent. There were 21 SAEs prior to dosing including 5 deaths among 14 patients. Two SAEs (rash and hypotension) were considered possibly related to SM-88 Therapy. No deaths were drug-related. 9 subjects had either a CEA or CA-19.9 decrease with 2 having both; 96.5% of subjects had CTCs detectable at baseline with 70% experiencing > 30% decline for at least 1 cycle with a median CTC best response decrease of 73%. Prior Lines of Therapy Subjects (n) Current Median OS 2-month Target Lesion Response CTCs Median Best OR % Alive 1 4 +5.7m 1 PR, 2 SD, 1 n/a* -74% 75% 2 14 +4.7m 6 SD, 3 PD, 5 n/a* -84% 79% 3+ 10 +3.5m 1 PR, 4 PD, 5 n/a* -55% 50% Total 28 +4.3m 2 PR, 8 SD, 7 PD, 11 n/a* -73% 68% *Not available RECIST clinical benefit (SD + PR) was 47.1% (8/17). 68% of subjects were alive at a median follow up of +4.3 months. EORTC global health and QOL measures did not deteriorate on treatment. Conclusions: Both doses of SM-88 were well tolerated without clinically significant toxicity. Anti-tumor activity was observed in this heavily pretreated population warranting expansion of the study for further efficacy evaluation. Clinical trial information: NCT03512756.
The bone marrow stroma capacity to confer resistance to leukemia cells from Ara-C treatment as a prognostic factor for overall survival in AML.
Authors: Macanas-Pirard Patricia , Vargas-Salas Sergio , Broekhuizen Richard , Coronado Romina , Bizama Carolina , Muñiz-Muñoz Sabrina , Torres Vivianne , Montecinos Viviana , Ernst Daniel , Melo Francisco , Roa Juan Carlos , Nervi Bruno
Published: March 2020

e18500

Background: The interaction of acute myeloid leukemia (AML) with the bone marrow stroma (BMS) determines a protective microenvironment that favors leukemia development and resistance to chemotherapy. We developed an in vitro platform to study leukemia and stroma interaction, and showed that BMS secretes soluble factors protecting AML cells from Ara-C-induced apoptosis, which correlated with clinical patient outcomes. Methods: BMS from AML patients and healthy donors were cultured to perform chemo-sensitivity studies with Ara-C on THP-1 cells. A Resistance Factor was calculated (RF = IC50 stroma conditioned medium (CM)/IC50 control medium) to classify BMS as “protective” (PS: confers chemo-resistance) or “non-protective” (NPS: does not confer chemo-resistance). Characterization of myofibroblasts in BMS cultures was performed by WB. Quantification of cytokines from primary BMS CM was performed by Luminex. The differential expression of epithelial-mesenquimal-like (EMT-like) and stem cell-markers in THP-1 cells incubated with primary BMS CM was measured by qPCR. Results: We recruited 90 AML patients and 10 healthy BM donors. AML cohort showed 31 patients with PS and 59 patients with NPS. PS patients had a significant poor overall survival (OS) compared with NPS patients (44% versus 70% OS in 2.5 years, median survival 7.3 months versus 20.7 months, HR 2.36). The stroma from healthy BM donors did not confer resistance to THP-1 cells. BMS in both, PS and NPS have activated myofibroblasts and analysis of cytokine expression showed differential expression between groups. THP-1 cells incubated with PS showed significant expression of EMT- and stem cell-markers like Twist, Vimentin, CD44 and CD34 compared to THP-1 cells incubated with NPS and control medium. Conclusions: The capacity of the BMS from AML patients to modulate chemoresistance is a strong prognostic factor for OS, and PS patients have a worst OS compared with NPS patients. Stroma from healthy donors has a NPS phenotype. We propose that the leukemia is capable of educating the stroma to acquire secondarily the capacity to confer resistance to leukemia cells to favor tumor progression and chemoresistance.
Effects of obesity on overall survival (OS) of patients with acute myeloid leukemia (AML).
Authors: Dhakal Prajwal , Lyden Elizabeth , Lee Andrea , Michalski Joel , Al-Kadhimi Zaid S. , Maness Lori J. , Gundabolu Krishna , Bhatt Vijaya Raj
Published: March 2020

e18510

Background: The relationship between obesity and prognosis of AML has not been established. Our retrospective study aimed to determine the effect of obesity on OS of AML. Methods: AML patients diagnosed from 2000-2016 at University of Nebraska Medical Center were included. Body mass index (BMI) at the time of AML diagnosis was divided into 3 groups: normal (18.5≤25 kg/m2) or underweight (<18.5 kg/m2); over-weight (25-30 kg/m2); and obese (≥30 kg/m2). Chi-square test, Kruskal-Wallis test and ANOVA were used to look at the association of different BMI groups with other patient characteristics. Mann-Whitney test was used for pairwise comparisons of hematopoietic cell transplant (HCT) co-morbidity index and Bonferroni correction was used to adjust p-values. OS, defined as time from diagnosis to death from any cause, was determined by Kaplan-Meier method and comparisons were done using log-rank test. Cox Regression was performed to detect survival effect of BMI (as continuous variable). P<0.05 was considered statistically significant. Results: A total of 314 patients were included in the study (Table): 46% were female, 35% had adverse cytogenetics, 15% had FLT3-ITD mutation, 68% received intensive chemotherapy and 30% underwent HCT. 38% of total patients were obese. Baseline characteristics were similar in all 3 BMI groups except co-morbidity index (p=0.04). OS for normal/underweight, overweight and obese groups at 1 year was 85%, 92%, and 94% respectively (p=0.84). BMI, as a continuous variable, was not a significant risk factor for death (HR 1.00, 95% CI 0.98-1.03). Conclusions: Obese patients, compared to non-obese patients, did not differ in baseline characteristics other than increased comorbidity burden. Obesity, when adjusted for other characteristics, did not have any effect on OS of patients with AML. Patient characteristics. [Table: see text]
Bayesian network meta-analysis (NMA) of complete remission without or with incomplete hematologic recovery (CR/CRi) to CPX-351, FLAG, and standard 7+3 (7+3) chemotherapy in the treatment of newly diagnosed secondary acute myeloid leukemia (sAML).
Authors: Oh Mok , Marini Bernard , Perissinotti Anthony , Benitez Lydia , Burke Patrick William , Bixby Dale L. , Pettit Kristen Marie , Abraham Ivo , McBride Ali
Published: March 2020

e18514

Background: Patients (pts) sAML have poor outcomes (CR/CRi= 25-35%) with standard 7+3 induction chemotherapy (7+3). CPX-351 (liposomal encapsulated daunorubicin + cytarabine at a synergistic 5:1 molar ratio) was approved recently for sAML based on improvements in CR/CRi and survival but high cost and toxicity has discouraged its use. FLAG (fludarabine + high-dose cytarabine + granulocyte colony stimulating factor) have emerged as a lower cost, safe alternatives; however, outcomes between CPX-351 and FLAG have yet to be compared. In the absence of a direct trial, we aimed to estimate indirectly by Bayesian NMA the comparative efficacy of CPX-351, FLAG, and 7+3 therapy for sAML patients. Methods: Publications that compared FLAG or CPX-351 to 7+3 in newly diagnosed sAML were identified through a search of PubMed. CR/CRi rates were used in a Bayesian NMA to assess the direct (CPX-351 vs 7+3; FLAG vs 7+3) and indirect (CPX-351 vs FLAG) comparative efficacy of these regimens. Fixed (FE) and random effect (RE) analyses were conducted to estimate pooled odds ratios (OR) with 95% credible interval (CrI). Results: Of 169 identified articles, four studies (three RCT and one retrospective cohort) on a total of 781 pts in three treatment arms were retained. NMA showed no significant difference in pooled CR/CRi rates between CPX-351 and FLAG in both FE and RE models. However, pts receiving either FLAG or CPX-351 had significantly higher CR/CRi than those receiving 7+3 in both FE and RE models as shown in the table. Conclusions: This NMA suggests that both CPX-351 and FLAG prevail in CR/CRi efficacy over 7+3. In indirect comparison, CPX-351 and FLAG are equivalent in efficacy. The cost implications of these results remain to be established. [Table: see text]
Role of IL27 and IL35 as biomarkers and potential targets in acute myeloid leukemia.
Authors: Ahmed Heba A. , Maklad Ahmed M. , Elyamany Ashraf
Published: March 2020

e18516

Background: Acute myeloid leukemia (AML) is one of the most common leukemia affecting adult. Regulatory T cells (Tregs) are a subset of CD4 (+) T cells that plays a central role immune tolerance. Objective: We aimed to explore the role of interleukin- 27 (IL27) & interleukin- 35 (IL35) produced by T regs and its associations with clinical characteristics and prognostic markers of AML patients. Methods: The study included 70 patients with acute myeloid leukemia (AML) and 30 healthy controls. We used flowcytometry immunophenotyping to confirm the diagnosis of AML. Serum level of interleukin- 27 (IL 27) & interleukin- 35 (IL 35) were measured at diagnosis by enzyme-linked immunosorbentassay (ELISA). Results: Higher levels of IL27 and IL35 were detected in AML patients than the control group (p ≤ 0.001). We used Receiver operating characteristic (ROC) analysis for detection of optimum IL27 & IL35 cut off level needed for predicting AML. ROC curve analysis demonstrated IL27 optimum cutoff is > 43, AUC 0.926 with a sensitivity 74% and Specificity 96.6% (P-value <0.00). IL35 optimum cutoff was > 27.8 AUC 0.972 with 88% and 98% sensitivity and specificity respectively (P-value <0.001). Serum IL27 & IL35 could well identify AML patients from healthy individuals. More importantly IL27 & IL35 correlated with clinical variable, and could be served as an independent prognostic factor. Conclusions: IL27 & IL 35 might have an application as a diagnostic and prognostic indicator for AML patients and could be served as an independent prognostic factor.
Survival outcomes in patients with good risk acute myeloid leukemia: A single-center retrospective review.
Authors: Bower Kathryn , Wen Sijin , Cumpston Aaron , Shah Nilay Arvind
Published: March 2020

e18519

Background: Cytogenetics and gene mutations play a significant role in determining necessity of allogeneic transplant in patients with AML. Core binding cytogenetic factors (CBF) such as t(8;21), inv 16, and t(16;16) as well as molecular mutations in nucleophosmin-1 (NPM1) and bi-allelic CCAAT/enhancer binding protein alpha (CEBPA) mutations in cytogenetically normal patients have conferred improved relapse-free survival (RFS) and overall survival (OS) rates. We report outcomes of these “good-risk” patients in an Appalachian population, to evaluate differences from previous reports. Methods: A total of 79 patients with AML diagnosed between July 2007 and July 2017 at West Virginia University (WVU) who qualified for good-risk disease per ELN 2017 criteria were retrospectively analyzed for RFS and OS. Eighteen of these patients were excluded from our final analysis: 10 for primary refractory disease and 8 for proceeding to transplant in first remission. Results: A total of 61 patients were included in our analysis, with a median age of 56 (range 11-81), 32 females, and 29 males. Good-risk features included 29 patients with NPM1, no patients with CEBPA, 19 with inv 16, 9 with t(8;21), and 1 with t(16;16). All patients received cytarabine and an anthracycline induction chemotherapy, and a median of 4 cycles (range 1 -4) of high-dose cytarabine consolidation chemotherapy. The RFS and OS at 4 years was 36% and 50%, respectively. There were no occurrences of treatment-related mortality among the patients. Among the 22 patients relapsing, 12 (55%) were able to achieve a second remission and received allogeneic transplant. Conclusions: Our outcomes appear somewhat lower than previous reports, but continuing to highlight the ability to achieve long-term remissions in this subset of patients, without the need for allogeneic transplant. Continued efforts should focus on improving outcomes in these patients, to further prevent relapses.
Incidence, characteristics, and risk factors of venous thromboembolism in adolescent and young adult acute lymphoblastic leukemia patients receiving peg-asparaginase.
Authors: Underwood Brynne , Zhao Qiuhong , Walker Alison R. , Mims Alice S. , Vasu Sumithira , Behbehani Gregory , Blachly James Stewart , Larkin Karilyn T.M. , Wang Tzu-Fei , Bhatnagar Bhavana
Published: March 2020

e18520

Background: Venous thromboembolism (VTE) is common in acute lymphoblastic leukemia (ALL) patients (pts) receiving peg-asparaginase (ASNase) however there is limited data regarding the incidence of VTE and risk factors for VTE in adolescent and young adults (AYA) treated with ASNase. Methods: This is a single institutional retrospective analysis of AYA pts with ALL who received ASNase from January 2013 to December 2018. Time to VTE was calculated from date of starting treatment to onset of VTE or censored at last assessment date, treating death as a competing risk. The cumulative incidence of VTE was estimated and the Fine and Gray regression models accounting for competing risks were used to examine the association between risk factors and VTE. Results: Forty-six AYA ALL patients were included. Pt characteristics are shown in the Table. Twenty pts had a VTE following ASNase with the cumulative incidence rate of 35% (95% CI: 22-48%) at 100 days. The most common VTE sites were cerebral (n=6) and upper extremity (n=6). Nine pts (43%) had at least one recurrent VTE. After initial VTE, ASNase was continued in 13 pts (62%), stopped in 6 pts (29%), and dose reduced in 2 pts (10%). Nine pts (45%) of those who developed VTE received antithrombin. Out of the 6 pts with VTE who had ASNase discontinued or dose reduced, 2 (33%) had progression of ALL. The hazard ratios (HR) for risk of VTE from univariable regression models are listed in Table 1. Male sex was associated with increased VTE risk, with HR=3.33 (95% CI: 1.13-9.77). Conclusions: Our study estimated the incidence of VTE in the AYA cohort. Only male sex was identified as a risk factor for VTE. Additional studies are needed to assess VTE risk factors in AYA pts with ALL. Pt characteristics and hazard ratios for risk of VTE. [Table: see text]
Blinatumomab is safe and effective in relapsed and MRD-positive B-ALL CD19+ patients: The Bologna Compassionate Program Experience.
Authors: Martinelli Giovanni , Paolini Stefania , Cerchione Claudio , Santoro Alessandra , Robustelli Valentina , Soverini Simona , De Benedittis Caterina , Imbrogno Enrica , Ghelli Luserna di Rorà Andrea , Parisi Sarah , Sartor Chiara , Marconi Giovanni , Lo Monaco Silvia , Abbenante Maria Chiara , Fontana Maria Chiara , Padella Antonella , Ferrari Anna , Simonetti Giorgia , Papayannidis Cristina
Published: March 2020

e18522

Background: Adult B-ALL patients still have a dismal prognosis, due to a high incidence of relapse even after allogenic SCT. Safety and efficacy of Blinatumomab, anti CD3-CD19 Bite antibody, has been demonstrated both in MRD pos patients and in relapsed/refractory (R/R) setting. To evaluate safety profile and efficacy of Blinatumomab, obtained through a compassionate use, in a cohort of 18 adult patients affected by MRD+ or R/R B-ALL treated at Bologna University. Methods: From March 2015 to December 2017, 18 patients received Blinatumomab at the standard dosage (9 mcg/d x 7 days, 28 mcg/d x 21 days) in 28-days courses. All the patients were hospitalized to receive the 1st course of therapy. The following courses, based on the good safety profile of the compound, were administered in outpatient setting. 18 patients (M/F = 10/8; median age 43, r. 18-73) have been treated. Ph chromosome was detected in 8/18 . 10 were MRD+ (5 Ph pos and 5 Ph neg); E2A-PBX1 and MLL-AF4 rearrangements were found in two patients. 8 patients had a R/R disease (3 Ph pos/5 Ph neg). Median WBC count before starting therapy with Blinatumomab was 5400/mmc (r. 500-76500). All patients had previously received many lines of therapy (median 4, r. 1-7). In 4 cases an alloTMO was already performed, and two patients had received two transplants. 12/18 patients were referred to us by other Institutions. All the patients received at least one course of Blinatumomab. Bone marrow evaluations, including cytogenetics, molecular biology and immunophenotyping analysis were performed at the beginning of every course of therapy in order to assess patients' disease status. MRD evaluation was assessed through BCR-ABL fusion transcript quantitative analysis in Ph pos ALL patients and Ig rearrangment in Ph neg patients. Monitoring of adverse events was periodically performed. 16/18 patients are evaluable for response, at least to one cycle. Results: 9/16 (56%) patients obtained a CR (7/9 MRD+ and 2/7 R/R). In 7/9 (78%) responders patients a molecular CR was reached, (in 6 patients after the first course, in one case after the second one). 5 responders proceeded to alloBMT and are actually alive in CR (median follow-up after transplant 240 days). In terms of toxicity, one patient developed a grade IV neurological event (mental confusion, tremor), which completely resolved after a transient drug withdrawal. Conclusions: Our results confirm the high rate of response and to Blinatumomab in a poor patients' population, and the good management profile of the compound.
Evaluation of prognostic factors after induction therapy in AML.
Authors: Devoe Craig E. , Bao Delong , Trotta Christina , Lee Chung-Shien , Fishbein Joanna Stein
Published: March 2020

e18528

Background: Acute myeloid leukemia (AML) is a hematologic myeloid malignancy that carries a poor prognosis. Standard of care is induction chemotherapy with daunorubicin and cytarabine also known as 7 + 3. Bone marrow aspirates are assessed on day 14 (D14) and day 28 (D28). Achievement of CR (complete remission) is predicative of overall survival (OS ).Morphological review of BM (bone marrow) on D14 remains the standard evaluation for any indication for CR. Methods: Our primary objective was to determine if blast % on the D14 bone marrow aspirate is a prognostic indicator for remission in acute leukemia patients who underwent induction chemotherapy. Institutional review board was approved. A retrospective chart review was conducted at North Shore University Hospital. Adult patients with AML who received standard induction chemotherapy from 2010 to 2015 were included. 150 patients were reviewed and their D14 blast %, initial marrow blast %, gender, age, cytogenetics and initial WBC were assessed. The patients’ D14 blast % biopsies were divided into blast percentiles: < 1%, 1-10%, 10-30%, 30-60% and > 60%. CR was defined as patients having < 5% blasts on their D28 bone marrow or day 63 and corresponding neutrophil count > 1,000 and platelet count > 100,000. Results: Fisher’s exact test was used to compare the proportion of patients who reached CR among the D14 blast % categories. The Wilcoxon test was utilized to compare CR on continuous variables. Results were considered statistically significant if p < 0.05. D14 hemoglobin and D14 platelets were not significantly associated with CR status (p = 0.67, p = 0.33, and p = 0.13, respectively). D14 WBC was significantly associated with CR (p = 0.02), but when both D14 WBC and initial blasts % were included in a multiple logistic model, WBC was no longer a significant predictor of outcome. Only initial blast percent at time of diagnosis was deemed predictive of CR response at day D63 (p = 0.0142). Conclusions: Initial blast > 60% was found to be significantly associated with the greatest CR rate. This study provides evidence of initial blast % being a prognostic factor for CR.
HCT related toxicities and mortality in frail recipients.
Authors: Pamukcuoglu Merve , Bhatia Smita , Weisdorf Daniel Jordan , DeFor Todd E. , Ustun Celalettin , Nayar Manju , Holtan Shernan , El Jurdi Najla H. , Thyagarajan Bharat , Brunstein Claudio , Bachanova Veronika , Warlick Erica D. , Arora Mukta
Published: March 2020

e18534

Background: Frailty is a state characterized by diminished physiological reserve and increased vulnerability to stress, and adversely affects outcomes in older patients with cancer. Geriatric assessments are not routinely used to screen older HCT (hematopoietic cell transplant) recipients. There is limited knowledge of the impact of pre-HCT frailty on severe/ life-threatening (CTCAE, version 5.0) grade 3-4 non-hematologic toxicities within 1y after HCT. We aimed to determine the relationship between pre-HCT frailty and grade 3-4 non-hematologic toxicities and mortality in HCT recipients, and also examined whether age at HCT moderated that association. Methods: In a prospective longitudinal study of 117 patients undergoing HCT at age ≥ 40y, we performed pre-HCT geriatric assessments. Frailty was assessed using Fried’s criteria. Post-HCT toxicities were abstracted through chart reviews Results: Median age at HCT was 60y (40-73). Pre-HCT frailty could be evaluated in 98 (84%) patients [(51 autologous, 47 allogeneic (allo)]. Pre-HCT comorbidity index (CI) was high in 27%, intermediate in 40% and low in 33%. The prevalence of pre-HCT frailty was 21%. Overall, frail recipients (vs. non-frail) had a higher cumulative incidence of any grade 3-4 toxicity [86% (95% CI: 62-100%) vs. 70% (57-83%), p = 0.03]; and the following organ specific grade 3-4 toxicities: non-neutropenic infections [(38% (17-59%) vs. 13% (6-20%), p < 0.01)]; nervous system disorders [(19% (3-35%) vs. 4% (0-8%), p = 0.02)]; and pneumonia [(38% (17-59%) vs. 10% (4-17%), p < 0.01]. Frail recipients also had a higher overall mortality [52%, (30-75%) vs. 19%, (11-28%) (p < 0.01)]. In Cox regression analysis controlling for age, donor type, disease risk, conditioning and HCT-CI, frail recipients were 1.9 fold more likely to suffer any grade 3-4 toxicities (p = 0.03), 4-fold more likely to suffer non-neutropenic infections and pneumonia, both p = 0.01; and 8.6-fold more likely to suffer nervous system disorders, p = 0.01. Frail recipients who underwent an allo-HCT were at 2.7 fold higher risk of death vs. non-frail allo- HCT recipients, p = 0.06. Conclusions: The higher toxicity and mortality in frail recipients needs attention. Studies focusing on pre-HCT interventions to reduce frailty are needed.
Outcomes of autologous blood collection prior to bone marrow harvest for matched unrelated donors.
Authors: Ramnaraign Brian Hemendra , Rogers Brittany Kayla , McGorray Susan P. , Sugrue Michele , Murthy Hemant S. , Hiemenz John W. , Hsu Jack W. , Wingard John R. , Farhadfar Nosha
Published: March 2020

e18535

Background: Autologous (auto) blood collection prior to bone marrow (BM) harvest is a common procedure however there is little data to say whether this is beneficial. Methods: This is a retrospective study evaluating the efficacy of pre-op auto blood collection in healthy unrelated donors who underwent BM harvesting at our institution between 9/2009 and 8/2017. Unrelated donors aged 18 or older who underwent their first BM harvest were included. Comparisons were made using two sample t-tests. Results: Among the 73 BM donors, 54 (74%) underwent auto blood collection resulting in 78 units collected. The cohorts with and without auto blood collected were similar in age and gender (mean age 31.0 vs 30.2; female 59% vs 41%). Those with auto blood collected donated larger volumes of marrow (mean 1395 mL vs 799 mL, p = 0.0002). Baseline hemoglobin (Hb) was similar between the cohorts (mean 14.1 g/dL vs 14.0 g/dL, p = 0.87). However, those with auto blood collected had lower pre-harvest (mean 13.1 g/dL vs 13.8 g/dL, p = 0.0430) and post-harvest Hb (mean 10.0 g/dL vs 11.3 g/dL, p = 0.0120). Of the 78 auto blood units collected, 45 units (58%) were used with 92% of women and 56% of men receiving their auto blood post-op. 33 (42%) auto blood units were discarded. Donors who were given back their auto blood were more likely to be female and have lower pre- and post-harvest Hb. Reasons for auto blood transfusion were blood availability (31%), donor post-op symptoms (i.e. hypotension, dizziness, syncope, and bleeding; 23%), intra-operative transient hypotension (26%), post-op anemia (11%) and patient request (9%). None of the patients who were transfused auto blood, or donors without auto blood collection, required allogeneic blood. Conclusions: Based on our results, collection of auto blood prior to bone marrow harvest leads to lower pre-op Hb and increases the likelihood of post-op blood transfusion. In addition, availability of auto blood can lead to over transfusion which may be detrimental to donor health. Although there may be a subset of donors who might benefit, routine auto blood collection prior to bone marrow harvesting is unnecessary and can be potentially hazardous to donors.
Pyridoxine impact on patients with myelodysplastic syndromes with ring sideroblasts: Single institution retrospective study.
Authors: Zblewski Darci , Nguyen Phuong L. , He Rong , Greipp Patricia T. , Begna Kebede , Patnaik Mrinal Mahesh , Gangat Naseema , Shah Mithun Vinod , Alkhateeb Hassan , Litzow Mark Robert , Al-Kali Aref
Published: March 2020

e18549

Background: Many vitamin deficiencies can cause anemia. It is prudent prior to diagnosing a myeloid neoplasm, to check for vitamin deficiencies and correct them. Myelodysplastic syndromes with ring sideroblasts (MDS-RS) are associated with anemia. Pyridoxine (Vit B6) replacement may improve anemia found in sideroblastic anemia. The study was to determine how frequently Vit B6 was assessed, replaced and impact replacement had on outcomes in MDS-RS. Methods: Study subjects were from the Mayo Clinic Myelodysplastic syndrome (MDS) database which contains 1315 patients (pts). Appropriate IRB approval was obtained. Diagnosis of MDS and its sub-classification was done according to World Health Organization 2016 criteria. A response was any improvement in hemoglobin. Overall survival (OS) estimates were calculated using Kaplan-Meier curves and univariate and multivariate analysis was done using JMP software version 13. Results: Among 1315 pts with MDS, 161 pts had a diagnosis of MDS-RS. Median age was 73, and 55 (34%) pts were females. Thirty-nine (36%) pts had very low, 53 (50%) low, 9 (8%) intermediate, 3 (3%) high, and 2 (1%) had very high revised international prognostic score. The median white blood cell count was 5.4 x109, platelet count was 255 x109, and hemoglobin was 9.9 gm/dL. Five pts (3%) had a Vit B6 levels done; out of whom, 4 (80%) were not Vit B6 deficient. Among 42 (26%) pts who had Vit B6 replacement, 21 (50%) had no response, 4 (10%) had a response and 17 (40%) had unknown response. 103 (64%) of the pts were transfusion independent (TI). Overall survival in pts who are transfusion dependent was 68 months compared to 85 in pts who are TI (Wilcoxon P =.03). There was an improvement in OS in the group that had Vit B6 replacement compared to the group with no Vit B6 replacement (92 months vs 68 months, Wilcoxon P =.07). Response to Vit B6 replacement did not show OS benefit. Acute Leukemia transformation in Vit B6 replacement was 2% and 6% in pts. who did not have Vit B6 replacement (P= .4). Conclusions: Vit B6 was not checked often in MDS-RS pts. There was a borderline improvement in OS in Vit B6 replacement group (p= .07). Response did not affect OS. A larger prospective study is needed to study Vit B6 role in MDS-RS.
Thrombotic episodes in myeloproliferative neoplasms: A population based study.
Authors: Ball Somedeb , Bandyopadhyay Dhrubajyoti , Hajra Adrija , Ghosh Raktim K , Tijani Lukman Aderoju , Maiti Abhishek
Published: March 2020

e18554

Background: Myeloproliferative neoplasms (MPN) are complicated with high incidence of thrombotic episodes, often requiring chronic anticoagulation in high risk patients (pts). To improve our knowledge on risk stratification, we undertook a large population study on National Inpatient Sample (NIS) to investigate the demographic and health factors associated with venous thromboembolism (VTE) and acute coronary syndrome (ACS) in pts with MPN. Methods: In this retrospective cohort study using the most recent 2016 NIS, we included all pts with discharge diagnosis (dx) of MPN with or without current or prior dx of VTE and ACS using appropriate ICD-10 codes. Demographic and health characteristics were compared between groups. Multivariate logistic regression was done to compare length of stay and cost of care. STATA 13.0 was used for statistical analysis. Results: Among 162,435 pts with MPN, 3750 (2.3%) had VTE and 2820 (1.73%) had ACS. MPN pts with VTE had significantly higher age (mean 61.3 years) compared to those without VTE (mean 59.3 years). Smoking, obesity, and JAK2 mutation were significantly more common in MPN with VTE group. Pts with MPN and ACS were significantly older than those without ACS (67.85 vs. 59.2 years). These pts were mostly males and more likely to have hypertension, diabetes, smoking, dyslipidemia, obesity, and chronic kidney disease as comorbidities. Total hospital cost was significantly higher in MPN pts with VTE and ACS. Conclusions: In agreement with prior reports, age, smoking, and presence of JAK-2 mutation seem to be an important prognostic factors for both VTE and ACS in MPN. Other common comorbidities mandate critical consideration in assessment of thrombotic risk in MPN pts. [Table: see text]
Role of ethnicity in thrombotic and hemorrhagic complications of myeloproliferative neoplasms.
Authors: Peseski Andrew , Saliba Antoine , Sayar Hamid
Published: March 2020

e18555

Background: Philadelphia-chromosome negative myeloproliferative neoplasms (MPN) are a group of hematologic malignancies with known complications of hemorrhage and thrombosis. Age and a previous history of thrombosis are well-documented risk factors for future vascular events. Variations in the rates of these complications among ethnicities and sexes have not been extensively explored. Methods: Our retrospective analysis included 301 adult patients with a diagnosis of MPN without a history of thrombosis or hemorrhagic event seen at the Indiana University Simon Cancer Center between 1992 and 2019. Relationships between ethno-racial backgrounds and vascular complications and disease outcomes were evaluated using multivariate logistic regression analysis and Cox regression models. Results: Two hundred seventy-one patients (90.0%) were Caucasian and 30 patients (10.0%) were non-Caucasian. Non-Caucasian patients were comprised of African America, Asian, and Middle Eastern ethnicities. Median age at diagnosis was 56 years, and 43.9% were male. No association was found between the incidence of thrombotic complications and ethnicity using the log-rank test ( p 0.68). The incidence of hemorrhagic events was significantly increased in non-Caucasian patients (OR = 4.33; 95% CI [1.15 – 16.36], p 0.03). Patients with higher hemoglobin concentration at diagnosis were at a significantly lower risk of bleeding complications (OR = 0.79; 95% CI [0.65 – 0.95], p 0.01). Non-Caucasian patients were at 2.98 times (95% CI [1.19 – 7.44], p 0.02) higher risk when vascular complications were pooled together. Our models also showed that male sex (OR = 0.14; 95% CI [.02 – .98], p 0.048) and a higher platelet count at the time of diagnosis (OR = 0.99; 95% CI [.993 –.999], p 0.03) had a marginally significant association with decreased rate of progression to acute myeloid leukemia. Conclusions: This study suggests that in patients without a history of thrombosis or bleeding, non-Caucasian ethnicity was associated with an increased adjusted risk of hemorrhagic complications in patients with MPN. This observation may inform future studies to further characterize those disparities in outcomes at the genetic or socioeconomic level.