bluuebunny/crossref_metadata_2025 huggingface dataset:
DNA damage response gene alterations are associated with high tumor mutational burden and clinical benefit from programmed death 1 axis inhibition in non-small cell lung cancer.
Authors: Ricciuti Biagio , Cheng Michael L. , Recondo Gonzalo , Nishino Mizuki , Umeton Renato , Sholl Lynette M. , Awad Mark M.
Published: March 2020

9077

Background: DNA damage response (DDR) gene alterations are associated with increased tumor infiltrating lymphocytes, higher genomic instability, and higher tumor mutational burden (TMB) in cancer. Whether DDR alterations are associated with benefit from immune-checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) is unknown. Methods: Clinicopathologic and genomic data were collected from patients (pts) with advanced NSCLC at the Dana-Farber Cancer Institute treated with PD-(L)1 inhibitors. Targeted next-generation sequencing (NGS) by OncoPanel was used to determine DDR gene mutation status and TMB. DDR positive (DDRpos) cases were defined as those with pathogenic DDR alterations (per COSMIC and ClinVar databases). DDR negative (DDRneg) cases were defined as either DDR wild-type or those with non-pathogenic DDR alterations. Results: Of 468 pts with successful NGS who received ICIs, 242 (51.7%) were identified as having any DDR alteration. Of them, 74 (15.8% in the entire cohort) were defined as DDRpos with pathogenic alterations in the following genes: ATM (41.9%), MLH1/MSH2/MSH6 (18.9%), BRCA1/2 (16.2%), CHEK1/2 (9.4%), FANC genes (9.4%), BAP1 (5.4%), RAD genes (5.4%), ERCC4/6 (4.0%), POLE (2.7%), ATR (2.7%). DDRpos and DDRneg groups were balanced in terms of age, performance status, gender, histology, oncogenic driver mutation, smoking status, ICI line, baseline brain metastases. The median TMB was significantly higher in the DDRpos group compared to the DDRneg group (12.1 vs 9.8 mutations/megabase, P = 0.007). No difference in median PD-L1 tumor proportion score was observed between groups (30% vs 25%, P = 0.33). Compared to DDRneg pts (N = 394), DDRpos pts had a significantly higher objective response rate (31.1% vs 19.1%, P = 0.03), and longer median progression-free survival (4.3 vs 2.6 months, HR: 0.71 [95%CI: 0.53-0.95], P = 0.02) and overall survival (16.3 vs 9.8 months, HR: 0.63 [95%CI: 0.45-0.89], P = 0.009) with PD-(L)1 therapy. Conclusions: Pathogenic DDR alterations are frequent in NSCLC and are associated with higher TMB and improved clinical outcomes in NSCLC pts treated with PD-1 axis inhibition.
Phase II randomized trial of afatinib with or without cetuximab as first-line treatment for EGFR mutated non-small cell lung cancer (NSCLC) patients (IFCT-1503 ACE-Lung).
Authors: Cortot Alexis B. , Madroszyk Anne , Giroux Leprieur Etienne , Molinier Olivier , Quoix Elisabeth A. , Berard Henri , Otto Josianne , Rault Isabelle , Raimbourg Judith , Hureaux Jose , Moreau Lionel , Debieuvre Didier , Morel Hugues , Denis Marc G. , Amour Elodie , Morin Franck , Moro-Sibilot Denis , Cadranel Jacques ,   French Cooperative Thoracic Intergroup (IFCT)
Published: March 2020

9079

Background: First-line treatment of metastatic EGFR-mutated NSCLC relies on EGFR-TKIs. However, all patients (pts) eventually develop progression. Dual inhibition of EGFR with afatinib (A), an irreversible pan-erbB TKI, and cetuximab (C), an EGFR monoclonal antibody, has shown activity in EGFR-mutated pts with acquired resistance to TKIs, regardless of the T790M status. Methods: We conducted a phase II randomized trial in advanced NSCLC pts harboring an activating EGFR mutation, who had not received prior therapy. Pts were treated with A (40 mg/d) until progression alone or with C 500 mg/m² every 2 weeks during 6 months (mos) (beginning at D15 at 250 mg/m²). Primary endpoint was time-to-treatment failure (TTF) at 9 mos for pts with del19 and L858R mutations. Secondary endpoints include safety, progression-free survival (PFS), overall survival (OS). Prospective monitoring of the T790M mutation was performed on circulating tumoral DNA (ctDNA) by digital PCR. Results: Trial was stopped early due to futility analysis after 118 pts were enrolled (59 in each arm). Baseline characteristics were balanced between the 2 arms, and especially for the types of EGFR mutation (del19, 55.9 vs 50.8%; L858R, 39 vs 40.7%; others, 5.1 vs 8.5% in AC and A arms, respectively). Treatment-related AEs of any grades were similar, although there was an excess of grade 3 AEs in the AC arm (50 vs 37.3%), but no of grade 5. The excess in grade 3-5 AEs was essentially due to cutaneous (96.6 vs 81.4%), eyes (32.8 vs 27.1%), hematological (22.4 vs 15.3%) but not to digestive toxicities (89.7 vs 98.3%). Among the 117 pts included in the efficacy analysis, 9-months TTF was 63.3% (47.5-75.6) in arm A and 65.8% (50.1-77.66) in arm AC. Median TTF was 11.1 mos (8.3-not reached [NR]) and 10.8 mos (9.2-13.7) in arms A and AC, respectively. Median PFS was 11.1 mos (8.3-NR) and 12.8 mos (9.2-13.7), respectively. Median OS was 20.8 mos (17.5-NR) and NR (17-NR), respectively. Conclusions: Efficacy of AC was similar to that of A alone. These results don’t support further evaluation of this combination in this setting. Results of ctDNA monitoring will be reported during the meeting. Clinical trial information: NCT02716311.
Health-related quality of life (HRQoL) results from ALTA-1L: Phase 3 study of brigatinib vs crizotinib as first-line (1L) ALK therapy in advanced ALK+ non-small cell lung cancer (NSCLC).
Authors: Campelo Rosario Garcia , Lin Huamao Mark , Perol Maurice , Jahanzeb Mohammad , Popat Sanjay , Zhu Yanyan , Zhang Pingkuan , Camidge D. Ross
Published: March 2020

9084

Background: Results from ALTA-1L (NCT 02737501 ), an international, multicenter trial, showed that brigatinib vs crizotinib as 1L ALK therapy significantly prolongs progression-free survival (PFS; HR: 0.49, 95% CI, 0.33, 0.74) in advanced ALK+ NSCLC. HRQoL was evaluated as a secondary objective. Methods: ALK+ NSCLC patients were randomized 1:1 to brigatinib 90 mg daily for 7 days, then 180 mg daily or crizotinib 250 mg twice daily as 1L ALK therapy; treatment cycles were 28 days. HRQoL was assessed with the EORTC QLQ-C30 and LC13. Change from baseline, duration of improvement and time to worsening were analyzed in the ITT-PRO population (n = 131 for both groups). Results: HRQoL compliance was > 90% for brigatinib and crizotinib. Global health status (GHS)/QoL improved starting at cycle 2, with clinically meaningful improvement (≥10-point increase) noted with brigatinib at cycles 5−8, 10−13, 17 and 19 and crizotinib at cycle 6. Brigatinib substantially improved overall HRQoL vs crizotinib, as demonstrated by the estimated mean difference on change from baseline (4.1, P< 0.05) and duration of improvement for GHS/QoL (HR = 0.16, P< 0.001). Improved GHS/QoL with brigatinib vs crizotinib was also supported by improvement in several functional domains (Table) and for these symptoms ( P< 0.05): fatigue, nausea/vomiting and appetite loss. No domains significantly favored crizotinib. Brigatinib showed a trend to prolong time to worsening of dyspnea vs crizotinib (HR 0.65, 95% CI 0.38, 1.12). Table: HRQoL results brigatinib vs crizotinib Clinical trial information: NCT02737501. Conclusions: Consistent with the prolongation of PFS seen in 1L treatment of advanced ALK+ NSCLC, brigatinib improved HRQoL and prolonged the duration of improvement in GHS/QoL, and the majority of functional and symptom domains vs crizotinib.[Table: see text]
Pembrolizumab alone or with chemotherapy for PD-L1 positive NSCLC: A network meta-analysis of randomized trials.
Authors: Doherty Mark , Delos Santos Seanthel , Rahmadian Amanda Putri , Everest Louis , Chan Kelvin K.
Published: March 2020

9087

Background: Pembrolizumab (P) has replaced chemotherapy (C) as first-line treatment for advanced non-small cell lung cancer (NSCLC) with tumor PD-L1 expression > / = 50%. Among PD-L1 unselected patients, P+C is superior to C alone. This network meta-analysis compared P alone with P+C in patients with > / = 50% PD-L1 positive NSCLC. Methods: An indirect network was constructed to compare P and P+C through the control arms of the Keynote 024, 189 and 407 (PD-L1 > / = 50% subgroup) trials. Baseline characteristics and chemotherapy outcomes were examined for heterogeneity. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and toxicities including immune-related adverse events (irAE) were extracted from trial results. Toxicity results were unavailable for the PD-L1 > / = 50% subgroups of KN 189 & 407, so overall study results were used. Survival outcomes are expressed as hazard ratios (HRs) or restricted mean survival time (RMST) ratios, and toxicity and ORR as risk difference (RD). Results: 507 patients were included: 154 on P, 430 on C and 483 on P+C. Patient characteristics across trials were similar in age, sex, performance status and smoking history. All trials had similar chemotherapy outcomes (PFS 6, 4.9, 4.8 mos) suggesting similar populations. Network meta-analysis showed no difference between P+C and C alone in OS (HR 0.85, 95%CI 0.45-1.59, p = 0.60) or PFS (HR 0.73, 95%CI 0.48-1.1, p = 0.13), but P+C was associated with higher ORR (+16.9%, 95%CI 0.7-33%, p = 0.04). RMST analysis suggested fewer early PFS events with P+C (0-6 mo RMST ratio 1.25, RMST difference 1.02 mo, p = 0.002), with the difference disappearing at 1 year (0-12 mo RMST ratio 1.16, p = 0.07). No difference in RMST for OS was found. Overall toxicities, hematologic and grade 3-5 toxicities were higher with P+C compared with P alone (table). Conclusions: Among patients with > / = 50% PD-L1 positive NSCLC, P+C did not improve OS or PFS compared with P alone, but was associated with higher ORR. RMST analysis suggested fewer early progression events using P+C. [Table: see text]
A plasma miRNA signature classifier identifies PD-L1 ≥ 50% NSCLC nonresponders to immune checkpoint inhibitors.
Authors: Proto Claudia , Prelaj Arsela , Verri Carla , Signorelli Diego , Lo Russo Giuseppe , Ferrara Roberto , Galli Giulia , Trevisan Benedetta , Mavis Mensah , De Braud Filippo G. , Garassino Marina Chiara , Sozzi Gabriella , Boeri Mattia
Published: March 2020

9096

Background: A sizable proportion of PD-L1≥50% NSCLC patients (pts) do not respond to single agent immune checkpoint inhibitors (ICI) and no biomarker is able to identify non responders. A three levels plasma microRNA signature classifier (MSC), reflecting an immunosuppressive profile of immune cell subsets, has already shown its ability to identify pts treated with ICI with a worse prognosis independently from PD-L1 expression. Aim of this trial is to prospectively test the ability of MSC to identify at diagnosis PD-L1≥50% non responders to ICI. Methods: we prospectively collected baseline plasma samples from 41 consecutive advanced EGFR/ALK/ROS1 wild-type NSCLC pts with PD-L1 TPS ≥50% treated with ICI as first (n = 28) or further line treatment to run the MSC molecular test. Pts were stratified in high (H) vs intermediate/low (I/L) risk levels. Overall response rate (ORR) and the relative risk of response (RR) were evaluated by 2x2 contingency table using Fisher exact test. Cox proportional hazard models were used to define crude and adjusted hazard ratio (HR). Results: According to RECIST 1.1 criteria, 14 (34%) pts respond to ICIs. With a global median follow-up of 9.8 months, median progression free survival (PFS) and overall survival (OS) were 7.9 months and not reached, respectively. Ten (24%) NSCLC pts were MSC H risk level. ORR was 0% in MSC H vs 45% in MSC I/L risk pts (RR = 0.10; 95%CI = 0.00-0.90; p = 0.0080). Median PFS was 11.4 months for MSC I/L pts vs 2.3 months for MSC H risk (HR = 0.26 95%CI = 0.11-0.62; p = 0.0021). Median OS was not reached for MSC I/L vs 2.7 months for MSC H risk pts (HR = 0.17 95%CI = 0.06-0.48; p = 0.0008). Data remained significant adjusting for age, sex, pack-years and ECOG performance status at the baseline: PFS HR = 0.24 (95%CI = 0.09-0.66; p = 0.0054) and OS HR = 0.15 (95%CI = 0.05-0.51; p = 0.0023). Conclusions: plasma MSC shows promising results for treatment selection with ICI. So far, MSC is the only molecular test able to identify a group of NSCLC pts with PD-L1≥50% who do not respond to single agent immunotherapy. Ongoing trials are validating these results and testing the possible predictive effect of MSC in chemotherapy plus immunotherapy combinations.
DNA damage response and repair (DDR) gene mutations and correlation with tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC).
Authors: Mamdani Hirva , Chen Jerry , Kim Seongho , Ibrahim Yahya , Asad Mohammad Fahad Bin , Nieva Jorge J. , Feldman Rebecca , Naqash Abdul Rafeh , Liu Stephen V. , Ma Patrick C. , Portnoy David Craig , Borghaei Hossein , Abdel Karim Nagla Fawzy , Boumber Yanis , Vanderwalde Ari M. , Spira Alexander I. , Jalal Shadia Ibrahim
Published: March 2020

9100

Background: Loss of DNA repair fidelity is a common feature of human cancers and can drive genomic instability and tumor evolution. DNA repair deficiency has also emerged as a predictive biomarker of response to PARP inhibition and more recently to immune checkpoint inhibition. Information on relationship between DNA repair defects and TMB in NSCLC is limited. Methods: We analyzed molecular profiles of 5667 NSCLC tumors harboring mutations in DDR genes ( ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, ERCC2/3, FANCA/C/D2/E/F/G/L, MLH1, MSH2/6, MRE11, NBN, PALB2, POLE, PTEN, RAD50/51, WRN). Profiles included next-generation sequencing of 592 genes, TMB, and PD-L1 (22c3) by immunohistochemistry. Association of DDR gene mutations with immune biomarkers (TMB and PD-L1) was assessed. Results: Of the 5667 samples, 54% (n = 3060) had high TMB (defined as ≥10 mutations/Mb) with median TMB of 14 (range, 10-168). Among the remaining 46% (n = 2607) with low TMB, median TMB was 7 (range, 1-9). PD-L1 expression was high (≥50%) in 33% (n = 1878), intermediate (1-49%) in 26% (n = 1446), and negative ( < 1%) in 41% (n = 2343). Among all DDR mutated pts, 19% (n = 1058) had both high PD-L1 and high TMB, 35% (n = 2002) had high TMB alone, 15% (n = 820) had high PD-L1 alone. Most commonly mutated genes were RAD50 (52%), WRN (29%), CHEK2 (20%), ATM (19%), MRE11 (19%), and ATR (18%). Genes with a high likelihood of being associated with high TMB were ATM, ATR, BARD1, BRCA1, BRCA2, ERCC2, ERCC3, FANCA, MSH2, PALB2, and POLE. Strongest association was seen with BRCA1 (OR 1.81, 95% CI 1.47-2.22), PALB2 (OR 1.76, 95% CI 1.40-2.21), and POLE (OR 1.71, 95% CI 1.45-2.01). DDR genes mutations were not mutually exclusive - 77.5% (n = 4397) had 2 or more mutated genes. Tumors with ≥3 mutated genes were more likely to be associated with high TMB. No such correlation was observed with PD-L1 expression. Conclusions: The majority of NSCLC pts harboring DDR gene mutations have high TMB. Presence of ≥3 gene mutations and BRCA1, PALB2, and POLE mutations strongly correlate with high TMB. These patients may represent a unique subset that is more likely to benefıt from immune checkpoint blockade and PARP inhibition.
Real-world characteristics and outcomes of patients with advanced non-small cell lung cancer (aNSCLC) receiving immune checkpoint inhibitor.
Authors: Khozin Sean , Zhi Jizu , Jun Monika , Chen Li , Rubinstein Wendy S. , Walker Mark S. , Komatsoulis George Anthony , Roberts Jeremy , Fukushima Ryan , Lau Denise , Hyde Brigham , Stepanski Edward , Miller Robert S.
Published: March 2020

9110

Background: Immune Checkpoint Inhibitors (ICIs) were first approved for the treatment of aNSCLC in 2014, and since this time have seen rapid adoption in the marketplace. We sought to describe the characteristics of patients with aNSCLC receiving ICIs in the real-world, as well as to examine treatment patterns and outcomes in the time since initial ICI approval. Methods: We conducted a retrospective, observational cohort study using statistically de-identified data from January 2011 to November 2018 in CancerLinQ, ASCO’s real-world oncology database. Adult patients with a curated diagnosis of Stage III or IV NSCLC who received ≥1 dose of an ICI and had ≥2 clinical visits were eligible for inclusion. Stage III patients were excluded if they received any local therapy < 1 year prior to receiving ICI. Patients were also excluded if they received ICI prior to the first FDA approval date. Demographic and clinical characteristics of aNSCLC patients receiving ICI are reported. Outcomes including time to treatment discontinuation (TTD), time to next treatment (TTNT), real-world progression free survival (rwPFS) and overall survival (OS) were examined via the Kaplan Meier method. Results: Among 2,425 aNSCLC ICI patients included in this analysis, median age was 68.0 years (IQR 60.7, 75.2], 54% were male and 73% of patients were white. Non-squamous histology accounted for 64% of aNSCLC ICI users, and 81% had Stage IV disease. Eastern Cooperative Oncology Group (ECOG) performance status was 0-1 in 77% and 2+ in 23% of patients, and 70% were current or former smokers. The majority (75%) of patients received ICI as second-line or later therapy. Treatment outcomes and survival are reported in the Table. Conclusions: This analysis demonstrates that aNSCLC patients receiving ICI therapy in the real-world are older than what was reported in some clinical trials, though survival outcomes were similar. Further research to examine impact of covariates on outcomes is warranted. [Table: see text]
A retrospective, real-world population-based analysis of treatment patterns and outcomes in adult patients with relapsed/refractory acute myeloid leukemia in Alberta, Canada.
Authors: Geddes Michelle N. , Saini Lalit , Liu Fei Fei , Yusuf Dimas , Schwann Kiersten , Billawala Alkarim , Kurniawan Jessica A. , Cheung Winson Y. , Brandwein Joseph M.
Published: March 2020

e18505

Background: In order to describe the impact of future targeted therapies on treatment outcomes of patients (pts) with relapsed and/or refractory (RR) acute myeloid leukemia (AML), a better understanding of the clinical management pathway in these pts is needed. We therefore evaluated the treatment patterns and associated outcomes in a real-world cohort of pts with RR-AML using a population-based cancer registry and patient medical records. Methods: Pts newly diagnosed wih AML between January 2013 and December 2016, aged ≥ 18 years were identified from the provincial-wide Alberta Cancer Registry (ACR). Data for pts who met the criteria for RR-AML were assessed by hematologists and were extracted from medical records. RR-AML pts were then categorized as: receiving intensive therapy (IT); receiving non-intensive therapy (NIT); or treated with best-supportive care (BSC) following a diagnosis of RR-AML. Results: 572 AML pts were identified from the ACR, of which 199 met criteria for RR-AML and were included in the analysis (124 males, 75 females; median age at diagnosis of RR-AML 66.8 years; median follow-up 4.7 months). In this RR-AML cohort, 26 (13%) pts received ≥ 2 lines of prior therapy. Unadjusted median overall survival (mOS) was 5.3 months, with a 12-month overall survival rate of 29.6% (95% CI 29.0–30.3%) from the time of RR. Following RR, 46 (23%) pts received IT, 65 (33%) pts were treated with NIT, and 88 (44%) pts received BSC, with unadjusted mOS of 13.8, 9.4, and 2.1 months, respectively ( P < 0.001). When stratified by European LeukemiaNet risk classification at diagnosis, unadjusted mOS was 12.4, 4.7, and 4.0 months for favorable risk, intermediate risk, and adverse risk groups, respectively ( P < 0.01). Conclusions: This retrospective, real-world study in Alberta Canada confirms the poor prognosis reported to date in the RR-AML population. Notably, a large proportion of pts received BSC which was associated with dismal survival outcomes. These data also highlight that effective and tolerable alternatives to current treatment options are urgently needed.
Safety and feasibility of outpatient high-dose cytarabine (HIDAC) and intermediate-dose cytarabine (IDAC) for consolidation therapy in acute myeloid leukemia (AML).
Authors: Li Wenhui , Simondsen Katherine , Lee Jamie , Elharake Maher , Kubal Timothy Edward
Published: March 2020

e18509

Background: Patients with acute myeloid leukemia (AML) who achieve complete remission with induction therapy require consolidation therapy. The standard of care consolidation is HIDAC or IDAC depending on age and risk stratification. Consolidation therapy has historically been administered in the inpatient setting. The rising cost of AML care has prompted institutions to consider shifting therapy to the outpatient setting. However, the safety and feasibility of outpatient HIDAC/IDAC consolidation therapy has not been established. Moffitt Cancer Center (MCC) developed an Inpatient/Outpatient (IPOP) program to facilitate administration of complicated regimens in the outpatient setting. We hypothesized that IPOP administration of HIDAC/IDAC consolidation therapy is safe and may have cost-savings implications. Methods: We conducted a retrospective chart review on AML patients who were 18 years or older and received HIDAC/IDAC consolidation therapy at MCC following induction therapy from January 1, 2015 to November 1, 2018. Data collected included age, risk stratification, treatment history, clinic visits, number of cycles received in the IPOP versus inpatient setting, supportive care, hospitalizations, and chemotherapy related adverse events. Results: 258 of 270 cycles of HIDAC/IDAC were delivered outpatient over the reviewed time period to 122 patients. 45 patients (37%) required hospitalization during consolidation with the primary reason being neutropenic fever (72%), consistent with historical data (50 to 90%). No patients receiving outpatient consolidation required hospitalization during chemotherapy. Specific details regarding administration of HIDAC/IDAC in IPOP, including infusion times, frequency of visits, laboratory frequency, supportive medications, and home antimicrobials will be reported. 1,290 hospital days were saved through IPOP administration. Financial assessment of cost-savings is being determined and will be reported. Conclusions: Outpatient administration of HIDAC/IDAC consolidation therapy for AML is a safe option for AML patients undergoing consolidation.
The prognosis of NF1 mutations in newly diagnosed AML: A single-center retrospective study.
Authors: Telfah Mohammad , Abdelhakim Haitham , Balmaceda Nicole , Gharaibeh Eyad , Godwin Andrew K. , Pessetto Ziyan Y. , McGuirk Joseph , Lin Tara L.
Published: March 2020

e18525

Background: Several recurrent genetic mutations have been described in acute myeloid leukemia (AML), which have both prognostic and therapeutic implications. Recurrent mutations in the Neurofibromin 1 ( NF1) gene are reported in 1-5 % of AML patients; however, there are limited data regarding its prognostic implications. Here, we report the outcomes for patients with newly diagnosed AML with a somatic NF1 mutation at our center. Methods: A retrospective chart review included patients with newly diagnosed AML at KUMC from 01/2016 through 09/2018. All patients had targeted next-generation sequencing (NGS) at diagnosis. Baseline characteristics were compared between patients with NF1 mutations and those who were wild-type using Fisher’s exact test for categorical variables, and the Wilcoxon rank-sum test for continuous variables. The primary outcome was overall survival (OS), which was measured from the time of diagnosis to the time of death from any cause. A stepwise Cox proportional-hazard model was used to adjust for potential confounders. Results: Data on 110 patients were included. Out of the 110 patients, 15 (13.6%) had a delectable NF1 mutation, while 95 (86.4%) patients were NF1 wild-type. The baseline characteristics of the two groups are displayed below. Median OS for patients with an NF1 mutation was 7.3 months, while it was 18.4 months for patients with NF1 wild-type, Log-rank test p-value 0.02. After adjusting for potential confounders, including age, ELN risk category, induction regimen, presence of other mutations such as TP53, the hazard of death remained significantly higher for patients with NF1 mutations, HR 2.4, CI (1.05-5.6), p-value 0.04. Conclusions: In this single-center retrospective study, the presence of a NF1 mutation was associated with worse overall survival in patients with newly diagnosis AML. [Table: see text]
Analytical validation of a 47-gene NGS panel for molecular profiling of myeloid neoplasms.
Authors: Rosenthal Sun Hee , Gerasimova Anna , Li Hai-Rong , Qu Kevin , Acab Allan J , Chong Hansook K , Zhang Xi , Nguyen Quoclinh , Smolgovsky Alla , Wolfson David , Grupe Andrew , Elzinga Christopher , Chen Rebecca , Owen Renius , Catanese Joseph J , Racke Frederick KARL , Lacbawan Felicitas L.
Published: March 2020

e18526

Background: Molecular profiling can help diagnose, classify, and guide treatment of myeloid neoplasms. Next generation sequencing (NGS) is a powerful platform that can facilitate identification of actionable genetic alterations in multiple genes simultaneously. To serve clinical management needs, we developed and validated a NGS panel for 47 genes associated with diagnostic, prognostic, and/or therapeutic utilities for each of the subclasses of myeloid neoplasms: acute myeloid leukemia (AML, 42 genes), myelodysplastic syndrome (MDS, 36 genes), and myeloproliferative neoplasms (MPN, 26 genes). Methods: A total of 154 unique de-identified specimens were analyzed. Intra- and inter-assay precision studies were performed by standard laboratory practice. Single nucleotide variations (SNVs), insertions/deletions (indels), and FLT3 partial tandem duplications (PTD) were assessed for the entire coding regions of 23 genes and targeted exons of 24 genes. Target regions were captured by hybridization with complementary biotinylated DNA baits, and NGS was performed on an Illumina NextSeq500 instrument. Sequence reads obtained were analyzed using a bioinformatics pipeline that was developed in-house. At least 500 unique reads with base quality (Q) ≥20 (99% confidence) were required for coverage QC, except targets on X chromosome for male specimens, which required 250 unique reads. Results: On average, each sample generated 13.2 million reads, 100% (SD = 0.2%) mapped reads to the reference sequence, 61.7% (SD = 8.8%) on-target reads, and 1,952 (SD = 873) mean coverage. Data using ≥Q20 unique coverage of all target regions across all validation samples demonstrated that all target regions, even in the extreme end of GC spectrum (range: 12%-87%), met coverage requirements. Intra- and inter-assay precision studies, using 7 and 21 specimens, respectively, resulted in 100% concordance among replicates. An accuracy study of 131 unique specimens (a subset of the 154 specimens) yielded in 99.6% (755/758, 95% CI: 99.4%-100%) concordance for variants with allele frequencies ≥5% in comparison to other molecular methods including Sanger sequencing. No reportable variants were detected from any normal specimens (n = 17). Conclusions: We developed and validated a NGS panel for 47 genes with diagnostic, prognostic, and/or therapeutic utilities for each of the subclasses of myeloid neoplasms: AML (42 genes), MDS (36 genes), and MPN (26 genes). This panel will allow simultaneous analysis of the 47 genes with high sensitivity and specificity and may help manage clinical needs.
Safety and efficacy of CPX-351 in younger patients < 60 years old with secondary acute myeloid leukemia: An updated analysis.
Authors: Przespolewski Amanda Cecile , Talati Chetasi , Fazal Salman , Vachhani Pankit , Sanikommu Srinivasa , Thota Swapna , Baron Jeffrey , Griffiths Elizabeth A. , Thompson James E. , Sweet Kendra Lynn , Wang Eunice S.
Published: March 2020

e18530

Background: Patients (pts) with secondary acute myeloid leukemia (s-AML) have poor long-term outcomes following standard induction chemotherapy with 7+3. In 2017 CPX-351 was FDA approved for upfront treatment of s-AML. The phase 3 trial demonstrated improved overall survival in pts aged 60-75 years old. Although CPX-351 treatment is indicated in all adults with s-AML, it is unclear whether CPX-351 is safe and effective in younger pts < 60 years. We sought to address this unanswered question by retrospective review of clinical experience since FDA approval. Methods: Medical records were retrospectively reviewed at five large academic centers to identify pts aged 18-59 years old with untreated s-AML, prior cytotoxic therapy, or AML-MRC treated with CPX-351 as induction therapy. Results: 30 pts with confirmed s-AML received CPX-351 therapy. Mean age was 53 years (range 23 – 59), 18 were male (60%). The majority (60%, N = 18) had AML-MRC, 7 (23%) had treatment-related AML (t-AML) and 6 (20%) had antecedent MDS. 6 pts had received prior HMA therapy. 19 pts had a complex karyotype (70%), and 4 patients were found to have a normal karyotype (15%). The most common molecular event was TP53 mutation observed in 10 pts (36%), followed by FLT3-ITD identified in 4 pts (14%). Overall response rate (CR/CRi/PR) was 46.7% with 5 CR (17.2%), 3 CRi (10.3%), and 6 PR (20.7%). The remaining pts (15/29, 51.7%) were non-responders. 8 pts have received an allogenic stem cell transplant. The most common AE was infection (80%, 24/30) with 4 clinically significant bleeding events. Thirty-day mortality was 13.3%, with 60-day mortality of 16.7%. Overall survival was 7 months (range 0.5 – 12.4 months), with mean follow up of 4.4 months. Conclusions: This multi-institutional retrospective analysis suggests that CPX-351 results in lower response rates (CR/CRi 27.6%) and shorter overall survival (7 mos) than reported in the recently published phase 3 trial in pts aged 60-75 years old. Potential explanations for this discrepancy include short follow up, small sample size, retrospective design, and the significant proportions of pts with complex karyotype and TP53 mutations. Historically, patients < 65 years old with s-AML have had a reported overall survival of approximately 7 months. Further investigation of this regimen in younger pts with s-AML as compared with 7+3 and other approaches is warranted.
A novel anti-CD19 chimeric T cell therapy platform ET019002 was safe and effective in inducing CR in blast crisis of CML: A case study.
Authors: He Pengcheng , Liu Hong , Liu Haibo , Li Qijing , Luo Mina , Feng Hui , Ye Kai , Nejadnik Bijan , Shi Bingyin , Liu Cheng
Published: March 2020

e18540

Background: CML can progress to blast crisis in which the disease behaves like an acute leukemia. A novel chimeric T-cell therapy ET019002 is built upon Eureka Therapeutics ARTEMIS platform and co-expressed with an additional anti-CD19 scFv fused to the CD28 protein. ET019002 demonstrated superior preclinical anti-tumor activities to the classical anti-CD19 CAR-T cells. Herein we describe the first-in-human clinical study of ET019002 in a blast crisis of CML subject with T315I mutation, breast, skin, nasal sinus, liver, CNS involvement and heavily previous lines of therapy. Methods: The subject received infusions of ET019002 T cells at the dose of 1x106 receptor+ T cells/kg on Day 0, 66 and 122. The primary objective is safety and the secondary objectives include ET019002 T-cell engraftment and anti-tumor efficacy. Results: The subject developed a transient fever and chills with a maximum temperature of 40.2°C 4 days post the 1st infusion. Fever was resolved within 3 days after giving NSAIDs. No inflammatory cytokines except IL-6 were elevated during the study. IL-6 elevated 4 days post the 1st infusion, reached peak level at 507.18 pg/ml on Day 6 and decreased to 37 pg/ml on Day 8. This was not seen after the 2nd and the 3rd infusion. Lumps from breast and skin disappeared and the enlarged liver and spleen were back to normal size. Bone marrow biopsy at day 12 showed lymphoblast cells were significantly decreased from baseline of 38% to the level of 1%. The leukemic cells in cerebrospinal fluid were cleared on Day 14. The copy number of tumor-related fusion gene BCR-ABL/ABL was reduced from 1.489 x 100 to 3.942 x 10-5. However, 2 months post the 1st infusion, BCR-ABL/ABL rebounded to 3.795 x 10-4. The 2nd infusion showed no effect on the relapse of the leukemia in molecular level. The 3rd infusion resulted in CR which relapsed 1 month post the infusion. Flow cytometry analysis showed the loss of CD19 on the leukemic cells. Conclusions: Repeated infusion of autologous ET019002 was safe and achieved a three-month CR after the ET019002 T cells therapy, which could provide a window for the patient to receive curative therapies such as bridging allogeneic hematopoietic stem cells. Clinical trial information: NCT03642496.
Molecular prediction of chronic myeloid leukemia risk and resistance to imatinib.
Authors: Jankovic Radmila , Krivokuca Ana , Boljevic Ivana , Radulovic Sinisa , Cavic Milena
Published: March 2020

e18543

Background: Chronic myeloid leukemia (CML) is characterized by the Bcr-Abl genetic translocation which leads to constitutive tyrosine kinase signaling. Treatment with tyrosine kinase inhibitors as imatinib eliminates CML cells, but resistance often occurs. No specific molecular risk factors or imatinib-resistance predictors have been validated so far, thus the aim of this study was to determine genetic factors that would allow for a better management of this disease. Methods: An age and gender matched case-control study of 57 CML patients and 63 healthy controls was performed. In vitro experiments were performed on K562 cells and an imatinib-resistant K562R cell line. CML patients were treated with imatinib and stratified into responders (complete molecular response after three months, CMR) and non-responders. RNA was isolated from blood leukocytes or cells and used for cDNA synthesis. Gene expression levels were evaluated by real-time PCR and the results analyzed using the delta-delta-Ct method. Differences in expression levels and their prognostic/predictive potentials were evaluated by t-test, linear regression analysis and receiver operating characteristics curve, with statistical significance set at p < 0.05. Results: In CML patients, the Bcl2 and IGF-1R mRNA expression level were higher than in controls (1.03 ± 0.06 vs. 0.92 ± 0.18, p < 0.0001; 1.14 ± 0.15 vs. 1.03 ± 0.15, p = 0.0001, respectively). Prior to treatment, the Bcl2 mRNA levels were lower for the K562 than for the resistant K562R cell line (1.13±0.04 vs. 1.62±0.01, p < 0.0001), and the same was observed for IGF-1R (1.22±0.01 vs. 1.29±0.01, p = 0.001). Patients who achieved a CMR after imatinib treatment had significantly lower pre-treatment levels of Bcl-2 and IGF-1R (0.99 ± 0.05 vs. 1.04 ± 0.06, p = 0.005; 1.12 ± 0.02 vs. 1.15 ± 0.04, p = 0.0123, respectively) compared to patients who did not achieve a CMR, which confirmed the in vitro observed data. Conclusions: High levels of Bcl-2 and IGF-1R mRNA were detected in CML patients, and the analysis of their expression might be used as a low-cost CML screening tool. Successful imatinib treatment was correlated with significantly lower pre-treatment Bcl-2 and IGF-1R levels in vitro and in vivo, which might also be used as a low-cost molecular predictor of a favorable clinical response .
Admissions for neutropenic fever in myelodysplastic syndromes (MDS).
Authors: Ali Ambreen Fatima , Gerds Aaron Thomas , Advani Anjali S. , Mukherjee Sudipto , Sobecks Ronald M. , Sekeres Mikkael A. , Hamilton Betty Ky , Jha Babal , Hilton Cameron Beau , Kerr Cassandra M. , Adema Vera , Waldron Madeline , Siebenaller Caitlin , Nagata Yasunobu , Maciejewski Jaroslaw P. , Nazha Aziz
Published: March 2020

e18548

Background: MDS are associated with a risk of severe infections due to disease course, patient (pt) age, co-morbidities and treatment. While infection rates have been reported for MDS patients enrolled in clinical trials, the real-world incidence of infections that require hospitalization, and how disease related factors (e.g. genetic mutations) affect the likelihood of infection remain unclear. Methods: Clinical data for MDS pts (per 2016 WHO criteria) diagnosed between 1/2010-12/2016, and treated at the Cleveland Clinic were included. TET2 mutation data obtained by NGS (in the context of genomic panel) was also included. Results: Our dataset included 214 pts of median age 70 years (range 13-99), with 33%, 54%, and 12% having low, intermediate, and high risk MDS according to IPSS-R. Overall, 100 admissions for neutropenic fever were recorded with a median length of stay of 5 days per admission; 63 (29%) pts required at least one admission, and of these 9 (14%) pts required 3 or more (up to 6) admissions. Blood cultures were positive in 17 (27%) pts with common organisms including Staphylococcus (38%), Enterococcus (35%), and Pseudomonas (12%). Urine cultures were positive in 6 (10%) pts, with organisms including E. Coli (50%), Pseudomonas (17%) and Klebsiella (17%). Fungal work up was sent in 18 (29%) pts and was positive in 3 (17%) pts. 13 (21%) pts required ICU transfer, and of those 7 (51%) pts required vasopressor support, and 10 (77%) pts required mechanical ventilation. Median ICU length of stay was 3 days (range 1-26). 13 (21%) pts were discharged on IV antibiotics. Median OS for the entire cohort was 18 months (95% CI 7.9 – 34.7), and median OS for admitted patients was not significantly shorter at 48 or 65 months. The number of admissions for neutropenic fever, length of stay, IPSS-R risk category, TET2 mutation, and ICU transfer did not impact survival. Conclusions: The risk of admission for neutropenic fever was 29% with blood cultures positive in 27% of pts. TET2 mutation status and IPSS-R risk did not impact admission rate, length of stay or ICU transfer.
Validation of the EORTC QLQ-C30 Summary Score in patients with hematological malignancies.
Authors: Cottone Francesco , Efficace Fabio , Sommer Kathrin , Caocci Giovanni , Fazi Paola , Vignetti Marco , Giesinger Johannes M.
Published: March 2020

e18551

Background: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) is a widely used questionnaire, which assesses 15 patients’ self-reported health domains, including physical and emotional functioning and key cancer symptoms. As this poses analytical challenges such as multiple testing, a single QLQ-C30 summary score (SS) was recently validated in solid tumors. In this work, we investigated its validity in patients with hematological malignancies. Methods: According to the published scoring algorithm, the SS is the mean of 13 QLQ-C30 scale scores, a higher SS rating reflecting a better health status. We performed univariate linear regression analysis to investigate the ability of the SS to discriminate between patients groups differing on known characteristics, i.e. ECOG performance status (0-1 vs. 2-3), comorbidity (yes vs. no), red blood cells transfusion dependency (TD, yes vs. no, MDS patients only), age (≤ 60 vs. > 60 years) and sex. We used linear mixed models to assess responsiveness of the SS to change, comparing baseline versus post-induction scores. For all analyses, we compared the SS performances to those of each original QLQ-C30 scale by Cohen's effect size (ES). Results: Analyses were based on pooled data from 2,134 patients diagnosed with myelodysplastic syndromes (MDS, n = 1,031), chronic myeloid leukemia (n = 382), acute myeloid (AML, n = 477) and promyelocytic leukemia (n = 244). Overall, 56.4% patients were male and the mean age was 51.5 years. Comparing groups by ECOG and comorbidity, SS outperformed 12 of the QLQ-C30 scales for ECOG (ES = 0.66) and 11 scales for comorbidity (ES = 0.17). With patients grouped by age (ES = 0.17) and sex (ES = 0.25), SS outperformed 13 and 12 scales respectively. For TD the SS (ES = 0.21) showed better discrimination than eight QLQ-C30 scales. When comparing baseline versus post-induction scores (AML patients), SS was more sensitive to change (ES = 0.41) than 10 of QLQ-C30 scales. Conclusions: Our findings provide support for the validity of the EORTC QLQ-C30 summary score as an endpoint in patients with hematological malignancies, when previous knowledge does not allow for domain-specific hypotheses.
Minimal residual disease and survival outcomes in patients with chronic lymphocytic leukemia: A systematic review and meta-analysis.
Authors: Molica Stefano , Giannarelli Diana , Montserrat Emili
Published: March 2020

e19003

Background: Chronic lymphocytic leukemia (CLL) patients with undetectable minimal residual disease (U-MRD) (i.e., < 10-4) after upfront chemotherapy (CT) or chemo-immunotherapy (CIT) have better outcomes than those with detectable MRD (D-MRD). To validate the importance of achieving U-MRD and to assess the magnitude of improvement in progression free survival (PFS) and overall survival (OS) we conducted a systematic review and meta-analysis. Methods: The screening process adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. The search strategy yielded 365 records, including 22 articles assessed for eligibility. Results: Eleven studies comprising 2457 CLL patients treated upfront with CT or CIT were considered suitable for inclusion in the quantitative meta-analysis. Four studies (n = 924) analyzed the impact of U-MRD on both PFS and OS while 8 studies (n = 1984) provided data only on PFS and 6 (n = 1074) exclusively on OS. U-MRD status was associated with significantly longer PFS overall (P < .001) and in patients who achieved complete remission (CR) according to the International Workshop on CLL (IWCLL) guidelines (P = 0.01). Tests of heterogeneity revealed significant differences across studies evaluating PFS in both patients with U-MRD (Q = 49.27; P = 0.00; I2= 80%) and D-MRD (Q = 199.15; P = 0.00; I2= 95%). OS was also longer in patients with U-MRD overall (P < .001). Test of heterogeneity revealed no significant differences across studies evaluating OS in patients with U-MRD (Q = 9.16; P = 0.06; I2= 56%). Of note, U-MRD did not predict for a longer OS in patients who achieved IWCLL CR. (P = 0.82). This contrasts with data from single series and needs prospective assessment. Conclusions: This study validates the importance of achieving U-MRD in newly diagnosed patients with CLL treated with CT or CIT and provides quantitative evidence of the improvement regarding PFS and OS. MRD status should be incorporated as endpoint into prospective clinical trials and in the evaluation of new agents for CLL therapy as already accepted by the European Medicines Agency (EMA). The clinical significance of MRD in patients treated with BCR or BCL2 inhibitors is largely unknown and warrants study.
CAP-100: First-in-class antibody for CCR7+ hematological malignancies.
Authors: Cuesta Carlos , Munoz-Callega Cecilia , Loscertales Javier , Terron Fernando , Mol Wim
Published: March 2020

e19008

Background: CCR7 is highly expressed in many hematological malignancies including CLL, several B-cell non-Hodgkin lymphomas (NHL), and various T-cell neoplasias with nodal involvement. Upon engagement by its ligands (CCL19 and CCL21), CCR7 controls trafficking of cells to locations where these chemokines are expressed, such as the lymph node (LN) and central nervous system. In these protective microenvironments CCR7 ligands contribute to tumor cell survival and proliferation. Indeed, both high CCR7 surface expression levels and high migratory responses to CCR7 ligands correlate with LN involvement, adverse prognostic factors, and shorter patient survival. Thus, strategies targeting CCR7 could provide a novel therapeutic approach for CCR7+ hematological malignancies. Methods: We have generated CAP-100, the first humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds to human CCR7 and neutralizes ligand-mediated signaling from both CCL19 and CCL21, and evaluated the antibody in various in-vitro and in-vivo preclinical models. Results: CAP-100 effectively inhibited in vitro migration of primary patient samples of CLL, B-cell NHLs and T-cell neoplasias such as T-PLL or T-ALL. Furthermore, in in vivo pre-clinical studies, CAP-100 was shown to inhibit entry of CCR7-expressing cells to LNs. CAP-100 also abrogated survival elicited by CCR7 in CLL, and showed potent cell killing activity against CLL or CCR7+ T-lymphomas cells. This Fc-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) clearly outperformed anti-CD20 or anti-CD52 standard-of-care antibodies in B-NHL and T-lymphomas respectively. In all cases, ADCC and migration inhibition were both independent of prognostic markers for high risk disease. Finally, when given as monotherapy in disseminated B-NHL and CLL xenograft tumors in SCID mice, CAP-100 exhibited tumor growth inhibition and extended survival significantly. Conclusions: Our results demonstrate that CAP-100, the first-in-class anti-CCR7 mAb, is a potent antagonist with biological activity in several CCR7+ hematological malignancies, including relapsed/refractory disease. Moreover, these results highlight the relevance of the CCR7-CCL19/CCL21 pathway as a therapeutic target in these diseases. CAP-100’s unique propensity to block migration of tumor cells to the LN, in combination with its potent cell killing activity provides the biological rationale for use of CAP-100, either as monotherapy or in combination with novel agents. Clinical trials in CLL and CCR7-expressing NHL will be initiated soon.
Long-term time trends in incidence, survival and mortality of Hodgkin lymphoma in the United States: A surveillance, epidemiology, and end results (SEER) database study 1975-2015.
Authors: Asif Samia , Raza Shahzad
Published: March 2020

e19014

Background: We examined epidemiological trends and patient characteristics such as age, gender, race, incidence and survival in Hodgkin Lymphoma (HL) using the updated largest population-based cancer registry in the US. Methods: Patients diagnosed with HL between 1975-2015 were identified in SEER registries. We incorporated SEER 9 registries to calculate incidence, race, disease characteristics and relative survival. Age-standard incidence rates (AI) were calculated using SEER 18 data and overall survival (OS) trends compared among different groups. Results: Rates for HL cases have been falling on average 1.8% per year and mortality rates (MR) have been falling on average 2.8% per year from 2006-2015. Males had higher incidence rates than females (3/100000 vs.2.3/100000). Bimodal distribution with prominent peaks at ages 20-24 and 75-79 years were noted among all groups except black (B) men. AI for women are higher at age of 20-24 years, but for men, higher at the later peak of 75-79 years. The AI for B men was highest at 50-54 years. The 10-year OS is 83.1% (Cl 82.3-83.9) in women with no significant difference between B, non-Hispanic white (NHW) or Asian Pacific Islander (API). In men, 10-year OS was 79.3% (Cl 78.4-80.1); lowest for B compared to NHW and API (72.6% vs. 80.0% vs.78.6). B patients had higher proportion of cases diagnosed with stage III/IV HL than NHW and API (48%. vs.40.6% and 39.9%, p < 0.001). Males and patients > 50 years were more frequently diagnosed with stage III/IV HL. The 10-year OS was only 40.8% for patients > 65 years (CI 38.2-43.5) in contrast to 86.8% for patients < 65 year (CI 86.3-87.4, p < 0.001). Interestingly, first year MR was 33.1% (CI 34.7-31.7) for patients > 65 years compared to 4.1% (CI 3.9-4.3) to those < 65 year. Conclusions: Epidemiological trends show improved OS in HL among all groups. B men, patients with advanced age and stage III/IV have poor outcomes. First year MR are exceptionally high in patients > 65years among all groups. Since B men have poor survival than B women, we postulate underlying disease biology may be a potential factor for worse outcome in this group.