bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-arm, phase II study of pyrotinib in advanced non-small cell lung cancer (NSCLC) patients with HER2 exon 20 mutation.
Authors: Gao Guanghui , Li Xingya , Wang Qiming , Zhang Yiping , Chen Jianhua , Shu Yongqian , Hu Yanping , Fan Yun , Fang Jian , Chen Gongyan , Zhao Jun , He Jianxing , Wu Fengying , Zou Jianjun , Zhu Xiaoyu , Zhou Caicun
Published: March 2020

9089

Background: HER2 exon 20 mutation is a well-known oncogenic driver in non-small cell lung cancer (NSCLC) and its testing is recommended by NCCN guidelines for NSCLC patients. However, up to now, there has been no approved targeted therapy for this patient population. Pyrotinib is an oral, irreversible pan-Her tyrosine kinase inhibitor (TKI) against HER1, HER2 and HER4, which, combined with chemotherapy, has recently been approved in China for HER2 positive advanced breast cancer. Methods: Stage IIIB or IV NSCLC patients with HER2 exon 20 mutation (confirmed in a central lab) and previously treated with at least one platinum-based chemotherapy were enrolled in this open-label, multi-center, single-arm phase II study. Patients with active brain metastases or prior use of HER2 TKI agents were excluded. Eligible patients received pyrotinib 400 mg once daily until disease progression, intolerable toxicity or withdrawal of consent. The primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints included safety, progression-free survival (PFS), time to disease progression (TTP), duration of response (DOR) and overall survival (OS). This trial is registered on ClinicalTrials.gov (NCT02834936). Results: Between October 20, 2016 and December 10, 2018, 60 patients (33 female, 27 male) were enrolled. The median age was 57 years (range: 40, 72). A majority were stage IV patients (95%). Over 58% of patients have been treated with two or more prior chemotherapy regimens. As of Jan 21, 2019, the ORR as evaluated by investigators was 31.7% (95% CI 20.3%, 45.0%). Median DOR was 7.0 months (95% CI 5.5, 11.0) and median PFS was 6.8 months (95% CI 4.1, 8.3). 26.7% patients reported treatment-related grade 3 AEs. Diarrhea (20.0%) was the only treatment-related grade 3 AE that occurred in ≥ 2 patients. Treatment-related grade 4 AE was reported in 1 subject (elevated gamma-glutamyl transferase). The anti-tumor activities of pyrotinib was shown in various mutation types. Conclusions: Pyrotinib as a single agent demonstrated promising anti-tumor activity and acceptable safety profile in heavily pretreated HER2 mutant NSCLC patients. Clinical trial information: NCT02834936.
Preliminary immunogenicity, safety, and efficacy of JNJ-64041757 (JNJ-757) in non-small cell lung cancer (NSCLC): Results from two phase 1 studies.
Authors: Brahmer Julie R. , Johnson Melissa Lynne , Dols Manuel Cobo , Viteri Ramirez Santiago , Coves Juan , Sukari Ammar , Awad Mark M. , Salgia Ravi , Papadimitrakopoulou Vassiliki , Rajan Arun , Allred Alicia Jones , Wade Mark , Mason Gary , Zudaire Enrique , Knoblauch Roland Elmar , Stone Nicole L. , Lorenzi Matthew V. , Hassan Raffit
Published: March 2020

9093

Background: The immunogenicity, safety, and efficacy of JNJ-757, a live attenuated, double-deleted Listeria monocytogenes-based immunotherapy expressing human mesothelin (MSLN), were evaluated in patients (pts) with advanced NSCLC (adenocarcinoma) as monotherapy (phase 1) and in combination with nivolumab (phase 1b/2). Methods: Adult pts with Stage IIIB/IV NSCLC who had received prior systemic therapy (including 1 platinum-based chemotherapy, prior PD-1/PD-L1 therapy allowed) were included. Dose-limiting toxicities, adverse events (AEs), tumor response, T cell response, and JNJ-757 bacterial shedding profile were evaluated in pts treated with JNJ-757 (108 or 109 colony forming units [CFU]) alone or JNJ-757 (109 CFU)+nivolumab 240 mg combination therapy until progression. Results: In the monotherapy trial, 18 pts (median age 63.5 years; women 61%) were treated with JNJ-757 108 or 109 CFU with a median duration of 1.4 months (range 0-29). Most common AEs were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours, suggesting transient activation of an innate immune response to JNJ-757. Treatment-related grade ≥3 AEs were infrequent (4 [22%]). Induction of peripheral proinflammatory cytokines and lymphocyte activation was observed post-treatment with transient MSLN-specific T cell responses in 10/13 evaluable pts, consistent with the mechanism of action of JNJ-757. With monotherapy, 4/18 response-evaluable pts had stable disease (SD) ≥16 weeks, including 1 pt with a 53% reduction in target lesions. In the combination therapy study, 12 pts were enrolled (median age 63.5 years; women 33%). The most common AEs were pyrexia (67%) and chills (58%); 6 pts had grade ≥3 AEs including 2 cases of treatment-related fatal pneumonitis. Best overall response for the combination was SD in 4/9 evaluable pts. JNJ-757 in combination with nivolumab suggested increased risk of pneumonitis. Conclusions: As monotherapy, JNJ-757 was tolerable with mild infusion-related fever and chills supporting the initiation of the combination therapy study. However, the risk-benefit profile of JNJ-757+nivolumab, did not support proceeding to phase 2. Clinical trial information: NCT02592967, NCT03371381.
Deep learning-based predictive biomarker for immune checkpoint inhibitor response in metastatic non-small cell lung cancer.
Authors: Park Sehhoon , Ahn Chang Ho , Jung Geunyoung , Lee Sarah , Paeng Kyunghyun , Shin Jiwon , Yoo Inwan , Jung Hyun Ae , Sun Jong-Mu , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil , Choi Yoon La , Song Sang-Yong , Lee Se-Hoon
Published: March 2020

9094

Background: In the era of immunotherapy, immune checkpoint inhibitor (ICI) has changed the treatment paradigm in metastatic non-small cell lung cancer (NSCLC). Along with clinical trials, there is an ongoing investigation to discover the predictive biomarker of ICI which so far has unsatisfactory reliability. As an effort to enhance the predictive value of ICI treatment, we applied deep learning and developed artificial intelligent (AI) score (range from 0 to 1) to analyze the specific context of immune-tumor microenvironment (TME) extracted by scanned images from H&E slides. Methods: As a ground work, deep learning-based H&E image analyzer, Lunit SCOPE, has been trained with H&E images (n = 1824) from ICI naive NSCLC samples. For the calculation of AI score, training was conducted using responder/non-responder labeled ICI treated samples from the exploratory cohort. The ICI responder was defined as the patient with a best overall response of partial or complete response and stable disease for more than 6 months. The positivity of PD-L1 immunohistochemistry (IHC) was assessed manually by pathologists. Results: The exploratory cohort is composed of NSCLC patients treated with ICI (n = 189) in Samsung Medical Center, and response to ICI was observed in 72 (38.1%) patients. Median follow-up duration was 6.8 months (6.6~8.2). Samples with PD-L1 IHC positive, defined by ≥ 1%, was observed in 138 (73.0%) patients. AI score was significant higher in the responder group (median: 0.391 vs 0.205, P = 6.14e-5), and the patients with AI score above the cut-off (0.337) showed a better response to ICI (odds ratio [OR] 3.47 P = 7.34e-5) which is higher than patients with PD-L1 ≥ 1% (OR 1.92, P = 0.069). High AI score group (n = 83) showed significantly favorable PFS compared to low AI score group (n = 106, median PFS: 5.1m vs 1.9m, hazard ratio [HR] 0.51, P = 9.6e-5) and this outcome was independent with PD-L1 status (P = 6.0e-5). In subgroup analysis, PFS of PD-L1 high / AI score high group (n = 63) had longer median PFS (6.7m) compared to both PD-L1 high / AI score low group (n = 70, 4.0m, P = 0.001) and PD-L1 low/AI score low group (n = 35, 1.9m, P = 4.0e-6). Tumor infiltrating lymphocyte (TIL) density of cancer epithelium was significantly correlated with AI score (Pearson’s r = 0.310, P = 1.43e-5), which suggests that AI score may partly reflect TME represented by TIL. Conclusions: The AI score by machine-learned information, extracted from H&E images without additional IHC stain, could predict responsiveness and PFS of ICI treatment independent of PD-L1 IHC positivity.
Phase 1 dose-expansion study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1 (ASS1)–deficient non-squamous non-small cell lung cancer.
Authors: Wimalasingham Akhila Ganeshi , Phillips Melissa Mary , Lim Louise , Rashid Sukaina , Hall Peter Edward , Khadeir Ramsay , Steele Jeremy P. C. , Conibear John , Feng Xiaoxing , Ellis Stephen , Chan Pui Ying , Thomson Jim , Johnston Amanda L. , Bomalaski John S. , Pacey Simon , Sheaff Michael , Szlosarek Peter Wojciech
Published: March 2020

9097

Background: Pegylated arginine deiminase (ADI-PEG20) targets ASS1-ve tumors, including non–small-cell lung cancer (NSCLC), by potentiating pemetrexed cytotoxicity via arginine depletion. In Beddowes et al (JCO 2017) we showed a 100% disease control rate in thoracic cancers treated with ADI-PEG20, cisplatin and pemetrexed (ADIPemCis). Thus, we tested ADIPemCis in a phase I dose-expansion cohort study of patients (pts) with non-squamous NSCLC. Methods: Good performance (ECOG 0-1) advanced non-squamous NSCLC pts were enrolled at the maximum tolerated dose (MTD) of ADIPemCis, using tumoral ASS1 loss as a selection biomarker. Pem (500mg/m2) and Cis (75mg/m2) were given every 3 weeks with weekly IM ADI-PEG20 (36mg/m2) for up to 4 cycles with maintenance ADI-PEG20 or Pem in responding pts. Primary endpoint was tumor response rate (RR by RECIST 1.1), with secondary endpoints including progression-free survival (PFS), overall survival (OS), and toxicity. We also measured plasma [arginine] and [citrulline], anti-ADI-PEG20 antibodies, and PD-L1 expression. Results: 21 of 70 screened pts (median age 60.1) were enrolled between April 15 and August 17. A confirmed partial response (PR) was observed in 55.6 % (n = 10/18 evaluable pts). Median PFS and OS were 4 months (95% CI 2.9-4.8) and 7.2 months (95% CI 5.1-18.4), respectively. 9% (n = 2/21) remain alive on subsequent therapies. 43% (n = 9/21) experienced grade 3/4 treatment-related toxicities, commonly non-febrile neutropenia. Plasma [arginine] declined rapidly and [citrulline] increased; both changes persisted at 16 weeks. 55% of pts’ tumors (n = 6/11 ) were PD-L1 < 1% by immunohistochemistry. Conclusions: The ADIPemCis regimen is active and safe in ASS1-ve NSCLC pts almost doubling the expected RR. However, the short survival compared with ASS1-agnostic historical controls indicates that ASS1 (and frequent PD-L1) loss selects for a biologically more aggressive and immunorefractory NSCLC phenotype. The iTRAP study opening Q2 of 2019 will assess the safety and tolerability of ADIPemPlatinum(Carbo) with atezolizumab in pts with ASS1-deficient non-squamous NSCLC. Clinical trial information: NCT02029690.
Early mortality in metastatic lung cancer: A SEER population data analysis.
Authors: Globus Opher , Bar Jair , Onn Amir , Uri Inbal , Lieberman Sivan , Weidenfeld Jonathan , Manu-Sitton Rakefet , Eshet Yael , Lawrence Yaacov Richard , Urban Damien
Published: March 2020

9103

Background: Millions of dollars invested in improving outcomes for metastatic lung cancer patients are essentially aimed at extending long term survival, with significant benefits being achieved over the last decade. However, little is known about lung cancer patients who die rapidly after diagnosis, potentially being deprived of these advances. We analyzed population-based data to describe real-world outcomes in metastatic lung cancer patients focusing on patients with early mortality. Methods: Using the Survival, Epidemiology and End Results (SEER) Database we analyzed adult metastatic lung cancers diagnosed between 1994-2014. This period was divided into 3 equal time periods: 1994-2000 (TP1), 2001-2007 (TP2) and 2008-2014 (TP3). Early mortality was defined as death within 2 months of diagnosis. Correlations between categorical variables were analyzed with chi squared tests and survival was analyzed using the Kaplan-Meier method. Results: Of 276,527 patients diagnosed with metastatic lung cancer, median age was 67 (range 20-105) and 154,465 (56%) were males. Thirty eight percent (103,830) of all patients died within 2 months of diagnosis. Of these early deaths, 96,344 (92.8%) were due to lung cancer. While the 2-year survival almost doubled from TP1 compared to TP3 (6% vs 11%, p < 0.001), the percentage of patients who died within 2 months only marginally improved (39.7% vs. 36.2% in TP1 vs TP3, respectively). For patients surviving at least 2 months, 2-year survival increased from 10% to 18% in TP1 vs TP3 (p < 0.001). Factors associated with early mortality include age > 65 (45% vs 31%), unmarried status (42% vs 34%), male sex (39% vs 36%), liver metastases (47% vs 32%) and large cell carcinoma vs adenocarcinoma (44% vs 36%) (all p < 0.001). Conclusions: While there has been a steady improvement in the long-term overall survival of patients with metastatic lung cancer, over one third of patients still die within 2 months of diagnosis. This has only marginally improved in the last 20 years. Research is urgently needed to identify causative and treatable factors.
Randomized phase I/II trial of pembrolizumab with and without radiotherapy for metastatic non-small cell lung cancer.
Authors: Welsh James William , Menon Hari , Tang Chad , Verma Vivek , Altan Mehmet , Hess Kenneth R. , de Groot Patricia , Nguyen Quynh , Simon George R. , Skoulidis Ferdinandos , Chang Joe Y. , Papadimitrakopoulou Vassiliki , Heymach John
Published: March 2020

9104

Background: We present findings of a randomized phase I/II trial studying PD-1 blockade with and without radiotherapy to lung lesions in patients with metastatic NSCLC. Methods: Patients with metastatic NSCLC were randomized to receive pembrolizumab with or without lung-directed radiotherapy (RT). RT referred to stereotactic body radiation therapy (SBRT, 50 Gy in 4 fractions or 70 Gy in 10 fractions) or traditional fractionation (45 Gy in 15 fractions). Pembrolizumab (200mg IV) was started on day 1 and given every 3 weeks for up to sixteen cycles. The primary endpoint was out-of-field response rate (RR), which refers to complete (CR) or partial response (PR) per irRC criteria. Results: Of 124 enrolled patients, 103 received treatment, 5 withdrew consent, 15 screen failures, and 1 was not financially cleared. Twenty-one patients completed 16 cycles of pembrolizumab; 16 patients received SBRT and 20 received traditional RT. Seven patients received salvage RT after progression on pembrolizumab alone and 15 patients received RT six months before starting the trial. In the combined-modality arm, there were 2 grade 4 toxicities and 9 grade 3 toxicities related to treatment. In the pembrolizumab arm, there were zero grade 4 toxicities and five grade 3 toxicities. At the present time, 72 patients were evaluable for response, 36 in both arms; median follow-up was 15.4 months (range: 1.4-125.2 months). RR for out-of-field lesions was 22% and 25% for the pembrolizumab + RT vs pembrolizumab respectively (p = 1.00); median PFS was 10.9 months (95% CI, 8.1-15.3 months) and 8.4 months (95% CI, 3.9-17.1 months) respectively (p = 0.83). When comparing the SBRT vs traditional fractionation sub-cohorts, non-irradiated RR was 38% and 10% respectively (p = 0.10); median PFS was 21.1 and 6.8 months respectively (p = 0.03). Within the pembrolizumab arm, comparing patients who received prior RT vs those that did not, RR was 33% and 19% respectively (p = 0.26). Conclusions: RT, while safe, did not increase the out-of-field response rate in NSCLC patients treated with pembrolizumab. Exploratory analysis suggests responses may be enhanced by SBRT, but not traditional fractionation, which warrants further investigation. Clinical trial information: NCT02444741.
Viagenpumatucel-L (HS-110) plus nivolumab in patients with advanced non-small cell lung cancer (NSCLC) after checkpoint inhibitor treatment failure.
Authors: Morgensztern Daniel , Sanborn Rachel E. , Bazhenova Lyudmila , Waqar Saiama Naheed , McDermott Lori , Hutchins Jeff , Rimm David L. , Raez Luis E. , Langer Corey J. , Cohen Roger B.
Published: March 2020

9109

Background: Viagenpumatucel-L (HS-110) is an allogeneic cellular vaccine derived from a human lung adenocarcinoma cell line transfected with the gp96-Ig fusion protein that functions as an antigen chaperone for cross presentation and dendritic cell activation. DURGA is a multi-cohort study evaluating the combination of HS-110 and anti-PD-1 monoclonal antibodies in patients with advanced NSCLC. We report on Cohort B, consisting of patients with progressive disease (PD) after receiving a minimum of 4 months of treatment (tx) with a checkpoint inhibitor (CPI) at any time prior to study entry. Methods: Patients (pts) with previously treated NSCLC received weekly HS0110 (1 X 107 cells) intradermally for 18 consecutive weeks and nivolumab IV 240 mg every 2 weeks until intolerable toxicity or PD. Tissue was tested at baseline for PD-L1 expression (≥ 1% or < 1%) and tumor infiltrating lymphocytes (TILs). TIL high was defined as > 10% CD8+ lymphocytes in the tumor stroma. The primary endpoint was objective response rate by RECIST 1.1. Results: As of the September 2018 data cut-off, 20 pts were enrolled. 18 pts (90%) had PD after both chemotherapy and CPI, and 14 (70%) had CPI as their most recent line of tx. The median number prior tx lines was 2 [range 1 to 6]. 3 pts (15%) achieved partial response and 8 pts (40%) had stable disease. Disease control rate was 55%. Progression-free survival (PFS) was 2.7 months (95% CI, 1.8 – 4.0 months) with a median follow up of 6 months. Pts experiencing injection site reactions (ISR) had improved PFS (median NR vs 2.2 months; HR 0.23, p = 0.063) compared to those without ISR. Of 3 patients with confirmed response, 2 were TIL low/PD-L1 positive, and one was TIL high/PD-L1 negative. All pts experienced at least one adverse event (AE), 80% of which were grade 1 or 2. The most common AEs were fatigue (42%), cough and dyspnea (22.6% each) and anemia (16.1%). There were no grade 5 AEs. Conclusions: The combination of HS-110 and nivolumab is well tolerated. Pts continue to be enrolled in this cohort and early data suggest that the addition of HS-110 to nivolumab may restore responsiveness after tumor progression on prior CPI therapy. Clinical trial information: NCT02439450.
Combination therapy with CpG oligodeoxynucleotide and imatinib can reverse the drug resistance when applied alone through promoting BAX activation and overcoming BCR-ABL1-independent PI3K/AKT activation.
Authors: Bai Ling , Chen Wei , Li Wei , Zhou Lei , Niu Chao , Chen Jingtao , Han Wei , Cui Jiuwei
Published: March 2020

e18502

Background: Philadelphia chromosome is an independent prognostic factor in B-cell acute lymphoblastic leukemia (B-ALL). Due to the emergence of TKIs resistance such as imatinib, new methods are yet to be explored. Toll-like receptor 9 (TLR9) agonists have been used in many cancers as immune adjuvants, due to the immune effects as well as direct effects. However, the effect of TLR9 agonists on Ph(+) B-ALLs remain unknown. Methods: Expression levels in primary B-ALL cells from 41 patients in our hospital were determined by real-time quantitative PCR and correlated to clinicopathological factors. WST-1 cell viability assay and flow cytometry were used to confirm the biological behaviors of proliferation, cell cycle arrested, apoptosis, and surface molecules expression in Ph(+) B-ALL cell line. GST pull-down, western blot, and relevant inhibitors were used to detect the mechanism of the monotherapy and combination therapy. All data were analyzed using SPSS 24.0 software. Results: Expression of TLR9 in 19 patients with Ph chromosome was higher than that in 22 patients with the normal chromosome (Median: 0.10 vs. 0.03, P= 0.047). Sup-B15, one of imatinib resistance Ph(+) B-ALL cell line, showed no proliferation suppression, no cell cycle arrested and no apoptosis after CpG 685 stimulation. However, the combination use of CpG 685 and imatinib significantly increased apoptotic cells and upregulated the expression of CD40, MHC class Ⅰ and PD-L1. By comparing the downstream signaling pathway of TLR9 in B-ALL cell lines, Sup-B15 also promoted apoptosis through P38/P53/BAX signaling pathway as other B-ALLs. After imatinib pre-treatment, the inhibition of BAX activation by BCR-ABL kinase as well as C-MYC was exposed, and the resistance of CpG 685 was reversed. In addition, CpG 685 downregulated miR-21, further upregulated PTEN, and ultimately reversed the drug resistance of imatinib which caused by BCR-ABL1-independent AKT phosphorylation in Ph(+) B-ALL. Conclusions: The combinational use of imatinib and CpG 685 to treat B-ALL cells can reverse the drug resistance when applied alone. This method can not only kill Ph(+) B-ALL directly, but also increase the immunogenicity and enhance the recognition by CD8+ T cells. Besides, due to the increasing of PD-L1, adding PD-L1 antibody with imatinib and CpG ODNs in Ph(+) B-ALL warrants more data before moving into clinical practice.
Comparison of PEG-rhG-CSF and common rhG-CSF after induction chemotherapy in patients with newly diagnosed acute myeloid leukemia.
Authors: Liu Kaiqi , Wei Hui , Wang Ying , Mi Yingchang , Wang Jianxiang
Published: March 2020

e18507

Background: To compare the PEG-rhG-CSF (brand name:jinyouli) with ordinary rhG-CSF in the myelosuppressive phase after induction chemotherapy in newly diagnosed acute myeloid leukemia (AML) patients promotes the recovery of neutrophils. At the same time, the effects of the two drugs on the incidence of infection and hospitalization were compared. Methods: A prospective randomized controlled trial was conducted in which patients with newly diagnosed AML who met the enrollment criteria were randomized into 1:1 groups: 1. PEG-rhG-CSF group: patients ≥45 kg for 6 mg/time, <45 kg for 3 mg/time, subcutaneous injection once on the 5th day after stopping chemotherapy; 2. rhG-CSF group: 5 μg/kg/day until neutrophils count ≥0.5×109/L and/or leukocytes count ≥1.0×109/L. The neutrophil recovery time (duration from day 1 of chemotherapy to neutrophils count ≥0.5×109/L and/or leukocytes count ≥1.0×109/L), infection rate and hospitalization time were collected from the two groups, and the two groups were analyzed and compared using SAS 9.4. Results: From August 2014 to December 2017, 60 patients with newly diagnosed AML were enrolled: 30 patients in the PEG-rhG-CSF group and 30 patients in the rhG-CSF group. Except for the gender composition (P=0.018), there were no significant differences in age, chemotherapy regimen, neutrophils count before chemotherapy, leukocytes count before chemotherapy, and induction efficacy between the two groups. The median time (range) of neutrophils recovery in patients with PEG-rhG-CSF and rhG-CSF was 19 (14-35) days and 19 (15-26) days, P=0.36. The number of patients (ratio) with infection during neutropenia in the PEG-rhG-CSF group and the rhG-CSF group were 27 (90.0%) and 28 (93.3%), P=1. The median length of hospitalization (range) was 20.5 (17-49) days and 21 (19-43) days, P=0.53. Conclusions: In patients with AML induction chemotherapy, there was no significant difference between the application of PEG-rhG-CSF and daily rhG-CSF in neutrophil recovery time, infection incidence and hospitalization time.
The impact of infection on health-related quality of life (HRQoL) in patients with Philadelphia negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (Ph- R/R BCP ALL) in a randomized, open-label, phase 3 study (TOWER).
Authors: Schuh Andre C. , Li Yan , Topp Max S. , Zhang Xinke , Cannell Paul , Dombret Herve , Maertens Johan , Stein Anthony Selwyn , Franklin Janet
Published: March 2020

e18511

Background: In the phase 3 TOWER study (NCT02013167), blinatumomab (BLIN) significantly improved overall survival in adults with Ph- R/R BCP ALL, and these patients (pts) also reported better HRQoL (EORTC QLQ-C30 measures) compared with standard of care (SOC) chemotherapy. This analysis assessed the impact of grade 3+ infection, which was reported in 34.1% of BLIN pts vs 52.3% of SOC pts, on HRQoL in TOWER. Methods: Pts were stratified into two groups: those with infection vs those without infection, between baseline and Day 8, Day 15, and Day 29. A difference-in-difference (DID) model investigated the impact of infection on HRQoL. A 5-point change is considered the minimum clinically important difference in the EORTC QLQ-C30 for between group comparisons (King et al. 1996). Results: In total, 342 pts (n = 247 BLIN; n = 95 SOC) had a non-missing baseline and ≥1 post-baseline HRQoL score for any scale. Grade 3+ infection was reported in 15 (4.5%) pts before Day 8, 49 (14.5%) pts before Day 15, and 76 (22.6%) pts before Day 29. Pts with grade 3+ infection reported clinical meaningful deterioration in global health status (GHS) score and in almost all functional subscales across timepoints assessed (Table). At Day 29, grade 3+ infection was associated with statistically significant and clinically meaningful deterioration in GHS and most functional scales (Table). Similar but smaller effects were also observed for symptom scales/items (data not shown). Conclusions: Grade 3+ infection in pts with Ph- R/R BCP ALL was associated with clinically meaningful deterioration in HRQoL. The lower incidence of infection in pts treated with BLIN vs SOC may have contributed to the improved HRQoL for pts treated with BLIN. Clinical trial information: NCT02013167. [Table: see text]
Venetoclax (VEN) and tyrosine kinase inhibitor (TKI) combinations in Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) and chronic myeloid leukemia myeloid blast phase (CML MBP).
Authors: Maiti Abhishek , Ravandi Farhad , Cortes Jorge E. , Jabbour Elias , Marx Kayleigh , Daver Naval Guastad , Garcia-Manero Guillermo , Konopleva Marina , Benton Christopher Brent , Masarova Lucia , Dinardo Courtney Denton , Bose Prithviraj , Naqvi Kiran , Pierce Sherry A. , Kantarjian Hagop M. , Short Nicholas James
Published: March 2020

e18515

Background: Ph+ AML and CML MBP have poor outcomes. VEN synergizes with BCR-ABL TKIs in vitro and may eradicate Ph+ leukemic stem cells. However, the clinical activity of VEN+TKI regimens is unknown. Methods: We conducted a retrospective study on patients (pts) with Ph+ AML and CML MBP who received regimens with VEN+TKI at our institution. Results: We identified 6 pts with relapsed/refractory (R/R) Ph+ AML and 7 with CML MBP (2 transformed from chronic phase, 5 R/R). 10 pts (77%) were refractory to prior therapy and 3 (23%) had relapsed disease. Pt characteristics are shown in the Table. 5 AML pts (83%) had complex cytogenetics. Pts with CML MBP had received a median of 2 prior TKIs (range 1-3). 7 pts received decitabine-based combinations and 6 pts received intensive chemotherapy in combination with VEN+TKI. TKIs included ponatinib (n=7), dasatinib (n=4), bosutinib (n=1) and nilotinib (n=1). Among 12 evaluable pts, the overall response rate (CR + CRi + MLFS) was 50% (Table). In addition, 1 pt with AML developed aplastic marrow, underwent stem cell transplantation, and is still alive. Pts with CR/CRi vs. those without CR/CRi had higher median number of Ph+ metaphases (100% vs. 32%, p<0.01) and higher baseline BCR-ABL1 PCR (100% vs. 0.5% p=0.01). The only AML pt who achieved CR/CRi had 100% Ph+ metaphases. After a median follow-up of 10.9 months (mo), 5 pts are alive (1 AML, 4 CML MBP). The median overall survival for pts with AML and CML MBP were 2 mo and not reached, respectively. The median relapse-free survival was 8.2 mo. Conclusions: VEN+TKI combinations show encouraging activity in pre-treated, advanced Ph+ leukemias, particularly CML MBP. Clonal burden of Ph+ cells correlated with response. Prospective trials are needed to evaluate VEN+TKI combinations in Ph+ leukemias. Pt characteristics and outcomes (n/N [%] / median [range]). [Table: see text]
Real-world treatment patterns in adult patients (pts) with B-cell precursor acute lymphoblastic leukemia (BCP ALL) in first hematologic complete remission (CR1) with and without minimal residual disease (MRD).
Authors: Shah Shweta , Rose Darya , Cong Ze , Tibrewala Shruti , Chawla Anita , Zaman Faraz
Published: March 2020

e18517

Background: B-cell precursor acute lymphoblastic leukemia (BCP ALL) is a rare and debilitating hematologic cancer. Among patients (pts) in complete remission (CR), minimal residual disease (MRD) is a strong prognostic factor for worse survival outcomes. Limited real-world data is available from the United States to characterize treatment patterns in BCP ALL pts. Methods: A chart review was conducted to assess treatment patterns among adult BCP ALL pts with and without MRD in first hematologic CR (CR1) across National Cancer Institute designated cancer centers, academic and community hospitals, and integrated delivery systems. The study period was the date of CR1 until 12 months post-CR1, relapse, or death. Eligible pts were ≥18 years of age with BCP ALL in CR1 between 4/2015 and 3/2017, with no other cancer diagnoses. Results: Overall, 65 (52%) of the 125 pts included in the study received drug therapy for ALL. Of the 79 total unique treatment regimens, the most frequently administered were intensification/consolidation regimens (46.8%), followed by long-term maintenance (36.7%), and preparation for hematopoietic stem cell transplantation (16.5%). Common regimens among Philadelphia chromosome-negative pts included hyper-CVAD (50%), monthly vincristine/prednisone, weekly methotrexate, and daily 6-mercaptopurine (31%), and CALGB 8811 (16.7%). The proportion of pts receiving drug therapy among community hospitals and academic settings were considerably similar (52% vs 48.3%).The majority of physicians selected hyper-CVAD as the standard of care for pts with MRD+ in CR1 (70.3%), with 48.4% of physicians selecting CALGB 8811, 32.8% selecting multiagent chemotherapy, and 29.7% selecting Linker-4, and 23.4% selecting monthly vincristine/prednisone, weekly methotrexate, daily 6-mercaptopurin. Conclusions: Nearly 50% of pts included in this study did not receive drug therapy for ALL (mean age: 47.8 years). The real-world treatment regimens among treated pts observed in this study are consistent with the NCCN guidelines although there is substantial heterogeneity in the management of BCP ALL.
Intensive minimal residual disease monitoring to drive early intervention after allogeneic hematopoietic stem cell transplant for pediatric acute leukemia.
Authors: Pincez Thomas , Santiago Raoul , Bittencourt Henrique , Louis Isabelle , Teira Pierre , Richer Johanne , Cellot Sonia , Duval Michel
Published: March 2020

e18531

Background: Relapse of acute leukemia (AL) remains the main cause of death after allogeneic stem cell transplantation (HSCT) in children. Minimal residual disease (MRD) allows to detect leukemia cells in the bone marrow at low level. The impact of post-HSCT MRD monitoring to detect early leukemia recurrence, to guide therapeutic intervention, and to prevent overt relapse is unknown. We report our experience of systematic MRD monitoring after pediatric HSCT. Methods: All patients who underwent HSCT from January 2012 to December 2017 for an AL had bone marrow MRD performed for 2 years (months 1, 2, 3, 5, 7, 9, 12, 15, 18, 21 and 24). MRD was assessed by flow-cytometry (FC) and, when a molecular alteration was present, by nested RT-PCR. Results: Seventy-one HSCT were performed for AL of myeloid (n=38), lymphoid (n=31) or mixed (n=2) lineage in 59 patients at a median (range) age of 6.5 (0.7-18.4) years. Nine cases did not engraft or had a refractory disease at month+1 evaluation. In all other cases (n=62) MRD was monitored using FC (n=58) and/or RT-PCR (n=34). Thirty-three cases had a MRD detection and/or an overt relapse (≥5% blasts). In 23/33 cases (70%), MRD was detected without simultaneous overt relapse. In the 10 others, an overt relapse occurred without prior MRD detection. Among the cases monitored with RT-PCR, only one relapse occurred without a prior MRD detection. The follow-up protocol was not respected in this particular case. On early MRD detection, 20/23 cases underwent therapeutic intervention, the most frequent being the discontinuation of immunosuppressive drugs (n=13), with subsequent undetectable MRD in 6. Other interventions included chemotherapy (n=8), donor lymphocyte infusion (n=6) and/or interferon ± interleukine 2 (n=3), leading to an undetectable MRD in 3 cases. Overall after first MRD detection, 9/23 (39%) cases never experienced a subsequent overt relapse. Conclusions: Intensified MRD monitoring detected 70% of leukemia recurrences before overt relapse. Therapeutic intervention were taken in most of the cases and 39% never experienced overt leukemia relapse. More efficient immunotherapies may improve the impact of preemptive interventions.
CMV reactivation in allogeneic hematopoietic stem cell transplant patients receiving post-transplant cyclophosphamide.
Authors: Markowski Paul , Schaar Dale G. , Wei Catherine , Tyno Anne
Published: March 2020

e18533

Background: Post transplant cyclophosphamide (PTCY) has been shown to be an effective treatment for prevention of graft versus host disease (GVHD). However, this increased immune suppression rates may increase the risk of CMV reactivation. There is limited published data addressing CMV reactivation in this patient population. Additionally there is no data on the efficacy of prophylactic letermovir in the patients who have received PTCY. In this study we analyzed the incidence of CMV reactivation in patients treated with PTCY and those not treated with PTCY, as well as the efficacy of letermovir in preventing CMV reactivation in the PTCY population. Methods: We conducted a retrospective review of MUD, MRD, and haploidentical stem cell transplant patients at our institution from 1/1/2014 until 12/10/2018. We analyzed the incidence of CMV reactivation (PCR > 137 DNA IU/ml), peak of CMV PCR titer and time to reactivation within the first 100 days post-transplant. Results: There were 150 patients with at least 60 days of follow-up that were included in this study. These patients were split into three groups: No post-transplant cyclophosphamide (NPTCY) (N = 64), received post-transplant cyclophosphamide (PTCY) (N = 70), and received PTCY and letermovir prophylaxis. (L-PTCY) (N = 15). The incidence of CMV reactivation was increased in the PTCY patients when compared to the NPTCY (44% vs 29%). In the NPTCY patients the donor (D) serostatus increased the risk of CMV reactivation (Recipient (R)+ D+ 73% vs R+D-36%) conversely in the PTCY group the donor CMV status did not influence reactivation rates (R+D+ 52% vs R+D- 81%). The CMV reactivation rate in the L-PTCY patients was lower when compared to the PTCY patients (21% vs 44%), additionally the L-PTCY patients had much lower peak CMV titers compared to PTCY group (445 vs 2112 IU/ml). Conclusions: This study demonstrates that there is an increased incidence of CMV reactivation in patients who receive PTCY. Additionally, the donor CMV serostatus does not appear to influence the incidence of CMV reactivation in patients receiving post-transplant CY. Although the number of patients in the L-PTCY group is small, it does appear to be an effective prophylactic treatment in patients receiving PTCY.
Healthcare implications of Clodtridium difficile infection after bone marrow transplant: Nationwide Readmission Database review.
Authors: Hegazi Mohamed , Elsabbagh Eman
Published: March 2020

e18538

Background: Clostridium difficile infection (CDI) is a common complication following hematopoietic stem cell transplant in adults and is associated with substantial morbidity, and mortality. Despite this association, the first 90 days readmission rates and characteristics are poorly characterized. Objective: Utilizing the Nationwide Readmission Database (HCUP-NRD); we intended to analyze rates, predictors and hospitalization cost of CDI readmission after Hematopoietic Stem Cell Transplant (HSCT) in adults. Methods: Adult patients admitted after HSCT with at least 3 months of follow-up were included for analysis using administrative claim codes for CDI in the 2014 Nationwide Readmission Database. According to HSCT type, patients were stratified to either Umbilical Cord Blood Transplant (UCBT) or Bone Marrow Transplant (BMT) (autologous and allogenic). We subsequently evaluated for CDI readmission by day 90. Results: A total of 17,412 adult patients met the inclusion criteria, including 1.3 % that received UCBT, 98.7% that received BMT. All-causes readmission rate was 32.7% (5695/17412) and CDI readmission rate was 7.9% (450/5695). The median age was 60 years, 56.2% were male, median length of stay was 8 days and the median time lapsed after transplant discharge and CDI readmission was 28 days. The most common payer was private insurance at 57.6%. The median cost per CDI admission was $62,125 with net total cost $15.3 million. Conclusions: (1) CDI 90-day readmission rate among adult patients treated with HSCT is a significant morbidity and associated with considerable cost. (2) Further studies are warranted to evaluate factors that can contribute to decreased rate of CDI readmissions following HSCT.
CML patients presenting with priapism: Is there any disparity in outcome?
Authors: Jandial Aditya , Mishra Kundan , Sandal Rajeev , Lad Deepesh , Prakash Gaurav , Khadwal Alka , Varma Neelam , Malhotra Pankaj
Published: March 2020

e18545

Background: Priapism, a urological emergency that needs prompt treatment, is an uncommon presenting feature of chronic myeloid leukemia (CML). CML frequently occurs in younger males and adolescents in developing countries. Occurrence of erectile dysfunction (ED) in this particular age group can severely decrease the quality of life. It is known that immediate treatment of priapism preserves erectile function. The data on the outcome of priapism in CML patients from developing world is limited. Methods: We analysed the CML patients treated at PGIMER Chandigarh from January 2003 to December 2018. Baseline spleen and liver size, hematological parameters, Sokal and Hasford score were documented. Duration of priapism, treatment received by the patients, and response to Imatinib were recorded. The severity of ED was assessed by SHIM (Sexual Health Inventory for Men) score. Results: Twenty-three patients (1.7%) out of total 1350 male CML-CP patients had priapism at diagnosis. The median age was 24 years (range 13 – 50 years); 60.8% patients belonged to 21 – 40 years age group. Median duration of priapism was 8 days (range 2 – 25 days). Splenomegaly and hepatomegaly were found in 91.3% and 56.5% patients, respectively. Baseline median hemoglobin was 9.9 g/dL; TLC was 283000/mm3 and platelet count was 352000/mm3. Based on Sokal score, 4/23, 16/23 and 3/23 patients belonged to low, intermediate and high risk categories, respectively. According to Hasford score, 7/23, 14/23 and 2/23 patients belonged to low, intermediate and high risk categories, respectively. All patients received cytoreductive therapy [hydroxyurea and Imatinib]; 21 patients underwent penile aspiration, 13 patients underwent therapeutic leucapheresis and 8 patients underwent distal penile shunt surgery. Majority of the patients (78.2%) achieved CHR at 6 weeks and 21 patients achieved MMR at 12 months. ED could be assessed in 14 patients on follow up. As per SHIM score, 2/14 and 12/14 patients had moderate and severe ED, respectively. The occurrence and severity of ED was unaffected by leucapheresis or shunt surgery. Conclusions: We found severe ED on follow up among majority of CML-CP patients with priapism at presentation. Despite favourable response to Imatinib, long duration of symptoms and hyperleucocytosis probably contributed to ischemic priapism and severe ED in the study cohort. We conclude that prolonged and untreated priapism in CML-CP patients is a major risk factor for ED. There is a need to sensitise the primary care physicians and surgeons in the developing world regarding this grave complication in CML patients.
LILRB4 expression in CMML and MDS based on response to hypomethylating agents.
Authors: Chien Kelly Sharon , Class Caleb A. , Montalban-Bravo Guillermo , Sasaki Koji , Naqvi Kiran , Ganan Gomez Irene , Wei Yue , Yang Hui , Kanagal-Shamanna Rashmi , Kantarjian Hagop M. , Garcia-Manero Guillermo
Published: March 2020

e18550

Background: Leukocyte immunoglobulin-like receptor B4 (LILRB4) is expressed on M4 and M5 monocytic acute myeloid leukemia (AML) cells and leads to negative regulation of immune cell activation via T cell suppression. Its expression and role in chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS) are unknown. We investigated LILRB4 expression in patients with CMML and MDS and correlated it with response to hypomethylating agent (HMA) therapy. Methods: We evaluated bone marrow samples from 19 patients with CMML and 27 patients with MDS from 2008-2014. Transcriptomic and splicing analysis by RNA sequencing were performed on CD34-positive cells in CMML and MDS patient samples in addition to AML or MDS cell lines (n = 6). Gene set enrichment analysis was used to identify pathways associated with increased LILRB4 expression. Results: By the WHO 2016 classification for CMML, there were 8 CMML-0, 5 CMML-1, and 6 CMML-2 patients, and there were 2 low-risk, 8 intermediate-1-risk, 12 intermediate-2-risk, and 5 high-risk MDS patients by IPSS. A total of 12 CMML patients and 27 MDS patients received HMA, with 6 and 12 showing response, respectively. RNA expression of LILRB4 was increased in CMML patients when compared to MDS patients and healthy controls (q < 0.1) with no difference in expression based on risk groups. Pathway analysis revealed upregulation of PD-1 signaling (p = 0.004), CTLA-4 signaling (p = 0.004), and inflammatory response (p = 0.004), and gene correlates revealed a positive association with CTLA-4 expression (p = 0.05). LILRB4 expression was slightly increased in CMML patients who responded to HMAs (q > 0.1). In cell lines, LILRB4 was expressed in MOLM13 (AML M5), SKM1 (AML M5), and U937 (histiocytic lymphoma), with an increase in HMA-sensitive MOLM13 cells compared to HMA-resistant MOLM13 cells (q < 0.01) and no difference based on HMAs seen in other cell lines. Conclusions: LILRB4 expression is increased in CMML, with further increase in those exhibiting response to HMA therapy. It is positively correlated with immune checkpoint signaling pathways, particularly CTLA-4 expression. This may set the basis for exploring the possibility of anti-LILRB4 and anti-CTLA-4 combinations.
The role of frailty and comorbidity in treatment (tx) of elderly patients with Hodgkin lymphoma (HL).
Authors: Rodday Angie Mae , Hahn Theresa , Lindenauer Peter K , Friedberg Jonathan W. , Evens Andrew M. , Parsons Susan K.
Published: March 2020

e19011

Background: While HL is highly curable in younger patients, older patients have higher rates of tx failure and death, which may reflect age-related factors, tx decisions, or disease biology. We described first-line tx in elderly patients with HL by frailty, comorbidity, and age. Methods: We analyzed Surveillance, Epidemiology and End Results (SEER)-Medicare data from 1999-2014. Patients with incident classical HL and Medicare Part A and B fee for service were included. First-line tx within 4 months of diagnosis (dx) was determined from inpatient, outpatient, and physician/supplier claims using chemotherapy J-codes, HCPCS codes, and DRG codes and was categorized as standard regimen, any other tx, and no tx. Pre-existing frailty and comorbidity ≤6 months prior to dx were separately defined using validated claims-based algorithms. Multinomial logistic regression estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI) to identify whether frailty, comorbidity, or age at dx were associated with first-line tx; their 3- and 2-way interactions were tested and removed if p < 0.1. We adjusted for race/ethnicity, Medicaid dual enrollment, population density, histology, stage, B symptoms, year (yr) of dx, and SEER registry. Results: Analyses included 2789 patients: median age was 76 yrs. 65% were frail, 79% of patients had ≥1 comorbidity, and 61% were frail and had comorbidity. 41% received a standard regimen, 32% received other tx, and 27% received no tx. No interactions were significant. Frailty, comorbidity, and older age were associated more use of other tx or no tx then standard regimens (Table). Conclusions: Frailty, comorbidity, and age were associated with first-line tx in elderly patients with HL. This may reflect physician tx decision, end-of-life care, or unique disease biology in older patients. Future research will study the relationships between first-line tx and outcomes. [Table: see text]
Activity of thymidine kinase as a prognostic marker of malignant proliferation in adolescents with lymphadenopathy.
Authors: Dmitrieva Viktoria V. , Frantsiyants Elena M. , Lysenko Irina B. , Pak Elena E. , Kozyuk Olga V. , Nikolaeva Nadezhda V. , Kapuza Elena A. , Shatokhina Olga N. , Shashkina Larisa Yu. , Kuznetsov Sergei A. , Mkrtchyan Gulnara A. , Starzhetskaya Maria V. , Bespalova Aleksandra I. , Yurchenko Darya Yu. , Popovyan Olga P. , Kutsevalova Olga Yu.
Published: March 2020

e19013

Background: Lymphadenopathy presents an important differential diagnostic problem. Thymidine kinase (TK) is an intracellular enzyme catalyzing the conversion of thymidine to thymidine monophosphate in the presence of adenosine triphosphate. TK is the product of certain genes for the progression from G1 through S phase. Determination of serum levels of the first TK isoenzyme is considered to have prognostic significance in malignant proliferation. TK increases significantly in the direct contact of malignant cells with biological fluids such as blood, lymph, or serous effusions, therefore its level changes most significantly in systemic blood diseases. Elevated serum TK has prognostic information and determines a high risk of tumor progression. The purpose of the study was to improve the accuracy of diagnosis of Hodgkin's lymphoma in adolescents, with its differentiation from lymphadenitis. Methods: The study included 34 patients: 13 – lymphadenitis, 21 – Hodgkin's lymphoma. Healthy donors served as a control group. Activity of TK1 (U/L) was determined in the blood serum by radioenzymatic method (in vitro) using a standard test system (Immunotech, BeckmanCoulter, Czech Republic). When TK1 activity was within 10.6-14.8 U/L, adenopathy of unclear etiology was considered lymphadenitis, and in 39.6-45 U/L – Hodgkin's lymphoma. Results: Activity of TK in the blood serum of patients with lymphadenitis (U/L) is shown in Table. Conclusions: Activity of thymidine kinase 1 can be measured as an objective marker for the proliferation of malignant cells, increasing the accuracy of Hodgkin's lymphoma diagnosis in adolescents.[Table: see text]