bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined modality therapy for early-stage Hodgkin lymphoma in the PET era: A real-world study.
Authors: Chohan Karan , Young Jason R. , Lester Scott , Alhaj Moustafa Muhamad , Rosenthal Allison Claire , Tun Han W. , Hoppe Bradford , Johnston Patrick B. , Micallef Ivana N. M. , Habermann Thomas Matthew , Ansell Stephen M.
Published: June 2022

e19532

Background: The traditional approach to the treatment of early-stage classical Hodgkin lymphoma (cHL) has been combined modality therapy (CMT) with both chemotherapy and radiotherapy (RT). CMT has shown improved disease control, but RT can lead to long-term adverse effects, including secondary malignancies and cardiac toxicity. Multiple clinical trials have assessed treatment de-escalation strategies to chemotherapy-alone regimens, but results are conflicting. We aimed to assess the real-world implications of these trials by comparing patient outcomes based upon treatment with CMT or chemotherapy-alone. Furthermore, we proposed to assess differences in treatment outcomes stratified by disease bulk, favorable/unfavorable disease, and PET2 response. Methods: We conducted a retrospective, multi-center cohort study of consecutive adult patients with early-stage (stage IA-IIB) cHL treated between January 2010-December 2020. Baseline characteristics, treatment modality, and outcomes were abstracted by chart review. Available PET2 scans (n=110) were independently reviewed by a blinded nuclear radiologist. Deauville score (DS) ≥4 was characterized as positive (+), and DS≤3 negative (-). All analysis was conducted using intention-to-treat principles based upon the initial treatment plan (CMT or chemotherapy-alone). Results: In 125 patients [58% male, median age 34 (range, 18-78)] with early-stage cHL, CMT was intended in 63 (50%) patients, with chemotherapy-alone in 62 (50%). Bulky disease was observed in 43 (34%), unfavorable disease in 81 (65%), and 15 (14%) were found to be PET2+. With median follow-up of 59.8 months (95%CI, 48.6 to 71.0), 5 (4%) deaths occurred, and 17 (14%) patients had relapsed/refractory disease. No significant differences in overall survival (OS) were seen based upon treatment intention. However, there was substantially reduced progression-free survival (PFS) (Table) with chemotherapy-alone in the whole cohort, and also in those with bulky, unfavorable, and PET2+ disease. No significant PFS differences were seen based upon treatment intention for patients with non-bulky, favorable, or PET2- disease. Conclusions: Based on our real-world experience, CMT appears particularly beneficial for patients with bulky disease, unfavorable prognostic factors, and PET2+ disease. However, while recent trials showed a benefit of CMT in non-bulky, favorable and PET2- patients, chemotherapy-alone may be comparable for these patients in actual clinical practice.[Table: see text]
PJP pneumonia in brentuximab vedotin recipients.
Authors: Scheckel Caleb , Abeykoon Jithma P. , Childs Daniel S , Higgins Alexandra , Hwang Steven Ray , Barreto Jason , Ansell Stephen M. , Bennani Nabila Nora
Published: June 2022

e19533

Background: Pneumocystis pneumonia (PJP) is a catastrophic infection seen in the context of low CD4 counts. Brentuximab vedotin (BV) is a drug antibody conjugate targeting CD30 and is used to treat patients with Hodgkin’s lymphoma (HL) and T-cell lymphoma (TCL). PJP prophylaxis is not currently recommended for patients receiving BV-based treatment despite co-expression of CD30 on CD4 cells. The frequency of PJP following BV remains poorly defined. Methods: We evaluated patients who received BV between January 1, 2011 and October 31, 2021 at Mayo Clinic for the development of PJP. Patient demographics and clinical characteristics including underlying disease, chemotherapy regimen, absolute lymphocyte count (ALC), and steroid exposure were collected. Patients who developed PJP more than 3 months after their last BV exposure were excluded. Results: Of 402 BV recipients identified, 63 received PJP prophylaxis and were omitted. Fourteen of the 339 (4.1%) not on prophylaxis developed PJP following BV. Those infected had a median age of 61 (22-87), 71% were male. The most common diagnoses were HL, TCL, and primary mediastinal B-cell lymphoma at rates of 57%, 21%, and 14% respectively. Therapy regimens included BV monotherapy, BV-CHP, and BV-AVD at rates of 43%, 21%, and 14% respectively. BV represented median 2nd line of therapy (1-10) and patients received median of 3 doses (1-10) prior to PJP diagnosis. Patients with PJP had median ALC of 620 (370-3500). 71.4% (10/14) had an ALC less than 750 and among those with ALC greater than 1000, 75% (3/4) had underlying diagnosis of HL. Three patients had CD4 count measured at time of PJP diagnosis with median value of 157 (5-175). 57.1% (8/14) had no steroid exposure beyond the treatment regimen. 14.3% (2/14) were on chronic doses of 5mg prednisone for autoimmune conditions. Short bursts of steroids (prednisone 40 mg) prior to PJP were seen in 21.4% (3/14) with median exposure of 8 days (7-10). One patient had prolonged steroid exposure but was weaned off 17 days prior to PJP diagnosis. 71.4% were older than 50 years at time of PJP. Conclusions: We observed rates of PJP above the commonly accepted threshold of 3.5% for recommending prophylaxis. Among patients with an ALC greater than 1000, 75% had HL raising the question of a qualitative defect in immunity. Close ALC monitoring is recommended for patients receiving BV with a low threshold to institute PJP prophylaxis, especially amongst those older than 50 or with a diagnosis of HL.[Table: see text]
Clinical applicability of targeted next-generation sequencing for precision medicine in diffuse large B-cell lymphoma.
Authors: Huang Dehong , Liu Yao , Li Jieping , Yang Tao , Liu Jun , Xiao Chunyan , Guo Bingling , Wu Jing , Liang Xiping , Zhang Wenjun , Luo Xin , Zhang Lingqian , Xiang Ying , Li Qiying , Nan Yingyu , Wang Xiaoxuan , Du Furong , Song Chao
Published: June 2022

e19538

Background: Comprehensive genomic analysis based on next-generation sequencing (NGS) allows a better molecular characterization of diffuse large B-cell lymphoma (DLBCL), offering a roadmap toward precision medicine. Methods: We analyzed somatic alterations of 37 DLBCL tissue or blood samples by a hybridization capture-based NGS panel targeting 188 lymphoma-related genes. Results: Totally, 279 single-nucleotide variants and small insertions or deletions affecting 103 genes were identified, with at least 1 mutation detected in 100% (37/37) of cases. The most frequently mutated genes were those involved in epigenetic modifiers ( DNMT3A, KMT2B and KMT2D), activated signaling ( TYK2, MYD88, NOTCH2 and BCR) and transcription factors/transcriptional regulator ( RUNX1, SPEN, IRF4, KLF2 and ASXL1). Significant co-occurrences were shown between RUNX1 mutations with NOTCH2, IRF4, ARID1A and BCR ( P< 0.05, respectively), BCR and IRF4 ( P< 0.01), etc. Additionally, we analyzed the association of genomic aberrations with clinicopathological features in DLBCL. Patients aged > 60 years harbored less LRP1B mutations than those aged ≤60 years (5.3% vs. 33.3%, P< 0.05). The mutation frequency of TP53 was significantly higher in LDH-high (> 244 U/L) group than that in LDH-low (≤244 U/L) group (40% vs. 6.25%, P< 0.05). Compared with germinal center B-cell (GCB), the mutation frequency of TYK was significantly lower in non-GCB (5% vs. 36.4%, P< 0.05). New potential therapeutic targets ( CREBBP, EP300, EZH2, SMARCB1, CD79A/B, BTK, CARD11, MYD88, THFAIP3, PIK3CA, PTEN and JAK) were identified in 55% (11/20) of newly diagnosed patients and in 41.2% (7/17) of relapsed/refractory patients. Ibrutinib, as a single agent, has demonstrated limited activity in DLBCL with mutant MYD88 and wildtype CD79. In this study, we identified 3 patients with mutant MYD88 and wildtype CD79A/B (8.1%), among whom 2 harbored MYD88 L265P variants and 1 had MYD88 S219C mutation. Conclusions: The utility of mutational profiling may facilitate the identification of potential drug targets, which in turns may represent new therapeutic possibilities.
Relma-cel (JWCAR029) in relapsed and refractory B-cell non-Hodgkin lymphoma: A two-year survival update of a phase I study.
Authors: Ying Zhitao , Song Yuqin , Zhu Jun
Published: June 2022

e19555

Background: B-cell non-Hodgkin lymphoma (B-NHL) has a very poor prognosis. Relma-cel (JWCAR029) is a CD19-targeted chimeric antigen receptor T (CAR-T) cell suspension. In a phase I trial performed in November 2017 in Beijing Cancer Hospital, China, JWCAR029 was used to treat relapsed/refractory B-NHL (R/R B-NHL) in adult patients, showing a high response rate and persistent response. This report aimed to update 2-year survival data generated in the above trial. Methods: This was an open-label, dose-escalating phase I study (JWCAR029-001, NCT03344367) involving patients with R/R B-NHL. The patients received a 3-day treatment with the conditioning chemotherapy regimen, consisting of fludarabine (25 mg/m2/day) and cyclophosphamide (250 mg/m2/day). Then, they received a single dose of intravenous JWCAR029 (25×106, 50×106, 100×106, or 150×106 CAR T cells). Two-year PFS and OS after JWCAR029 treatment were evaluated. The data were updated till the cut-off date of January 18, 2021. Results: A total of 23 patients with R/R B-NHL were enrolled, of whom 22 completed single-dose JWCAR029 cell infusion. All patients completed the 2-year follow-up, with a median time of 24.2 (95%CI 24.0-24.3) months. Based on the efficacy analysis set comprising 20 patients, the best ORR and CRR were 85.00% and 70.00%, respectively. In subgroup analysis, 1-year ORR and CRR in patients administered 100×106 cells were both 3/5 (60%); they were both 5/8 (62.5%) in those administered 150×106 cells. The 1-year and 2-year PFS rates (11 patients censored) were both 55.0%. Median PFS was not reached (95%CI 3.0 months-NA). The 1-year and 2-year PFS rates in patients administered 100×106 cells were both 60.0%; these values were both 62.5% in individuals treated with 150×106 cells. The 1-year and 2-year OS rates (3 patients censored) were both 68.6%. Median OS was not reached (95%CI 10.4 months-NA). The 1-year and 2-year OS rates in patients administered 100×106 cells were both 60.0%; these values were both 75.0% in those treated with 150×106 cells. A total of 6 patients (30%) died. No grade 3 and above CRS or NT were found. Conclusions: JWCAR029 was approved in China in September 2021 after the RELIANCE study (NCT04089215) reported its excellent efficacy and tolerable toxicity in the treatment of relapsed/refractory B-cell lymphoma. This report indicated that R/R B-NHL cases could benefit from JWCAR029. R/R B-NHL cases administered JWCAR029 at 100×106 or 150×106 cells had a promising response rate, with durable PFS and sustained OS benefits after 12 months. The effectiveness and safety of JWCAR029 need to be confirmed in the real-world setting. Clinical trial information: NCT03344367.
Efficacy and safety of orelabrutinib in diffuse large B-cell lymphoma: A real-world analysis.
Authors: Xu Peng-Peng , Liu Tingbo , Li Zengjun , Li Zheng , Huang Wei , Zhou Keshu , Cai Mingci , Shen Rong , Zhao Weili
Published: June 2022

e19556

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. Recently, based on in-depth genomic analysis, new taxonomies for DLBCL have been proposed. Genetic subtype MCD is predominantly enriched with B-cell receptor-dependent NF-κB activation and well responded to Bruton’s tyrosine kinase (BTK) inhibitors. Ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) proved the efficacy in patients with MCD DLBCL in PHOENIX study. Orelabrutinib is a novel BTK inhibitor with excellent target selectivity. This study aimed to evaluate the efficacy and safety of orelabrutinib-containing regimens for the treatment of patients with MCD DLBCL in a real-world setting. Methods: Eligible patients with pathologically confirmed MCD DLBCL, regardless previous treatment, were included from 6 centers between January and December 2021. All patients received orelabrutinib-containing regimens and underwent at least one treatment response evaluation. Patients with known CNS lymphoma and primary mediastinal lymphoma were excluded. The primary endpoint was complete response rate (CRR) assessed by investigator using PET-CT per the 2014 Lugano Response Criteria for Non-Hodgkin Lymphoma. Safety was assessed by adverse events (AEs) referring to Common Terminology Criteria for AEs version 5.0. Results: Fourteen patients (10 males) were included. The median age was 66 (range 45-77) years, and 35.71% (5/14) documented ≥2 extranodal involved sites. Most patients had an Eastern Cooperative Oncology Group score of 0-1 (9/14, 64.29%), Ann Arbor Stage III-IV disease (11/14, 78.57%), elevated lactate dehydrogenase (9/14, 64.29%), and International Prognostic Index score ≥3 (8/14, 57.14%). All patients received orelabrutinib 150 mg once daily. Among them, 8 (57.14%) were treated with R-CHOP or rituximab plus etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (R-EPOCH) as first-line therapy, and 6 (42.86%) with rituximab plus ifosfamide, carboplatin and etoposide (R-ICE), R-CHOP or rituximab with lenalidomide as second-line therapy. The CRR for the first-line and second-line therapy were 75.00% and 66.67%, respectively. The most common AEs were hematologic (platelet count decrease, white blood count decrease or lymphocyte count decrease), and non-hematologic AE was infection (urinary or respiratory). Reported AEs were generally manageable and resolved soon after supportive treatment. AEs associated with off-target activities such as atrial fibrillation, diarrhea, and major hemorrhage were not reported. Conclusions: Orelabrutinib-containing regimens demonstrated encouraging efficacy and well-tolerated safety profile among patients with MCD DLBCL. A large-scale prospective clinical study is on registration, which would offer a new potential therapeutic option for patients with MCD DLBCL.
Predicting response to naratuximab emtansine, an anti-CD37 antibody-drug conjugate (ADC), in combination with rituximab in diffuse large B-cell lymphoma (DLBCL), by analyzing the spatial arrangement of CD37 and CD20 positive cells using deep learning.
Authors: Pokorska-Bocci Anna , Micallef Sandrine , Dymkowska Mariola , Gabay Yuval , Gluskin Roman , Laniado Avi , Dicker Sagy Efrat , Bart Amit , Dicker Tomer , Rotbein Ifat , Achtenberg Albert , Zelichov Ori
Published: June 2022

e19565

Background: DLBCL is the most common type of Non-Hodgkin’s lymphoma, accounting for 30-40% of cases. Despite improvements in response and survival with standard of care treatment, up to 40% of patients have relapsed and/or refractory (R/R) disease. A phase 2 study (NCT02564744) evaluated the efficacy of naratuximab emtansine, an anti-CD37 ADC, in combination with rituximab, in 80 patients with R/R DLBCL. We performed an exploratory analysis of the study to find pathology-based biomarkers predictive of response. Deep learning (DL) models were used to extract spatial features from digitized slides stained with CD37 and CD20 and their predictive role was evaluated. Methods: A cohort of 47 DLBCL patients from the study were selected based on availability of CD20/CD37 IHC staining and were used for analysis. Patient characteristics of the analyzed cohort were similar to those of the full study cohort. Overall response rate (ORR) of the analyzed cohort was 44.7%, similar to the ORR of the full study cohort. For each patient, whole slide images (WSI) of two slides from a pre-treatment biopsy, one stained for CD20 and one for CD37, were analyzed. DL models were used to classify cells as positive or negative to the two markers and CD20/CD37 co-expression was analyzed. Over 140 spatial features were pre-defined based on drug mechanism of action and biological hypotheses, and were calculated for each patient using cell classifications. A repeated 5-fold cross-validation analysis was performed to identify features predictive of objective response. Results: Two spatial features related to the proximity of CD37 and CD20 positive cells, demonstrated a significant correlation with clinical outcome. Each feature identified patients in the cohort as having either a positive or a negative response. Feature performance was estimated using 2000 repetitions of 5-fold cross-validation. One feature classified on average 21% of patients as responders. Patients positive for this feature had an average ORR of 78% (95% CI 64%-82%), an increase of 34% in ORR relative to the original cohort (p < 0.05). The second feature classified on average 35% of patients as positive. Patients positive for this feature had an average ORR of 67% (95% CI 62%-71%), an increase of 23% in ORR relative to the original cohort (p < 0.05). Conclusions: DL analysis of the co-expression and spatial arrangement of CD37 and CD20 in pre-treatment biopsies of DLBCL patients could potentially be used as a predictive biomarker for a response to a combination treatment of anti-CD37 and anti-CD20 drugs in DLBCL, and may improve patient stratification for further clinical trials.
Real-world use of mogamulizumab among patients with mycosis fungoides and Sézary syndrome before and during COVID-19 in the United States.
Authors: Zhao Yang , Tang Jackson , Zhou Huanxue , Takahashi Takeshi , Nomura Takanobu , Dennis Eslie , Halwani Ahmad Sami
Published: June 2022

e19575

Background: Per label, mogamulizumab (Moga) is administered on days 1, 8, 15, and 22 of the first 28-day cycle (loading) and on days 1 and 15 of each subsequent cycle (maintenance) for adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) after ≥1 prior systemic therapy. During the COVID-19 pandemic, professional organizations suggested dosing intervals for systemic cancer therapies be extended to limit in-person visits. This study examined the real-world use of Moga before and during the COVID-19 pandemic in the United States. Methods: Using the Symphony Health Solutions database, adults with ≥1 diagnosis (dx) of MF or SS (ICD-10 CM: C84.0x or C84.1x) and ≥1 Moga claim during 10/1/2018-5/6/2021 were identified. Within the MF (no SS dx) and SS (any SS dx) cohorts, patients were divided into 2 subgroups based on their Moga initiation date: 10/1/2018-3/31/2020 (pre COVID-19) and 4/1/2020-5/6/2021 (COVID-19). Patient characteristics and dosing intervals between Moga doses 1-4 (loading) and between subsequent doses (maintenance) were examined. Results: Overall, 154 MF and 204 SS patients initiated Moga during the study period (mean age: 66.8 and 69.2 years; male: 64% and 55%, respectively). In the MF cohort, 98 and 56 patients were in the “pre COVID-19” and “COVID-19” subgroups. The mean dosing interval was shorter among patients in the “COVID-19” subgroup for both the loading (9.1 vs. 13.2 days) and maintenance doses (15.2 vs. 16.1 days) (Table). In the SS cohort, 121 and 83 patients were in the “pre COVID-19” and “COVID-19” subgroups. Mean loading (9.0 vs. 11.1 days) and maintenance (15.0 vs. 16.8 days) dosing intervals were shorter for patients included in the “COVID-19” subgroup. Conclusions: Among MF and SS patients, dosing intervals for Moga in loading and maintenance were not extended during the 1st year of the COVID-19 compared to pre COVID-19. There was a trend towards closer concordance with the label during COVID-19.[Table: see text]
Additional carbogen gas mixture and nicotinamide on chemotherapy in tumor hypoxic DLBCL patients.
Authors: Rizky Daniel , Pangarsa Eko Adhi
Published: June 2022

e19579

Background: Tumor hypoxia increases tumor aggressiveness, immunosuppression, & decreases sensitivity to chemoradiotherapy. The role of tumor hypoxia in DLBCL remains unclear. Hypoxia-inducible factor 1-alpha (HIF-1α) is an oxygen-dependent transcriptional factor that activates several tumor survival pathways. Hypoxia & inflammation have a positive correlation, one is defined by the HIF-1α & NFkB relationship. NFkB involves in cytokine regulations such as TNF-α & sIL-2R. Carbogen gas mixture (95% O2 and 5% CO2) & nicotinamide (an amide of vitamin B3) have been recently studied as a radiosensitizer in solid tumors & also improve tumor oxygenation level. We compared tumor size changes, TNF-α, & sIL-2R serum in DLBCL patients who received carbogen + nicotinamide during chemotherapy R-CHOP versus those who did not. Methods: This trial is an ongoing single-center, randomized controlled trial. Eligible DLBCL patients who had HIF-1α tissue expression ≥10% were included. Subjects were randomly assigned to the study group (nicotinamide 40 mg/kgBW + carbogen 10 liter/minute during R-CHOP) or control group (R-CHOP) for 1 cycle. The primary endpoint was tumor size reduction. Secondary endpoints were changes of TNF-α & sIL2R serum pre-& post-chemotherapy. Tumor MRI was used for examining the size reduction. Results: Between April-December 2021, 20 patients were enrolled (median age 56.5 years; min & max 21-65 years). For the baseline data, median tumor volume were 152.8 cm3 (4.3-1,542.5 cm3) & 172.2 cm3 (6.4-2,349.7 cm3), median sIL-2R serum were 304 U/mL (24-1,625 U/mL) & 417 U/mL (13-1,897 U/mL), median TNF-α serum were1.95 pg/mL (1.2-4.2 pg/mL) & 1.65 pg/mL (0.8-6.7 pg/mL) in control and subject group respectively, there were no statistically significant differences in these results. Post-chemotherapy, median tumor volume were 34.54 cm3 (1.86-297.5 cm3) & 112 cm3 (1.2-862.98 cm3), there were no significant differences of median Δ tumor size reduction in both groups (-118 cm3 & -85 cm3; p = 0.762) control & subject group respectively. Median sIL-2R serum in control group was increased; 519 U/mL (24-1,557 U/mL) & decreased in subject group; 157 U/mL (13-464 U/mL) although there were no statistically significance (p = 0.314 & p = 0.109 respectively). Median TNF-α serum were 2.1 pg/mL (0.8-6.9 pg/mL) & 1.8 pg/mL (0.4-3.3 pg/mL) in control & subject group respectively (p = 0.671 & p = 0.766). There was a positive correlation between Δ tumor size & Δ sIL-2R serum (p = 0.04 & r = 0.463). 2 patients complaint minor rash & itchy skin. Conclusions: We found no difference in tumor size reduction between two groups. However, we found a clinical reduction trend of serum sIL-2R in the subject group although it was not statistically significant, this is because of the incomplete sample collection. Serum sIL-2R level also had a positive correlation with tumor size reduction which showed an interesting field of study for the upcoming research. Clinical trial information: 77237304.
Safety and efficacy of Ibrutinib in Indian patients with chronic lymphocytic leukemia.
Authors: Gogia Ajay , Sharma Atul , Gupta Ritu , Rani Lata , Mallick Saumyaranjan
Published: June 2022

e19585

Background: Ibrutinib, an oral Bruton's tyrosine kinase inhibitor, is approved for the treatment of chronic lymphocytic leukemia (CLL) in both upfront and relapsed/refractory. The prevalence of CLL is very low in India compared to western countries. Hence, the real-world data regarding efficacy and safety of Ibrutinib among the Indian population is very scarce. In this study, we aim to examine the toxicity profile, treatment response, and survival outcomes among Indian patients with CLL treated with Ibrutinib. Methods: In this retrospective study, we recruited all consecutive patients diagnosed with CLL, both treatment naïve (TN) and relapsed/refractory (R/R) CLL, on Ibrutinib (daily dose of 420 mg), registered at the Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India between April 2016 and December 2021. Diagnosis of CLL, an indication of treatment, and response assessment were based on the recent guidelines (2018) from the International Workshop on CLL (iwCLL). Results: A total of 90 patients were recruited in this study, of which 33 were newly diagnosed and 57 had R/R CLL. Median age of the cohort was 60 years (range, 35–80 years) and male to female ratio was 3:1. The median total leukocyte count was 55x109/L and Del 17p was detected in 18% of cases. The R/R cases had received a median of 1(1-3) prior line of therapy. Overall response rate was observed in 76(84.4%), complete response was in 18 (20%) cases, partial response (PR) was in 49 (54.4%) cases, and in 9 (10%) cases PR with lymphocytosis (PR-L) was observed. With a median follow-up period of 15 months (4-60), 2-year progression-free survival (PFS) was 80% for the whole cohort. The median PFS was not reached in TN cases and was 18 months in R/R cases. Grade-3/4 adverse events (A/E) were seen in 17 (29.8%, n = 57) of R/R cases and in 3 (9.1%,n = 33) of TN cases. The most common Grade-3/4 A/E were infections in 19 (21.1%), (Varicella: 7, Pneumocystis: 6, Aspergilosis: 2, Mucormycosis: 1, Disseminated tuberculosis: 1, Encephalitis: 1, Others: 1) and cytopenias in 9 (10%) of cases. Other A/E were fatigue in 6 cases, arthralgia in 3, bleeding in 2, cutaneous rash in 2, reactivation of hepatitis-B in 2, diarrhea in 2, arrhythmia in 2, and autoimmune hemolytic anemia in one case. Ten patients (11.1%) had a dose reduction due to AE. The discontinuation rate was 27 (30%), due to progressive disease in 18 patients and due to adverse events in 9 patients. Twenty patients died, 14 due to disease progression or Richter's transformation, 5 due to infections, and 2 due to other reasons. Conclusions: This is the largest study of ibrutinib from India. Ibrutinib is safe and effective in upfront and R/R cases of CLL. Infections are the most common adverse event in R/R cases. Acyclovir and Co-trimoxazole prophylaxis can be considered in R/R cases of CLL in routine clinical practice . Arrhythmias were rare A/E as compared with the available literature.
Ethical challenges with CAR T slot allocation with idecabtagene vicleucel manufacturing access.
Authors: Kourelis Taxiarchis , Bansal Radhika , Patel Krina K. , Berdeja Jesus G. , Raje Noopur S. , Alsina Melissa , Cohen Adam D. , Siegel David Samuel DiCapua , Mailankody Sham , Htut Myo , Sidana Surbhi , Holstein Sarah A. , Cowan Andrew , Shah Nina , Bergsagel Peter Leif , Ailawadhi Sikander , Lin Yi
Published: June 2022

e20021

Background: CAR T cell therapies are FDA approved for patients with triple refractory multiple myeloma (MM) and >4 lines of therapy. The median survival of this is group is less than 12 months so salvage therapies need to be implemented quickly. Real-world access to CAR T remains challenging due to supply chain limitations impacting manufacturing. The goal of this study was to evaluate how centers are handling the challenges of CAR T slot allocation. Methods: MM CAR T physician leaders at each CAR T treatment center certified for idecabtagene vicleucel across the US were surveyed. Results: We received responses from 15/20 centers. Summary of CAR T volumes and outcomes of patient on waitlists are shown in the table. The median time on the waiting list was 6 months with only 25% of patients receiving CAR T eventually. For patient selection, all centers reported using a committee of experienced CART physicians to ensure consistency. Selection committee included: primary MD (n=9), CAR T MD (n=12), social workers (n=3), CAR T RN (n=10), APP (n=2), pharmacists (n=2) and ethicists (n=1). To ensure transparency, centers have clear selection criteria (n=10), priority score (n=8) and selection timeline (n=11) . To ensure accountability, centers document priority scores (n=5) and have pre-specified criteria (n=9) for selection. Centers also reported using ethical principles for selection: a) equal treatment: time spent on waiting list (n=8); b) priority to the worst-off: limited therapeutic options (n=10), MM burden (n=7), ineligible for trials (n=2); c) maximize benefit: most likely to complete apheresis (n=8) or infusion (n=8) or achieve response (n=6) and d) social value: younger pts (n=2). Maximizing benefit was considered the most important criterion by 7 centers. Conclusions: More stringent GMP manufacturing requirements with FDA approved CAR T and real-world practice with broader patient demographics can present challenges to implementation of CAR T in standard of practice. Our study is the first attempt to evaluate and highlight existing issues with MM CAR T access and the variability and challenges in patient selection. Learning from other models of resource allocation (ex: UNOS) and sharing experience across centers can help providers optimize slot allocation to improve accrual. Increasing supplies of key reagents and novel manufacturing methods(eg: non-viral vectors and allogeneic CAR) could help overcome these limitations. [Table: see text]
Cancer immunotherapy: Identifying cancer testis antigen peptides to enhance antitumor response.
Authors: Haque Syed Mahdee , Salman Abdul-Rahman , Abdeen Hamdi , Krieger Elizabeth , Manjili Masoud , Qayyum Rehan , Boikos Sosipatros Alexandros , Toor Amir A.
Published: June 2022

e20022

Background: Cancer testis antigens (CTAs) are highly immunogenic, tissue-restricted proteins that may be over expressed in hematological malignancies. In this study, an in silico analysis of CTA-derived peptide presentation on HLA class I molecules is reported with an aim to identify putative CTA peptides with a high estimated binding affinity to known HLA class I molecules. Methods: Eighty unique HLA Class I alleles (HLA-A, B, and C), across 78 hematopoietic cell transplant recipients were computationally studied for their ability to bind peptides derived from three CTAs. The amino acid sequences of all three CTA proteins were obtained from UniProtKB. NetMHCPan-4.1 was utilized for in silico prediction of HLA class I binding affinities of the 9-mer peptides generated from these CTAs. Results: The CTA MAGE-A1 had 1202 unique peptides predicted to bind at least one HLA class I allele and 176 of these peptides were classified as strong binders (Rank <0.5 and IC50<500nM). Conversely, 71 unique HLA class 1 alleles were predicted to bind strongly to at least one MAGE-A1 derived peptide. The ability of different MAGE-A1 peptides to bind HLA varied considerably, e.g., peptide TSYVKVLEY, was predicted to bind strongly to 22 different HLA class I alleles. Similarly, 41 CTAG-1B-derived and 164 MAGE-A2-derived peptides were predicted to generate strong binders with at least one HLA class 1 allele. Conversely, 37 and 71 unique HLA class I alleles were predicted to bind strongly to at least one CTAG1B peptide and one MAGE-A1 peptide, respectively. CTAG1-B derived peptide FATPMEAEL and MAGE-A2-derived peptide FAHPRKLLM were predicted to bind strongly to 17 and 22 HLA class 1 alleles, respectively. In aggregate most patients presented multiple peptides across the 6 HLA class I molecules studied (Table). The number of strongly binding MAGE-A1 and CTAG-1B peptides from unique patients. Strong binding defined by Rank <0.5 and IC50<500nM. Conclusions: Most patients presented several CTA derived peptides, suggesting that the aggregate HLA presentation across the 6 classical HLA class I molecules will yield high odds of presentation of CTA expressed by target tissues. These HLA genotype-informed quantitative analyses raise the possibility that agents such as checkpoint inhibitors and immunomodulatory drugs may synergize with hypomethylating agents and augment CTA-directed T-cell responses.[Table: see text]
Beyond BCMA: Outcomes of relapsed/refractory multiple myeloma after progression on anti-BCMA T cell redirecting therapy.
Authors: Arora Sankalp , Giri Smith , Godby Kelly Nicole , Ravi Gayathri , Costa Luciano J. , Bal Susan
Published: June 2022

e20026

Background: Immunotherapeutic strategies targeting B-cell Maturation Antigen (BCMA) have revolutionized the management of triple class refractory multiple myeloma (MM). However, the outcomes of patients (pts) who experience progressive disease (PD) after anti BCMA T-cell redirecting therapy (TRT) are unknown. Methods: We retrospectively analyzed pt and disease characteristics as well as post-BCMA outcomes for adults with relapsed/refractory MM who experienced PD after BCMA TRT at our institution. Responses were assessed by International Myeloma Working Group criteria. Survival outcomes were measured using Kaplan-Meier estimator. Results: Between 8/2018-2/2022, 63 pts received anti-BCMA TRT. With median follow up of 11.3 months (mos), 25 pts (40%) remain alive without MM progression and 7 pts (11%) died without progression. A total of 31 pts experienced PD and are the subject of this analysis. The median time from diagnosis to BCMA TRT was 36 mos with median 6 prior LoT (3-11) and 81% penta-refractory. The median time from BCMA TRT (CAR-T in 61%, bispecific T-cell engager in 39%) to post-BCMA PD was 3.19 mos. Overall response rate (ORR) to BCMA TRT for these 31 pts was 52% (≥very good partial response; VGPR 39%). Among the pts with post-BCMA PD, 45% had high risk cytogenetics (CHR), 45% extramedullary plasmacytomas (EMP), and 81% penta-refractory disease. The median overall survival (mOS) from time of post-BCMA PD is 4.3 mos (median follow up 8 mos). Eight pts with PD were not candidates for additional therapy and had mOS of 1 mo. The remaining 23 pts with PD were able to receive 1 or more additional LoT. For this group, median age was 64 years (42-77), 70% male, 52% had CHR, 22% ISS stage III. The median prior LoT was 6 (3-11) and 74% were penta-refractory. Median time from initiation of BCMA TRT to start of first post BCMA therapy was 4.3 mos (0.6-17). The most commonly used agents in next LoT are shown in the table. ORR to subsequent LoT was 35% (17% ≥VGPR). With 5 mos median follow up, 13 pts (57%) have died, median PFS and mOS to 1st post BCMA LoT is 2.2 mos and 8.1 mos. Eight pts were able to proceed with experimental therapies (88% non-BCMA TRT) with higher ORR 50% (25% ≥VGPR) resulting in longer mPFS (3.3 mos) and mOS (11 mos) with median follow up of 10.9 mos. One pt received BCMA directed CAR-T after progression on anti-BCMA T-cell engager and did not respond. Conclusions: The outcomes of pts progressing on BCMA TRT remain poor. However, failure of BCMA targeting TRT does not preclude response to T-cell engagers against non-BCMA targets. Participation in clinical trials evaluating novel mechanisms remains the best strategy for this challenging population.[Table: see text]
Clinical outcomes in immunotherapy and chemotherapy in minority populations with non-small cell lung cancer (NSCLC).
Authors: Shin Sang Ha , Gonzalez Teresita , Raez Luis E. , Samuels Shenae , Razi Syed , Hussein Atif Mahmoud
Published: June 2022

e20508

Background: Lung cancer is the leading cause of cancer deaths for Hispanics (HIS). Similarly, non-Hispanic blacks (NHB) are often disproportionately represented among cancer deaths compared to other racial/ethnic groups with lung cancer being the second most common cancer in black men and women, as well as the leading cause of cancer death. Despite these statistics, HIS and NHB remain underrepresented in non-small cell lung cancer (NSCLC) research. The aim of this study was to determine if there was a difference in outcomes between HIS, NHB and NH Whites (NHW) who had NSCLC and were treated with surgery, immunotherapy or chemotherapy. Methods: We studied 645,221 observations from the 2004-2018 National Cancer Database (NCDB), categorized as HIS, NHB or NHW, who received surgery, immunotherapy or chemotherapy for NSCLC. Categorical variables were analyzed using Pearson’s chi-square test or Fisher’s exact test. Continuous variables were analyzed using ANOVA. Survival outcomes were assessed using a Cox regression model and Kaplan-Meier curves with log-rank tests. Results: Regardless of treatment types, HIS had the highest median overall survival (OS) compared to other groups (NHW: 14.7 months; NHB: 15.0 months; HIS: 16.4 months) (P < 0.001). Regardless of the type of systematic therapy received (immunotherapy or chemotherapy), HIS had the highest median OS (P < 0.001) with HIS in the immunotherapy cohort having the highest survival advantage of all other race/ethnicity and chemotherapy groups. Multivariate Cox regression model further support the survival advantage of HIS compared to NHW (HR = 0.86; P = 0.009). OS was also assessed between patients who received surgery and/or chemotherapy. Patients who received a combination of surgery and chemotherapy had the highest OS compared to patients who underwent surgery only or received chemotherapy only. Among the cohort who received both, HIS had the highest median OS (NHW: 55.2 months; NHB: 55.5 months; HIS: 61.5 months). The surgery only cohort had the next highest median OS of all treatment groups; however, the HIS ethnicity group was non-estimable due to the small sample size. Of all three treatment groups, the chemotherapy only cohort had the lowest median OS while HIS had the highest median OS (NHW: 11.8 months; NHB: 12.9 months; H: 13.5 months) (P < 0.001). Conclusions: Results of our study suggest immunotherapy may offer an increased survival advantage for HIS and NHB compared to chemotherapy. For patients receiving chemotherapy, a combination of surgery and chemotherapy may offer a greater survival advantage for NSCLC patients. Hispanic ethnicity was associated with better survival regardless of the type of treatment received.
Integrated analysis of genomic and microenvironment characteristics associated with pathology and radiology features in patients with early multifocal lung nodules.
Authors: Jiang Ben-Yuan , Zhou Wenhao , Luo Haitao
Published: June 2022

e20519

Background: Pulmonary nodules are distinct clinical entities, and patients with different pulmonary nodules have different rates of progression to lung cancer. However, the genomic and microenvironment features of different pulmonary nodules are still unclear. Methods: 2 to 3 pulmonary nodules and matched paracancerous tissue were collected from 10 patients. Whole-exome sequencing and RNA sequencing were performed for each sample. The genomic and microenvironment characteristics were analyzed based on pathology (AIS/MIA/IA) and radiology (pGGO/mGGO/solid) features. Results: At genomic level, tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly increased with the development of the nodules. The most frequent mutation genes EGRF and KRAS were mutated exclusively. TMB and TNB in nodules with EGFR or KRAS mutation were significantly increased compared with nodules without these mutations and paracancerous. Transcriptome analysis revealed that energy metabolism signal pathways was upregulated in early stages (pGGO/AIS), while immune-related signal pathways were upregulated in latter stages (mGGO/IA). And in EGFR mutated nodules, cytokine-cytokine-receptor signal pathways were upregulated. Furter, tumor microenvironment was analyzed, and it was found that DCs, B cells and CD4+ T cells were significantly increased while endothelial and myocytes were significantly decreased with the development of the nodules. In addition, DCs were found to be significantly increased in EGFR mutated nodules when compared with KRAS mutated nodules. Conclusions: In this study, some genomic and tumor microenvironment biomarkers in different developmental stages of lung nodules were found, which may provide basis for the development of accurate diagnosis and classification of pulmonary nodules.
Assessment of antitumor effect of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in subcutaneous xenografts of A-549 tumor cell culture.
Authors: Lukbanova Ekaterina A. , Dzhenkova Elena A. , Engibaryan Marina A. , Ulianova Yulia V. , Goncharova Elena G. , Volkova Viktoriya L. , Komarova Ekaterina Fedorovna , Bauzhadze Mamuka V. , Komarova Elizaveta , Pustovaya Irina V. , Chertova Natalia A. , Gvaramiya Astanda K. , Cherkes Maria A. , Maldonado Mary L. , Shevchenko Nataliya , Mindar Maria V.
Published: June 2022

e20520

Background: The aim of the study was an assessment of antitumor effect of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone for subcutaneous xenografts of A-549 lung tumor cells in immunodeficient Balb/c Nude mice. Methods: 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone is a new compound in the series of 2-quinoline-2-yl-1,3-tropolone derivatives. The study included 50 immunodeficient Balb/c Nude mice divided into 5 groups depending on the dosage of the studied substance (0.0055; 0.055; 0.55 and 2.75 mg/g). The A-549 cells of lung cancer were used as the xenograft. Antitumor effect of tropolone was evaluated by the inhibition of tumor growth (ITG%) and the index of tumor growth (I). The experiment lasted for 36 days starting from the first administration of substances. Results: Indicators of the average tumor volume on day 36 of the experiment in experimental groups 1, 2, 3 and 4 and in the control group were 678.9; 952.3; 1746.4; 2150.8 and 2729.5 mm3, respectively. The indices of tumor growth in groups 1, 2, 3 and 4 were statistically significantly lower than in group 5 (controls) starting from days 15, 21, 21 and 24, respectively, and until the end of the experiment. Maximal differences between groups 1 and 5 were observed on days 33 and 36 – by 3.7 (p = 0.01) and 4.1 (p = 0.003) times, respectively. Antitumor effect of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone demonstrated by the study could be associated with various mechanisms. For example, its closely related compound – hinoktiol, according to numerous studies, has a cytotoxic effect associated with stopping the cell cycle, induction of apoptosis, DNA damage, and autophagic death of tumor cells. Conclusions: The study demonstrated statistically significant differences in xenograft volumes between all experimental groups and the control group. 2.75 mg/g of mouse weight was the most effective dosage of the studied compound leading to a slow decrease in tumor growth rates and a decrease in the volumes of subcutaneous xenografts.
Establishment of multiplex IHC staining panel and immune subpopulation quantificationsystem for cancer prognosis.
Authors: Ye Chih-Hung , Peng Guan - Ru , Hu Sui Yun , Yu Wei - Chieh , Theng Patrick , Yi Yap Kah , Yu Wei - Chen , Yu Shu-Han
Published: June 2022

e20525

Background: Tumor microenvironment (TME) is now an important direction for cancer prognosis research. For analyzing the immune component within TME, illustrating the distribution of the immune cells in patient tissue samples by immunohistochemistry (IHC) and image quantification analysis are now been applied in many cancer types. However, most of the TME studies only used the tumor microarray to investigate the composition of immune cells in TME, in which the views of immune component are restricted. In addition, with single biomarker staining to stratify therapy strategy shows limited efficacy in treatment since the complicated interactions of the immune components in TME. Based on these shortages, to increase the efficiency and identify the scarce immune subsets, a more systemic analysis approach for immune subpopulations quantification is now imperative. Methods: In this study, we first established an immune cell multiplex IHC staining panel (Opal Polaris, Akoya Bioscience) in non-small cell lung cancer (NSCLC) to investigate the immune components in all the tumor blocks of each patient. In this panel, we applied markers of infiltrating immune cells (CD8, CD68), regulatory markers (PD-1, PD-L1,CD163), and tumor marker (pan-cytokeratin) to explore the TME landscape in NSCLC. Then, with an in-house built quantitative software: SIMPiE, we could analyze the staining signal intensity of each cell markers generated from in Form software to define each lymphocytic immune subsets by phenotyping and quantifying. In addition, SIMPiE (Spatial Image cytometry Multiplex IHC analysis by phyton and in Form based Elements) software allowed us to generate image cytometry data to further explore the spatial context to map the organization and interactions of immune and tumor cells in the TME, and we can define thresholds for the graph to distribute the plurality of the mark points into a plurality of quadrants. Finally, we performed the survival analysis according to the clinicopathological and immune parameters of the patients, and to examine the prognostic significance of each immune subtypes. Results: We have built up an automation quantitative image analysis software to efficiently quantity the signal density and spatial context of all the immune subpopulations in all the tissue sections of each patient, and we further performed the integrative survival analysis to explore the prognostic significance of infiltrating immune cells and immunoregulatory molecules within the TME in NSCLC. Finally, in our study, we found that M1 macrophage patamars showed the most significantly regulatory effect to the patient’s overall survival rate, and M2 macrophage showed less effect compared with M1 macrophage. Conclusions: By this way, we can generate image cytometry data to further explore the spatial context to map the organization of immune and tumor cells in the TME for prognosis analysis.
High specificity lung cancer test to rule out cancer in non-malignant lung nodules found at LDCT.
Authors: Tsai Tung-Ming , Pamart Dorian , Hardat Nathalie , Herzog Marielle , Chen Jin-Shing
Published: June 2022

e20533

Background: Lung Cancer (LC) is the leading cause of cancer death worldwide and smoking is the leading risk factor. Only 15% of patients with LC are still alive 5 years after diagnosis due to advanced diseases stage at diagnosis. Low-Dose Computed Tomography (LDCT) is the widely accepted standard for screening of individuals at high risk of lung cancer. However, LDCT has several limitations including the high prevalence of non-malignant pulmonary nodules detected leading to overdiagnosis, the potential harms of cumulative radiation dose and poor adherence to recommended follow-up. Therefore, novel blood-based tests could offer a simple follow confirmation approach and this test is designed to find those patients who DO NOT have cancer. Methods: We measured levels of nucleosomes, CEA and CYFRA21-1in a cohort of 912 subjects and report data relating to 184 smoker subjects referred for CT scan at National Taiwan University Hospital. The smoker patients were later confirmed to have either a LC (n = 129, including 59 patients at early stage (stage 0-I), 15 at stage II, 47 at late stage (III and IV) and 8 with unknown stage), or non-malignant nodules (n = 41), or control with no-nodules (n = 14). Whole blood was collected in EDTA plasma tubes for analysis by six different Nu.Q chemiluminescent magnetic microparticle immunoassays (Belgian Volition, Belgium) targeting H3.1-nucleosomes or different histone modifications (H3K9Me3-, H3K27Me3-, H3K36Me3-, H3K9Ac-, H3K14Ac-nucleosomes). CEA was analyzed on the Abbott ARCHITECT analyzer. CYFRA21-1 was analyzed on the Roche Cobas E411 analyzer. We evaluated each biomarker levels individually and in a combinatorial approach by logistic regression for their performance in discriminating subject with a LC vs non-malignant nodules. Results: Among the eight individual markers evaluated, the best area under the curve (AUC) in discriminating LC vs non-malignant nodule were observed for CEA, H3K9Ac-nucleosomes and CYFRA21-1 with an AUC of 0.68, 0.69 and 0.74, respectively and a specificity at 95% sensitivity of 9.5%, 7.3% and 21.4%, respectively. A logistic regression approach defined H3K9Ac-nucleosomes, CEA and CYFRA21-1 as the best panel of biomarkers tested to improve the discrimination between LC and non-malignant nodules relatives to the markers alone, achieving a specificity of 34.1% at 95% sensitivity and an AUC of 0.80. 55 out of the 59 stage 0-I, 25/26 stage III and 20/21 stage IV LC were detected by this combination of markers while 34.1 % of the patients with benign nodules are found negative and not sent to unnecessary biopsy to ascertain the nodule status. Conclusions: Results of our proof-of-concept study indicate that a blood test combining H3K9Ac-nucleosome levels with CEA and CYFRA21-1 levels could help to rule-out patients with a non-malignant nodule offering a non-invasive tool as an aid to the decision-making process of the malignancy status of nodules detected by LDCT.