bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.