bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum B-cell maturation antigen as a prognostic marker for untreated chronic lymphocytic leukemia.
Authors: Soof Camilia M , Parikh Sameer Ashok , Slager Susan L. , Rabe Kari G. , Ghermezi Matthew , Spektor Tanya M. , Kay Neil E. , Berenson James R. 
Published: March 2020

7525 Background: New prognostic markers in chronic lymphocytic leukemia (CLL) are in demand. Different groups have developed models which combine multiple prognostic markers into a single index to classify CLL patients (pts). The CLL-International Prognostic Index (CLL-IPI) combines five parameters: age, clinical stage, TP53 status, IGHV mutational status, and serum β2 microglobulin levels. B-cell maturation antigen (BCMA) is a cell membrane receptor expressed exclusively on late stage B-cells and plasma cells with elevated serum (s) levels found in B-cell malignancies, such as multiple myeloma (MM). In MM, sBCMA levels can be used to monitor disease status and predict overall survival (OS). To further evaluate this biomarker in other hematologic malignancies, we studied it in CLL. Methods: Untreated (UNTX) CLL pts seen and consented at Mayo Clinic were identified. sBCMA levels were measured on stored sera of 331 UNTX CLL pts using an ELISA-based assay with a polyclonal anti-BCMA antibody from R&D Systems (Minneapolis, MN). The Mann-Whitney analysis was used to assess differences between CLL pts and healthy controls. The relationships between sBCMA and both time to first treatment (TFT) and OS were also assessed using Cox Regression models with an optimal sBCMA cutoff of 40.9 ng/mL. Results: The median age of pts was 61 years, and 71% were male. The distribution of CLL-IPI risk groups was as follows: 135 (41%) Low; 114 (34%) Intermediate; 67 (20%) High; 15 (5%) Very High. The median level of sBCMA in CLL pts (48.6 ng/mL) was higher (P <0.0001) than those of healthy controls (n = 104; 36.03 ng/mL). In CLL pts, sBCMA is significant in univariable analyses of TFT (HR 2.9 (95%CI, 2.0-4.2); P < 0.0001) and OS (HR 2.5 (95%CI, 1.5-4.0); P < 0.0003), and remains significant when adjusting for sex and CLL-IPI factors (HR 2.3 (95%CI, 1.6-3.3), P < 0.0001; HR 1.9 (95%CI 1.1-3.1), P = 0.01, respectively). Conclusions: sBCMA is elevated in CLL pts compared to healthy controls. After adjusting for CLL-IPI and sex, sBCMA levels provided independent prognostic value in predicting TFT and OS in this cohort. Measuring sBCMA with a readily accessible ELISA-based test, provides incremental value over the current CLL-IPI model in predicting prognosis of CLL.
Phase 2 study of acalabrutinib in ibrutinib (IBR)-intolerant patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
Authors: Rogers Kerry Anne , Thompson Philip A. , Allan John Nathan , Coleman Morton , Sharman Jeff Porter , Cheson Bruce D. , Izumi Raquel , Frigault Melanie M. , Quah Cheng Seok , Raman Rakesh K. , Wang Min Hui , Kipps Thomas J. 
Published: March 2020

7530 Background: In CLL pts treated with the Bruton tyrosine kinase (BTK) inhibitor IBR, the most common reason for discontinuation was adverse events (AEs; 50%-63%; Mato et al, 2018). This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in IBR-intolerant pts with R/R CLL. Methods: Pts with R/R CLL (≥1 prior therapy) who discontinued IBR due to Gr 3/4 AEs or persistent/recurrent Gr 2 AEs and had progressive disease (PD) after IBR discontinuation were eligible. Acalabrutinib was given at 100 mg BID PO in 28-d cycles until PD or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: 60 pts were treated (median age 70 y [range 43-88]). Pt characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%) and unmutated IGHV (79%). 52/55 (95%) pts with available baseline samples were wild type for BTK and PLCG2. Median number of prior therapies was 2 (range 1-10). Median duration of prior IBR therapy was 6 mo (range <1-55); common AEs that led to IBR discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%) and rash (12%). At a median follow-up of 19 mo (range 1-31), 67% of pts remain on acalabrutinib; discontinuations were mostly due to PD (13%) and AEs (10%; pneumonia [n=2], diarrhea, headache, ascites, arthralgia, subdural hematoma [all n=1]). Efficacy outcomes are in the Table. Common AEs (any grade) were diarrhea (48%), headache (40%), contusion (35%) and dizziness (32%). Serious AEs (≥2 pts) were pneumonia (10%), anemia (3%) and syncope (3%). Atrial fibrillation occurred in 3 pts (5%; all Gr 1/2) and major hemorrhage in 2 (3%; Gr 3 hematuria and Gr 2 subdural hematoma). Gr 5 AEs were pneumonia (n=2), bronchopulmonary aspergillosis (n=1) and ventricular fibrillation (n=1), all considered not related to treatment. Conclusions: Acalabrutinib is tolerable and effective in IBR-intolerant pts, providing a viable strategy for continuing BTK inhibitor therapy. Clinical trial information: NCT02717611. [Table: see text]
Assessing the potential of immunotherapy in treating chronic lymphocytic leukemia through meta-analysis.
Authors: Aljabban Jihad , Allen David , McDermott Sean , Wanner Ross , Salhi Hussam , Syed Saad A , Chen David , Hadley Dexter , Khoulani Dania 
Published: March 2020

7531 Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and has a heterogenous presentation. CLL is known to shape the immune response to survive. Studying these processes will help gauge the potential success of immunotherapy and point to therapeutic targets. Methods: We used our Search, Tag, Analyze, Resource platform to meta-analyze patient samples from Gene Expression Omnibus. We tagged peripheral B cells from 741 CLL patients and peripheral B cell samples from 150 healthy donors as a control. We also tagged and compared B cell samples from 84 CLL progressors to 91 patients with stable CLL. Lastly, we tagged peripheral T cells from 70 CLL patients and T cells from 35 healthy donors as a control. We then analyzed the signature in Ingenuity Pathway Analysis. Results: Analysis of CLL cell samples identified T cell exhaustion signaling as our top canonical pathway. IL2, IL5, and TGFB1 were top upstream regulators. We found upregulation of PDL1, CTLA4, and Lag3, known markers for immunosuppressive B cells. FMOD, which sequesters TGFB, was also upregulated along with molecules that modulate BCR signaling such as MIR155HG. EBF1, required for B cell differentiation, and the co-stimulatory molecule CD80 were downregulated. Analysis of progressing CLL versus stable CLL highlighted metabolic changes. S-adenosyl-L-methionine biosynthesis, methionine degradation to homocysteine, cysteine biosynthesis, and acetate conversion to acetyl-CoA were top canonical pathways. No difference was seen in PDL1, CTLA4, and Lag3 expression but EBF1 was upregulated. Lastly, our T cell analysis demonstrated NFAT in regulation of the immune response as the top canonical pathway. Conclusions: Our results reinforce the promise immunotherapy can have in treatment of CLL and suggests more aggressive cases of CLL are a function of metabolic changes as opposed to differences in immune escape. We also suggest a role of NFAT in T cell exhaustion in the context of CLL.
PET/CT alone versus PET/CT and MRI-guided therapy in patients with upper aerodigestive tract natural killer/T-cell lymphoma, nasal type: A prospective study.
Authors: Lin Tongyu , Ren Quanguang , Huang He , Li Xue Ying , Hong Huangming , Wang Zhao , Fang Xiaojie , Guo Cheng-cheng , Li Fangfang , Zhang Limei , Huang Ying , Li Zhi-Ming , Cai Qingqing , Tian Ying , Wang Hanyu , Lin Xiaoping , Fan Wei , Zheng Lie , Lin Suxia , Liu Qing 
Published: March 2020

7537 Background: Radiotherapy is extremely important in extranodal natural killer/T-cell lymphoma (ENKTL). [18F]-Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a routine pretreatment imaging technique used in ENKTL, while magnetic resonance imaging (MRI) plays a key role in head and neck (HN) cancer. The purpose of this study was to investigate the value of pretreatment HN-MRI and PET/CT-guided therapy in improving survival in upper aerodigestive tract ENKTL (UADT-ENKTL). Methods: We prospectively conducted a single center study on untreated patients with pathologically diagnosed UADT-ENKTL. Patients undergoing PET/CT with/without HN-MRI were decided by clinicians for staging and restaging. The patients were treated with L-asparaginase/Pegaspargase and non-anthracycline-based chemotherapy with intensity-modulated radiation therapy (IMRT). Results: We enrolled 171 patients (median age, 44 years; range, 18-75 years; 118 (69%) males) from April 2011 to March 2018. Overall, 71 patients underwent PET/CT and HN-MRI (PET/CT-MRI) and 100 patients underwent PET/CT alone. HN-MRI upgraded the clinical stages in 8 patients (8/71) undergoing PET/CT based on the Ann Arbor staging system and in 10 patients (10/71) based on the TNM staging system by detecting additional local lesions ( P=0.011 and P=0.019, respectively). With a median follow-up of 54 months, the 5-year overall survival (OS), local recurrence-free survival (LRFS) and progression-free survival (PFS) rates were 72.7%, 68.6% and 68.2%, respectively, for all patients. The 5-year LRFS rate was 100% in the PET/CT-MRI group and 64.3% in the PET/CT group ( P<0.001). Similarly, the 5-year OS and PFS were longer in the PET/CT-MRI group than in the PET/CT group (84.5% vs. 67.8% and 78.3% vs. 65.6%; P=0.04 and P=0.03, respectively). Conclusions: HN-MRI and PET/CT-guided therapy could assist in decreasing local recurrence, which improved prognosis in UADT-ENKTL patients. Therefore, HN-MRI and PET/CT should be incorporated into routine pretreatment imaging examinations in patients with UADT-ENKTL. Clinical trial information: NCT01788137.
Ibrutinib maintenance following induction for untreated mantle cell lymphoma (MCL): Initial safety report.
Authors: Karmali Reem , Abramson Jeremy S. , Stephens Deborah Marie , Barnes Jeffrey A. , Kaplan Jason B. , Winter Jane N. , Ma Shuo , Petrich Adam Matthew , Hochberg Ephraim P. , Takvorian Tak , Nelson Valerie , Gordon Leo I. , Pro Barbara 
Published: March 2020

7542 Background: Maintenance rituximab in MCL has improved survival, though the optimal approach is not yet defined. Ibrutinib, a selective BTK inhibitor, has profound activity in R/R MCL. Ibrutinib maintenance (I-M) following induction for treatment-naive MCL has not been explored. We report preliminary results of a multicenter phase II trial assessing efficacy and safety of I-M for MCL after frontline induction. Methods: Patients with MCL with CR/PR to frontline chemo-immunotherapy (+/- autoSCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3 year PFS rate. Secondary objectives were PR to CR conversions, median OS at 4 years and toxicity with MRD assessments planned. Results: Accrual is complete with 36 patients, median age of 60 (range 46-90), 28 males, 28 with advanced stage and 9 with extranodal disease. 18 (50%), 7 (19%) and 11 (31%) had low vs intermediate vs high risk MIPI respectively. 8/24 patients had a Ki-67 > / = 30%. For induction, 17 (47%) received BR, 18 (50%) a cytarabine-based regimen, 1 (3%) R-CHOP. 18 (50%) had autoSCT in CR1 prior to enrollment. 33 (92%) and 3 (8%) had CR and PR with induction respectively with 1 PR to CR conversion on I-M. At median follow-up of 19 mos, 24/36 (67%) patients remain on I-M (median 15 cycles, range 1-49) with 1 PD and 1 death. TRAEs led to dose reductions/interruptions in 25 (69%) patients, including permanent dose reductions in 7 (19%) and treatment discontinuation in 9 (25%; Table). 3 additional patients discontinued I-M, 1 for endometrial adenocarcinoma, 1 PD, 1 death, cause unknown. Conclusions: Ibrutinib maintenance is feasible in MCL patients who respond to frontline chemo-immunotherapy +/- autoSCT with manageable toxicities consistent with prior reports of ibrutinib. Additional follow-up and MRD status correlations with PFS and OS will provide insight on clinical relevance for this approach. Clinical trial information: NCT02242097. [Table: see text]
Changes in circulating tumor DNA levels are associated with treatment response and progression-free survival in relapse/refractory DLBCL subjects.
Authors: Lovejoy Alexander F. , Lin Hai , Tabari Ehsan , Saelee Seng Lor , Kurtz David Matthew , Vitazka Patrik , Morschhauser Franck , Chu Yu-Waye , Szafer-Glusman Edith , Venstrom Jeffrey Michael , Luong Khai , Klass Daniel M. 
Published: March 2020

7546 Background: Detection of an initial molecular response to therapy in DLBCL could help differentiate patients who will relapse (30-40% of frontline subjects) from those who will not. Recent studies in DLBCL showed ability to detect residual disease and molecular response to therapy from analysis of circulating tumor DNA (ctDNA). Here we performed targeted next generation sequencing (NGS) of baseline ctDNA vs. tumor tissue, and on-treatment ctDNA samples in 32 relapse/refractory DLBCL subjects from the ROMULUS study to assess correlation of outcome with molecular response. Methods: We sequenced plasma, plasma depleted whole blood (PDWB), and tumor DNA from 32 subjects (range 2-6 samples / subject). Library preparation and NGS were performed using hybrid capture-based workflows, with a panel of ~300 kb targeting regions relevant for disease detection in DLBCL. Variants were called from tissue and plasma data, and PDWB data were used to filter out non-tumor specific variants. Results: 83% of variants detected in tissue (1441/1745) were found in the corresponding plasma samples, and 78% of variants detected in plasma (1441/1846) were found in corresponding tissue samples, in line with previous reports. To follow ctDNA changes with treatment, tumor-specific variants were determined from tissue or cycle 1 day 1 (C1D1) plasma samples. These variants were then monitored in C1D1 and later timepoints, with similar ctDNA levels based on variants determined from C1D1 plasma or tissue (R2=0.99). Change in ctDNA levels from C1D1 to C2D1 separated subjects that responded from subjects that progressed (Wilcoxon p-value: 9.39×10-4). Subjects that showed a 10-fold or higher drop in ctDNA levels between C1D1 and C2D1 had significantly longer PFS than those with a smaller ctDNA fold change (HR: 8.06; p=0.0008). Conclusions: This study showed that tumor-specific variants can be identified in baseline plasma with similar performance as from tumor tissue, and that monitoring molecular response as an early change in ctDNA levels after one cycle of treatment correlated with outcomes in this DLBCL study. Clinical trial information: NCT01691898.
Allogeneic stem cell transplantation (AlloSCT) for patients (pts) with lymphoma and chronic lymphocytic leukemia (CLL) following targeted small molecules inhibitors (SMIs).
Authors: Mukherjee Akash , Milton Denai R. , Jabbour Elias , Gulbis Alison , Kadia Tapan M. , Thompson Philip A. , Keating Michael J. , Jain Nitin , Ledesma Celina , Fayad Luis , Nastoupil Loretta J. , Burger Jan Andreas , Ferrajoli Alessandra , Estrov Zeev , Kantarjian Hagop M. , Champlin Richard E. , Khouri Issa F. 
Published: March 2020

7550 Background: SMIs have improved outcomes in lymphoma/CLL. There is paucity of information about the safety and efficacy of alloSCT following SMIs. Methods: Data from 49 pts who received alloSCT between 2013-2018 at MDA and who have been previously treated with SMIs were retrospectively analyzed. Results: Histologies included CLL (n=31, 63%), mantle cell lymphoma (MCL) (n= 13, 27%), and follicular lymphoma (n= 5, 10%). Prior SMIs included ibrutinib [(n=46; 94%); 57% as ≥ 3rd line of therapy], venetoclax [(n=19, 39%); 68% as ≥ 3rd line of therapy], idelalisib (n=6, 12%). Ibrutinib was discontinued prior alloSCT in 31(67%) pts. due to refractoriness (n=25), or intolerance (n=6). Seven of 19 (37%) pts had venetoclax discontinued to due refractoriness (n=6) or intolerance (n=1). Risk factors for CLL pts at alloSCT included a prior Richter’s (n=14, 45%), unmutated IGHV (15/23, 65%), presence of del17p (n=23; 74%), and complex cytogenetics (n=15; 48%). In addition, 18/20 (90%) CLL pts had abnormal mutations: most frequent were TP53 (n=14; 78%), BTK (n=6; 33%), SF3B1 (n=4; 22%) and 8/18 (44%) pts had > 2 mutations. Risk factors for MCL pts included: Ki67≥ 30 % (n=10/12, 83%), blastoid histology (n=6, 46%). Median age was 51 years, and 9 (18%) pts had a HCT-CI >4. Median prior lines of therapies was 4. Median duration of SMI therapy was 4.6 months. At transplant 40 (82%) pts had sensitive and 9 (18%) had refractory disease. Conditioning was nonmyeloablative (BFR or FCR) in 62%, RIC in 20% and myeloablative in 18%. Most pts (61%) received matched unrelated or matched sibling donors (22%); 8 (16%) had an alternative donor. The median follow-up for survivors was 12.4 months (range, 1-41.6). OS and PFS at 1 year were 77% and 68%, respectively. The CI of acute grade 2-4 and 3-4 GVHD were 33% and 7%, respectively. CI of 1-year chronic GVHD was 19%. Disease refractoriness and acute 3-4 GVHD were predicators for inferior OS and PFS by MV analysis. Similar survival results were observed in pts with or without mutations. Fourteen pts died due to progression (n=9), infection (n=2), acute (n=2) or chronic GVHD (n=1). Conclusions: AlloSCT is an effective therapy in pts with lymphoma/CLL pretreated with SMI. Our results suggest that alloSCT can overcome high-risk mutations associated with exposure to SMIs. Prospective confirmation in a larger # of pts is needed.
Monitoring ctDNA in r/r DLBCL patients following the CAR T-cell therapy axicabtagene ciloleucel: Day 28 landmark analysis.
Authors: Frank Matthew Joshua , Hossain Nasheed M. , Bukhari Ali Abbas , Dean Erin , Spiegel Jay Y. , Claire Gursharan K. , Kirsch Ilan , Jacob Allison , Mullins Chelsea D. , Lee Lik Wee , Kong Katherine A. , Craig Juliana K. , Mackall Crystal , Rapoport Aaron , Dahiya Saurabh , Locke Frederick Lundry , Miklos David Bernard 
Published: March 2020

7552 Background: Axicabtagene Ciloleucel (Axi-cel) is an autologous anti-CD19 CAR T-cell therapy approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Long‐term analysis of the Zuma‐1 clinical trial showed ~40% of patients remained progression-free at 2 years (Locke, Lancet Oncology 2018). Early identification of patients who will later progress after CAR T cell therapy may improve clinical care and patient outcomes. Methods: As of 2/1/2019, we enrolled 50 patients on a multi-institutional, prospective study measuring circulating tumor DNA(ctDNA) minimal residual disease (MRD) in r/r DLBCL patients undergoing treatment with Axi-cel. Using an next generation sequencing-MRD assay (Adaptive Biotechnologies; Seattle WA), ctDNA levels were measured pre, 0, 7, 14, 21, 28, 56, 90, 180, 270, and 365 days following Axi-cel infusion. A pre-planned comparison between EDTA, Streck, and CFD tubes for the initial 10 enrolled patients determined the CFD tube provided optimal analyte stability over 144 hours following sample collection. CFD tubes are being used to collect all study samples. Results: 24 subjects have 3 or more months clinical follow up and their treatment ctDNA MRD significantly associated with clinical outcomes. A day 28 landmark analysis shows 12 patients were MRD negative and 12 patients were MRD positive as defined by detection of none or any tumor-associated ctDNA, respectively. 10 of 12 MRD+ patients subsequently developed progressive disease. In contrast, only 2 MRD- patients subsequently progressed and the 10 other patients remain in a CR. (p = 0.0033, Fisher's exact test). With a median follow up of 237 days, median PFS after Axi-cel infusion for day 28 MRD+ vs. MRD- patients is 93 days vs. not reach, p = 0.0010 by Log-rank test. Median OS for day 28 MRD+ vs. MRD- patients is 281 days after Axi-cel infusion vs. not reach, p = 0.0399 by Log-rank test. Conclusions: After Axi-cel infusion, day 28 ctDNA-based MRD significantly associates with PFS and OS and identified early at-risk patients prior to progression. These results provide a rationale for designing MRD-based risk-adaptive CAR T-cell clinical trials.
Long-term follow-up of patients (pts) with relapsed or refractory (r/r) follicular lymphoma (FL) treated with copanlisib.
Authors: Leppä Sirpa , Santoro Armando , Demeter Judit , Follows George , Lenz Georg , Kim Won Seog , Mollica Luigina , Nagler Arnon , Diong Colin Phipps , Provencio Mariano , Stevens Don A. , Trevarthen David R. , Wang MingLu , Wirtz Oliver , Miriyala Ashok , Garcia Vargas Jose , Childs Barrett H. , Zinzani Pier Luigi , Dreyling Martin H. 
Published: March 2020

7553 Background: The pan-class I phosphatidylinositol 3-kinase inhibitor copanlisib was approved by the FDA in September 2017 for treatment of relapsed FL based on results from the CHRONOS-1 study in pts with indolent non-Hodgkin lymphoma. We report efficacy and safety results of a 2-year (yr) follow-up of FL pts. Methods: Pts with indolent FL (grade [G] 1-3a) r/r to ≥2 prior lines of treatment received copanlisib (60 mg i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was objective tumor response rate (ORR) per independent radiologic review (Cheson et al. 2007). Adverse events were reported using MedDRA (v20.1). Data cut-off: February 20, 2018. Results: 104 FL pts were enrolled. Median age was 62 yr (39% >65 yr), the median number of prior lines of anti-cancer therapy was 3 (range 2-8), and 27 pts (26%) were classified as having G3a disease. The ORR was 59%, with complete responses (CR) in 20% ( n=21); 14 pts had a CR at the primary analysis in June 2016. The median duration of response (mDoR) was 12.2 months (mo) (range 0.03-43 mo). Stable disease (SD) was observed in 33% of pts; median duration of SD was 7.8 mo (range 1.3-23 mo). Median progression-free survival (mPFS) was 11.2 mo (range 0.03-44 mo) with 33% alive and progression-free at 2 yrs. Median overall survival (mOS) was 3.2 yr (range 0.06-4.2 yr) with 67% alive at 2 yrs. Median duration of treatment was 26 weeks (wk) (range 1-192 wk); median duration of safety follow-up was 29 wk. In the G3a subset, the ORR was 67% (26% CR), mDoR was 10.9 mo, mPFS was 12.5 mo, and mOS was 2.5 yr. The most common treatment-emergent adverse events occurring in >25% of pts included (all grade/G3+): diarrhea (37%/9%), neutropenia (26%/23%), and pyrexia (28%/5%). Hyperglycemia (49%/40%) and hypertension (29%/23%) were transient. Incidences of pneumonitis (6.7%/1.9%) and colitis (1.0% G4) were low. Conclusions: Long-term follow-up of r/r FL pts treated with copanlisib revealed robust and durable responses with CRs exceeding 20%, including in pts with higher grade disease. The safety profile continues to be both manageable and favorable, with no evidence of late-onset severe toxicities. Clinical trial information: NCT01660451.