bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes of stem cell transplant in patients with Richter transformation.
Authors: Wang Yucai , Tschautscher Marcella , Rabe Kari G. , Parikh Sameer Ashok , Call Timothy , Muchtar Eli , Kay Neil E. , Leis Jose Francisco , Koehler Amber , Johnston Patrick B. , Inwards David James , Porrata Luis F. , Hogan William J. , Kenderian Saad , Ding Wei 
Published: March 2020

7526 Background: Stem cell transplant (SCT) was considered to be beneficial in CLL patients with Richter transformation (RT). We report a single center experience of SCT for RT. Methods: CLL patients with biopsy-confirmed RT to DLBCL who underwent SCT were identified from Mayo Clinic CLL database, and clinical information was abstracted by chart review. Survival analysis was done with the Kaplan-Meier method. Results: Twenty-four of 204 RT patients underwent SCT, 20 autologous and 4 allogeneic. The median lines of prior CLL therapy was 1 (range 0-4). Only 4 patients were exposed to ibrutinib prior to RT. The median age at RT diagnosis was 62 (range 41-73). Five of 17 (29%) patients had bulky disease (≥ 5 cm), 12 of 20 (60%) had elevated LDH, and 6 of 15 (40%) had TP53 disruption (del(17p) or TP53 mutation). The median lines of RT therapy prior to SCT was 2 (range 1-4); treatments included R-CHOP-like alone (n = 7), platinum-based alone (n = 1), both R-CHOP-like and platinum-based (n = 11), novel agents (n = 2), and high dose MTX-based (n = 3). Response prior to SCT was CR in 12 (50%) and PR in 12 (50%) patients. The median time from RT diagnosis to SCT was 6.8 months (range 3.3-42.3). After a median follow-up of 52.7 months after SCT, there were 10 RT relapses, 4 CLL progression, and 11 deaths (7 RT, 1 CLL and 3 unrelated). The median progression-free survival (PFS) was 28.5 months (95% CI 8.3-NA; 1-year PFS 61.8%, 2-year PFS 50.5%). The median post-SCT survival was 56.3 months (95% CI 30.6-76.6; 2-year survival 82.0%, 4-year survival 65.6%). Elevated LDH was associated with worse PFS (median 8.9 months vs NA, P= 0.014) and a trend of worse post-SCT survival (53.7 vs 67.4 months, P= 0.153). Other factors including age, prior CLL treatment (untreated vs treated), bulky disease, response prior to SCT, and TP53 disruption were not associated with PFS or post-SCT survival. Among the 4 allogeneic SCT patients, 1 had RT relapse 10.5 months after SCT and was treated with venetoclax, ibrutinib and obinutuzumab and remained alive at last follow-up (12.9 months after SCT). All 3 other patients remained in remission and alive at last follow up (15.6, 16.1 and 108.5 months after SCT, respectively). Conclusions: SCT may benefit select RT patients. The role of SCT in the novel agent era needs further study.
Occurrence of other cancers in patients with chronic lymphocytic leukemia and mutations in protection of telomeres 1 (POT1) gene.
Authors: Molica Matteo , Dinardo Courtney Denton , Patel Keyur P. , Keating Michael J. , Wierda William G. , Thompson Philip A. , Jain Nitin , Takahashi Koichi , Kanagal-Shamanna Rashmi , Routbort Mark , Tang Guilin , Tang Zhenya , Ferrajoli Alessandra 
Published: March 2020

7529 Background: Mutations in POT1 gene in CLL lead to uncapping of the telomeric ends, causing fusion events and chromosomal aberrations. POT1 is mutated in approximately 4% of pts with CLL. Recent studies reported germline variants in POT1 in pts with familial CLL and in familial melanoma, cardiac angiosarcoma and glioma. We evaluated pts characteristics and the presence of other cancers (OC) in pts with CLL with POT1 mutation seen at our institution. Methods: We performed next generation sequencing (NGS)-based analysis for the detection of mutations in 29 genes frequently mutated in pts with CLL using blood and/or bone marrow samples containing a minimum of 10% clonal B-cells from 1467 pts diagnosed with CLL. Clinical characteristics, prognostic factors (FISH and IGHV status), personal and familial history of OC were collected in pts with POT1 mutations. Results: Mutations in POT1 were found in 52 of the 1467 pts studied (3.5%). Pts with POT1 mutation were young (median age 59 years), commonly presented with early stage disease (Binet stage A 69% vs B/C 31%: p=0.0046 and Rai stage 0-I 65% vs II-IV 35%; p=0.043) and predominantly male (37 male vs 15 female). According to FISH, the more frequent abnormalities were del13q (33%), no abnormalities (25%) and del11q (21%). IGHV status was more commonly unmutated (69%). The most frequent DNA mutations associated with POT1 were NOTCH1 (44%), TP53 (27%) and SF3B1 (23%). Other cancers (excluding non-melanoma skin cancer) were reported in 19 of the 52 pts with POT1 mutation (37%). The most common types were prostate cancer (12%), malignant melanoma (10%) and kidney cancer (8%). Twelve (23%) pts were diagnosed with OC before and 7 pts (13%) after the diagnosis CLL (Table). Four (8%) pts had more than one other cancer diagnoses. Twenty-eight (54%) pts had one of more first degree relatives with history of cancer. Conclusions: POT1 mutations were observed in 3.5% of pts with CLL. These pts are young and often have unmutated IGHV. We observed a high occurrence of OC, particularly malignant melanoma and kidney cancer in these pts. Additional studies are ongoing to determine the proportion of pts with germline POT1 mutation, the distribution of variant allelic frequencies and additional chromosomal abnormalities in pts with OC. Other Cancers in 52 CLL pts with POT1. [Table: see text]
Circulating tumor DNA to predict response and resistance by anti-PD-1 therapy in Chinese relapsed/refractory classic Hodgkin lymphoma.
Authors: Su Hang , Song Yongping , Jiang Wenqi , Sun Xiuhua , Qian Wenbin , Zhang Wei , Gao Yuhuan , Jin Zhengmin , Zhou Jianfeng , Jin Chuan , Zou Liqun , Qiu Lugui , Li Wei , Yang Jianmin , Hou Ming , Xiong Yan , Zhou Hui , Du Xinhua , Wang Xiong , Shi Yuankai 
Published: March 2020

7534 Background: A large fraction of patients with relapsed/refractory (r/r) Classic Hodgkin Lymphoma (cHL) enjoy a beneficial response induced by PD-1. However, no reliable predictive biomarkers for response or resistance are available. Sintilimab, an anti-PD1 agent, has recently demonstrated efficacy and safety in a multi-center, single-arm, phase II study of Chinese patients with r/r cHL (ORIENT-1). The predictive value of circulating tumor DNA (ctDNA) in longitudinal samples from patients in ORIENT-1 was investigated. Methods: A total of 192 plasma samples were collected from 75 patients prior to treatment and during therapy. After ctDNA extraction next-generation sequencing (NGS) was performed using the HiSeq Sequencing System to assess either a 619 or 659 gene panels at an average sequencing depth of 1260×. The panels include frequently mutated genes in cHL and other hematological malignancies. DNA from paired granulocytes was sequenced as presumptive germline control. Results: The genomic profiling of baseline ctDNA revealed a mean allele mutation frequency of 5.47%. Among the most frequently mutated genes in these cHL patients, PCLO and LRP1B are likely unique to Chinese r/r cHL patients. Truncating mutation of B2M, DNMT3, TNFRSF14 and KDM2B were found in patients with acquired resistance, of which TNFRSF14 and KDM2B have not been reported before and need to be confirmed in further study. The baseline ctDNA level was significantly different between objective response group (CR+PR, n = 41, median = 8.72) and non-responder group (SD+PD, n = 9, median = 2.9) ( p= 0.0070) Patients with ctDNA high achieved response earlier than others ( p< 0.05). A drop of 40% in ctDNA after three cycles of therapy confirmed as best cut-off to predict progression associated with clinical benefit, demonstrating 100% specificity. Patients with ctDNA drop ≥40% achieved response significantly earlier (median = 71 days) than others (median = 216 days, p= 0.0074). Conclusions: Our study demonstrated that ctDNA could serve as valuable biomarker for prediction of response or resistance to anti-PD1 immunotherapy.
Outcomes of patients (pts) ≥ 65 years of age in ZUMA-1, a pivotal phase 1/2 study of axicabtagene ciloleucel (axi-cel) in refractory large B-cell lymphoma (LBCL).
Authors: Neelapu Sattva Swarup , Jacobson Caron A. , Oluwole Olalekan O. , Munoz Javier , Deol Abhinav , Miklos David Bernard , Bartlett Nancy L. , Braunschweig Ira , Jiang Yizhou , Kim Jenny J. , Zheng Lianqing , Rossi John M. , Locke Frederick Lundry 
Published: March 2020

7555 Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of pts with relapsed or refractory LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%, and 39% of pts were in ongoing response (Locke et al. Lancet Oncol. 2019). Here we report efficacy and safety outcomes by age. Methods: Eligible pts with refractory LBCL underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed ORR. Additional key endpoints were adverse events (AEs), overall survival (OS), and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 pts; safety was evaluated for all treated pts (Phases 1 and 2). Pts were analyzed by ≥ 65 y vs < 65 y of age. Results: As of 8/11/2018, 108 pts were treated. Pts ≥ 65 y (n = 27) vs < 65 y (n = 81) had a median age of 69 y vs 55 y, respectively, were 81% vs 63% male, 70% vs 36% had an IPI score 3-4, 59% vs 57% had ECOG 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm2 vs 3574 mm2. Median follow-up was 27.1 mo for Phase 2 pts (n = 101). The ORR for pts ≥ 65 y (n = 24) and < 65 y (n = 77) was 92% and 81% (CR rate 75% and 53%), respectively, with ongoing responses in 42% and 38% of pts (ongoing CR 42% and 35%). The 24-mo OS rate was 54% for pts ≥ 65 y and 49% for pts < 65 y. Most pts experienced Grade ≥ 3 AEs (100% of pts ≥ 65 y; 98% of pts < 65 y), and 4% of each group (1/27 pts ≥ 65 y and 3/81 pts < 65 y) died due to AEs as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of pts ≥ 65 y vs < 65 y, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μl) or area under the curve (562 vs 448 d × cells/μl) was similar in pts ≥ 65 y vs < 65 y, respectively. Conclusions: The 2-y follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for pts ≥ and < 65 y. Axi-cel offers substantial clinical benefit for older pts with refractory LBCL who otherwise have limited treatment options. Clinical trial information: NCT02348216.
Rituximab-based maintenance therapy in Waldenström macroglobulinemia: A case control study.
Authors: Zanwar Saurabh , Abeykoon Jithma P. , Gertz Morie A. , Kumar Shaji , Inwards David James , Porrata Luis F. , Thompson Carrie A. , Witzig Thomas E. , Habermann Thomas Matthew , Go Ronald S. , Lacy Martha , Rajkumar S. Vincent , Dispenzieri Angela , Buadi Francis , Gonsalves Wilson I. , Leung Nelson , Hayman Suzanne R. , Kyle Robert A. , Ansell Stephen M. , Kapoor Prashant 
Published: March 2020

7559 Background: Waldenström macroglobulinemia (WM) is a rare indolent lymphoma commonly treated with rituximab (R)-based therapy. The use of rituximab maintenance (mR) in WM is controversial. We present a case-control study of patients (pts) with WM treated with mR. Methods: Pts evaluated at Mayo Clinic, Rochester with active WM that received mR between 1/2000 & 6/2018 were included. Cases comprised pts who received mR following R-based induction as primary therapy. Cases were matched based on the time of diagnosis in 1:2 ratio with a control group treated with R-based primary induction therapy without mR. Time to event analyses were performed from initiation of R-based induction. Results: Of 776 pts with active WM, 42 (5%) cases received mR and 84 pts were selected as controls. The median follow-up and the proportion of high risk pts were comparable between the two cohorts (Table). Pts in the mR cohort show a trend toward longer time to next therapy (TTNT) and a significantly longer overall survival (OS) compared to the control group (Table). The R-based induction therapies were comparable in the two cohorts (p = 0.6). Median duration of mR was 1.9 yrs (95% CI 1.6-2) and mR was used most frequently every (q) 2 (range 1-6) months. Of the 42 mR pts, 25 (60%) received an R-based combination for induction and 17 (40%) received R monotherapy as induction. Five (12%) pts discontinued mR due to toxicity, infections were reported in 13 pts (31%) during mR therapy and 3 pts (7%) received IVIg infusions for recurrent infections. Conclusions: R-based induction followed by mR demonstrates a longer OS in WM compared to R-treated control population not receiving mR, albeit at a high rate of infections. Despite limitations of a retrospective study, with a heterogeneously treated cohort, these data add to the body of literature supporting Rituximab maintenance. Results from an ongoing randomized controlled trial are awaited. [Table: see text]
Early imaging biomarker assessment to predict long-term responses for large B-cell lymphoma (LBCL) after CAR-T therapy.
Authors: Sirous Reza , Bukhari Ali Abbas , El Chaer Firas , Yared Jean , Hardy Nancy Maureen , Kocoglu Mehmet Hakan , Badros Ashraf Z. , Borogovac Azra , Hutnick Elizabeth , Gahres Natalie , Ruehle Kathleen , Rapoport Aaron , Saboury Babak , Dahiya Saurabh 
Published: March 2020

7560 Background: Axicabtagene Ciloleucel (Axi-cel), an anti-CD19 CART cell therapy, achieved 58% complete response (CR) rate, in patients with relapsed refractory (r/r) LBCL on the ZUMA-1 study (Neelapu, NEJM 2017). Early response assessment (PET-CT) at day 30 is a common clinical practice. Patients with partial response (PR) at day 30 pose a therapeutic dilemma. ZUMA-1 analysis showed 1/3rd PR patients would convert to a CR. No biomarkers exist to predict eventual response. We report comprehensive PET-CT biomarker analysis on patients with PR at day 30 treated with Axi-cel for r/r LBCL. Methods: Ten patients with PR based on PET-CT imaging at day 30 were retrospectively assessed. Day 30 PET-CT was compared to baseline and a day 90 PET-CT. Global burden of disease of each patient at every time-point were quantified using Total Tumor Glycolysis (TTG) methodology as the imaging biomarker. Using adaptive-thresholding method, each lesion on FDG PET image was segmented and the following parameters were quantified: metabolic-volume (MV), SUVmax, SUVpeak, Partial-Volume-Corrected SUVmean and five other imaging biomarkers. To evaluate the effect of baseline and early imaging biomarkers to predict the subsequent burden of disease multiple regression analysis was performed (STATA 15). Results: Day 90 PET-CT assessment revealed, 4 patients had progressive disease (PD), 4 had CR, and 2 had PR. TTG of patients with PD at day 90 was 900 vs. 29 in patients with non-PD (CR, PR). The Global-SUVmean of the patients with PD at day 90 was 725 vs. 86 in patient with non-PD. Regression analysis showed early-TTG as a significant predictor of subsequent-TTG (beta-coefficient = 1.26 (0.39-2.13); P-value = 0.02; adjusted-R-squared = 0.97), while the baseline-TTG didn’t have any effect on subsequent-TTG (P-value = 0.3). Additionally, the regression analysis didn’t show any significant predictive value in SUVmean and SUVmax of baseline and day 30 scans to predict subsequent burden of disease (TTG or Global-SUVmean) with P-values > 0.8. Conclusions: Early post-axi-cel TTG, rather than baseline, can predict subsequent response to treatment. None of the SUV indices, commonly used in daily practice, were predictive of eventual response.
Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: Updated results of a first-in-human (FIH) phase I dose escalation study.
Authors: Topp Max S. , Duell Johannes , Zugmaier Gerhard , Attal Michel , Moreau Philippe , Langer Christian , Kroenke Jan , Facon Thierry , Salnikov Alexey , Lesley Robin , Beutner Karl , Kalabus James , Rasmussen Erik , Riemann Kathrin , Minella Alex C. , Munzert Gerd Michael , Einsele Hermann 
Published: March 2020

8007 Background: Objectives of this study included assessing safety and activity of AMG 420/BI 836909, which binds BCMA (B-Cell Maturation Antigen) on MM cells and CD3 on T cells, in relapsed and/or refractory (R/R) MM. Methods: In this FIH study, 6-week cycles of AMG 420 were given for ≤5 cycles or until disease progression (PD), toxicity, or consent withdrawal; 5 more cycles could be given for benefit. Eligible patients had progression after ≥2 lines (incl PI and IMiD). Excluded were PC leukemia, extramedullary relapse, CNS involvement, or prior allo-SCT. MRD was defined as <1 tumor cell / 104 bone marrow cells per flow cytometry. Results: As of Dec 10, 2018, 42 patients received AMG 420 (0.2-800 µg/d). Patients D/C for PD (n=24), adverse events (AE, n=7, incl 3 DLTs), death (4), completed 10 cycles (2), and consent (1). Median age was 65 y, median MM duration 5.2 y, and median # prior therapies 4. Patients were treated for a mean (SD) of 2.5 (2.6) cycles. There were 2 deaths from AEs (acute respiratory distress from flu / aspergillosis; fulminant hepatitis related to adenovirus infection); neither treatment related. Of those with serious AEs (SAEs, n=21, 50%), 18 required hospitalization. SAEs occurring in >1 patient were infections (n=12) and polyneuropathy (PN, n=2). Treatment-related SAEs included 2 grade 3 PNs and 1 edema. Grade 2-3 CRS was seen in 3 patients. No anti-AMG 420 Ab were detected. In this study, 800 µg/d was determined to not be tolerable as 2/3 patients had DLTs, 1 case of grade 3 CRS and 1 case of grade 3 PN; both required hospitalization and subsequently resolved. At 400 µg/d, there were 5 minimal residual disease (MRD)-negative sCRs, 1 VGPR, and 1 PR, for a response rate of 7/10 (70%); at Dec datacut, responses lasted for 5.6-10.4 months with 4 patients ongoing on treatment. As of Feb 2019, some responses lasted >1 year. Overall, there were 13/42 responders (6 sCRs, 3 CRs, 2 VGPRs, 2 PRs). Median time to any response was 1 month. Conclusions: In this FIH study of AMG 420, a BiTE vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, a recommended dose for further investigation. Clinical trial information: NCT02514239.
Seeking light-chain amyloidosis very early: The SAVE trial—identifying clonal lambda light chain genes in patients with MGUS or smoldering multiple myeloma.
Authors: Zhou Ping , Kugelmass Adin , Toskic Denis , Godara Amandeep , Fogaren Teresa , Varga Cindy , Comenzo Ray 
Published: March 2020

8010 Background: In systemic AL amyloidosis (AL), caused by clonal Ig free light chains (LC) produced in 75% of cases by λ clones, patients often present with advanced organ damage, making earlier diagnosis a critical unmet need. Five λ IGLV germline genes account for 75% of AL λ-type ( IGLV 6-57, 1-44, 2-14, 1-51, 3-1) (Blood 2017;129:299), representing 56% of all AL patients. Relative risk of AL versus MM with these clonal genes can be high (7.3, 6-57; 2.5, 1-44), intermediate (1.7, 2-14; 1.2, 1-51) or low (0.8, 3-1) (Amyloid 2009;16:1). Progression to AL from smoldering multiple myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS) occurs but is not well appreciated (JCO 2014; 32:2679). SAVE is a trial for λ SMM or λ MGUS patients with a κ:λ FLC ratio < 0.26 and difference between involved and uninvolved FLC > 23mg/L (JCO 2014;32:2699). Methods: Eligible patients ship peripheral blood (PB) or bone marrow (BM) samples to us for RT-PCR with cDNA from CD138+ cells, using primers for the Vλ families (Blood 2001;98:714). Amplicons are sequenced and the IGLV germline genes identified in IMGT (ImMunoGene-Tics, www.imgt.org). If the germline gene is AL-related, further evaluation is pursued. Results: Twenty asymptomatic λ patients from 18 states have been enrolled (3M, 17F) and 23 PB and 4 BM specimens obtained. Medians of months from diagnosis, involved FLC, κ:λ ratios, MNC and CD138-selected cells were 20.5 months, 113mg/L, κ:λ 0.06, 8.1x106 (0.8-24) and 3x105 (0-30), respectively. Seventeen patients have had IGLV genes identified, 12 with the first and 5 with additional specimens including 4 BM. Increased risk of AL was identified in 7 patients, 2 of whom had undiagnosed AL (both with IGLV2-14 germline genes). One patient with SMM diagnosed in 2016 had AL λ-type with GI involvement and is 9 months status post MEL 200 stem cell transplant (SCT), and the second with SMM diagnosed in 2009 had cardiac AL λ-type by heart biopsy with an NT-proBNP 171 (but with a suggestive MRI) and is en route to SCT. Conclusions: The SAVE trial enables early diagnosis of AL λ-type based on the λ IGLV gene used by the clonal plasma cells. By RT-PCR in this pilot study we identified the clonal λ gene 85% of the time. Earlier diagnosis will enable treatment with effective therapy such as MEL 200 SCT. Clinical trial information: NCT02741999.
Prospective study to measure the impact of MMprofiler on treatment intention in newly diagnosed multiple myeloma patients (PROMMIS).
Authors: Hari Parameswaran , Lentzsch Suzanne , Siegel David Samuel DiCapua , Usmani Saad Zafar , Dhakal Binod , Rossi Adriana C. , Rosenbaum Cara Ann , Leng Siyang , Bhutani Divaya , Biran Noa , Vesole David H. , Bhutani Manisha , Stork-Sloots Lisette , De Snoo Femke , Dumee Belinda C. , Van Vliet Martin , Niesvizky Ruben 
Published: March 2020

8030 Background: Multiple Myeloma (MM) is recognized as a heterogeneous group of patients with varying response and outcome of their disease, associated with various risk factors including genetic aberrations. Risk adapted treatment strategies are beginning to emerge (e.g. mSMART), which include gene expression signatures. SKY92, a 92-gene prognostic signature, classifies MM patients as “high” or “standard” risk. It has been reported to be a robust predictor for Overall and Progression Free Survival (Kuiper 2012, 2015). Here we report the preliminary impact of SKY92 on risk classification and treatment intention decisions in newly diagnosed MM patients enrolled in the PRospective Observational Multiple Myeloma Impact Study (PROMMIS). Methods: Patients with MM had their BM aspirate analyzed using the MMprofiler with SKY92. The physician completed questionnaires with his/her treatment intention, before and after knowing SKY92 results. Results: 39 MM patients were enrolled from 5 US centers. The SKY92 signature classified 15 patients (38%) as high risk. Prior to knowing SKY92 results, physicians regarded 20 (51%) patients as clinically high risk, for whom SKY92 indicated 12 patients to be standard risk. Upon revealing SKY92, 8 patients were then considered standard risk by the physician. For 2 patients with concordant high risk classification results, the confirmation of the risk classification was considered helpful. The impact of treatment intention decisions in clinical high risk patients was 40% (8 out of 20). In the 19 patients (49%) that were regarded clinically standard risk prior to knowing SKY92, SKY92 indicated 7 patients to be high risk. Physicians agreed to this classification. For 4 patients with concordant risk classification, the confirmation was found helpful. The impact of treatment intention decisions in clinical standard risk patients was 37% (7 out of 19). Conclusions: Preliminary results from the PROMMIS trial indicate that SKY92 impacts the physician’s treatment intention for 38% of patients with newly diagnosed MM. Moreover, the physicians found the SKY92 result useful for 54% of the patients. This underlines the relevance and need for assessment of SKY92 in MM patients, and associated risk stratified treatment paradigm. Clinical trial information: NCT02911571.