bluuebunny/crossref_metadata_2025_split huggingface dataset:
Outcomes in large B-cell lymphoma progressing after axicabtagene ciloleucel (Axi-cel): Results from the U.S. Lymphoma CAR-T Consortium.
Authors: Spiegel Jay Y. , Dahiya Saurabh , Jain Michael D. , Nastoupil Loretta J. , Ghobadi Armin , Lin Yi , Lunning Matthew Alexander , Reagan Patrick Michael , McGuirk Joseph , Deol Abhinav , Munoz Javier , Locke Frederick Lundry , Neelapu Sattva Swarup , Tamaresis John S , Rapoport Aaron , Miklos David Bernard , Hill Brian Thomas 
Published: March 2020

7517 Background: Axi-cel, an anti-CD19 CART cell therapy, achieved 83% ORR, 58% CR rate, with 39% PFS at 2 years in patients (pts) with relapsed refractory large B-cell lymphoma (LBCL) on the ZUMA-1 study (Locke, Lancet Oncology 2018). Data from a 17-center consortium showed response rates were similar in 274 pts treated with commercial axi-cel (Nastoupil, ASH 2018). Here, we performed retrospective analysis of outcomes in pts with progressive disease (PD) after axi-cel. Methods: Response status was determined by Cheson 2014 and reported as date of radiologic relapse. 274 pts were infused by December 26, 2018 with maximum follow-up of 14 months; 116 pts had PD as of Feb 1, 2019. Twelve sites provided additional data, detailing 85% of PD pts (n=99) with a median time to relapse of 54 days (IQR 16-120). Results: Pre axi-cel pt characteristics: median lines of therapy were 4 (range 2-11), 86% were Stage III/IV and 22% were ECOG >1. Following relapse, 60% (n=61) were biopsied and 70% (43/61) had CD19 expression measured. Thirty percent (13/43) were CD19 negative by: IHC (3/13), flow (2/13) or both (8/13). Seventy percent (n=71) received salvage therapy for PD. Median lines of salvage therapy was 1 (range 0-4). The most common therapies were Lenalidomide-based (30%), checkpoint inhibitors (30%), chemotherapy (20%) and radiation (10%). First salvage therapy ORR by regimen: checkpoint inhibitors = 24%, lenalidomide regimens = 20% and chemotherapy = 11%. One patient received allogeneic transplant. Twelve pts enrolled on clinical trial, with one receiving 2nd CAR-T. Median OS following relapse was 108 days (95% LCL 71). Nineteen pts relapsed <3 months after axi-cel and did not receive therapy with median OS 17 days (95% CI 7-49); 33 pts relapsed <3 months and received therapy with 114 day median OS (95% LCL 82). In contrast, 30 pts who relapsed >3 months post axi-cel and received therapy had estimated median OS >220 days (95% LCL 81). Conclusions: Patients with LBCL relapsing less than 3 months following axi-cel have extremely poor outcomes supporting the development of novel therapies. Therapy for relapse >3 months appears promising. JYS and SD contributed equally; APR, DBM and BTH contributed equally.
Atrial fibrillation (AF) in patients with CLL treated with ibrutinib: Assessing prediction models and clinical outcomes.
Authors: Archibald William , Rabe Kari G. , Kabat Brian , Call Timothy , Ding Wei , Kay Neil E. , Kenderian Saad , Muchtar Eli , Leis Jose Francisco , Schwager Susan M. , Koehler Amber , Fonder Amie L. , Slager Susan L. , Shanafelt Tait D. , Parikh Sameer Ashok 
Published: March 2020

7522 Background: Ibrutinib therapy is associated with an increased risk (~15%) of AF. An accurate risk assessment model for the development of AF in pts starting ibrutinib is not established, and outcomes after AF are not well described. Methods: An IRB approved retrospective review of CLL pts treated with ibrutinib at Mayo Clinic between Oct 2012 and Nov 2018 was conducted. Results: 299 pts were identified with a total of 565 years of ibrutinib exposure (Table). After a median follow-up of 24 months (range 0–70 months), 51 pts developed treatment-emergent AF (13 [25%] CTCAE 3 or higher). Our study assessed 3 clinical prediction models, the Framingham (Schanbel:Lancet 2009), Italian (Visentin:Blood 2018;132:3118), and Shanafelt (Shanafelt:Leuk Lymp; 2017) risk scores. Based on a lower Akaike information criteria, the Italian score was best able to predict risk of treatment emergent AF (2-year risk of AF with score 0 6%; 1-2 8%; 3-4 26%; 5+ 47%). Thirty (61%) pts were treated with medical therapy for AF (27 rate control; 2 rhythm control; 1 both). 16 (31%) pts underwent interventional therapy (3 AV node ablation; 11 cardioversion; and 2 pacemaker). Twelve (23%) pts temporarily held ibrutinib and resumed their original dose, 22 (43%) pts continued reduced dose ibrutinib and 11 (22%) continued their initial ibrutinib dose. Six (12%) pts permanently discontinued ibrutinib. Of 51 pts with treatment-emergent AF, 41 (80%) had a CHA2DS2-VASc score of ≥2 (41% received anticoagulation alone; 12% received antiplatelet therapy alone; 10% received both). No pt developed a thrombotic stroke after treatment-emergent AF. Two major bleeds, (1 GI and 1 intracranial) occurred, one in a pt on concomitant antiplatelet and anticoagulation therapy, and one in a pt receiving neither. The development of AF was associated with shorter event-free survival (HR 2.5, 95%CI 1.5-4.2, p<.001) and shorter overall survival (HR 3.5, 95%CI 2.0-6.3, p<.001). Conclusions: The Italian score was the best predictor of AF development in this cohort of ibrutinib treated pts. Although the vast majority of pts who develop AF after ibrutinib are able to continue therapy, the occurrence of AF appears to be associated with shorter EFS and OS. [Table: see text]
Phase 1/2 trial of cirmtuzumab and ibrutinib: Planned analysis of phase 1 CLL cohorts.
Authors: Choi Michael Y. , Wierda William G. , Lee Hun Ju , Tzachanis Dimitrios , Ianopulos Xen , Jezior Deborah , Breitmeyer James Bradley , Jamieson Catriona HM , Kipps Thomas J. ,   CIRLL Study Group
Published: March 2020

7527 Background: Cirmtuzumab (C) is a humanized mAb that binds ROR1 and blocks Wnt5a from binding and activating ROR1 on CLL and mantle cell lymphoma (MCL); C does not bind normal adult tissues. A phase 1 trial of C showed excellent safety and inhibition of Wnt5a-ROR1 signaling. Ibrutinib (Ibr) does not inhibit the ROR1 pathway, and C+Ibr exert synergistic effects in CLL and MCL. The current clinical trial combines C+Ibr for patients (pts) with CLL and MCL. A planned analysis of the phase 1 CLL portion is presented. Methods: Eligible pts had CLL needing treatment according to iwCLL guidelines. C was given at 2, 4, 8, or 16 mg/kg q 2 wk for 8 wk, then q 28 d to 52 wk. Ibr 420 mg PO daily was started on d 28. Results: 3 pts were treated at each C dose level with age 57-86; 75% were previously treated (median 2); 3 pts had del(11q), 3 had trisomy 12, and 6 pts had unmutated IGVH genes. There were no discontinuations for toxicity and no dose limiting toxicities. Treatment with C alone and combined with Ibr was well-tolerated. One SAE occurred with C monotherapy (hospitalization for tonsillitis). Adverse events on C+Ibr were consistent with the known Ibr safety profile, with one grade 3 hyperkalemia and 1 atrial fibrillation event. All other AEs were grade 1 or 2. The overall response rate after 16-48 weeks of treatment was 67% with 1 confirmed complete response (CR) with no morphologic evidence of CLL in the marrow, 1 clinical CR, 6 partial responses (PR) and 4 stable disease. No patient had progressive disease. The typical redistributive lymphocytosis seen with Ibr was blunted, with only a 50% mean rise in ALC, rapidly returning to baseline. PRs were observed in all C dose levels. Conclusions: The combination of C+Ibr is well-tolerated and effective. CRs were observed in 2 cases, a result that would be highly unusual with Ibr monotherapy in CLL. Based on these findings, Cirm 600 mg was selected as the RP2D for the randomized phase 2 portion of this protocol, which will prospectively compare the complete response rates between C+Ibr and Ibr alone. Clinical trial information: NCT03420183.
Impact on survival of surveillance imaging after first remission in follicular lymphoma.
Authors: Mao Jimmy , Strouse Christopher Sun , Goldman Max , Chen Wanqi , Chen Zhengjia , Maurer Matthew John , Calzada Oscar , Churnetski Michael , Flowers Christopher , Cerhan James Robert , Link Brian K. , Thompson Carrie A. , Cohen Jonathon Brett 
Published: March 2020

7536 Background: While most patients (pts) with follicular lymphoma (FL) achieve an initial response to treatment, the majority relapse. Recently, Goldman et al. reported that surveillance imaging (SI) in FL is not associated with improved post-relapse outcomes and is frequently associated with false positive scans (ASH 2017). The goal of this study was to validate these findings. Methods: Pts were enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), a prospective cohort of newly diagnosed lymphoma pts. All pts were followed for events including relapse, re-treatment, and death, with events verified by medical records. Pts eligible for this study had biopsy proven FL grade 1, 2, or 3a who had achieved a response after induction therapy and later relapsed. Initial and post-treatment management was per treating physician. Medical records were re-reviewed in pts with events for clinical details at relapse in relationship to planned follow-up visits and SI. Relapse detection was categorized either by clinical suspicion (CS) via history, exam, and/or labs; or by SI in an asymptomatic pt. Univariate survival analysis was conducted for each variable. The hazard ratio with 95% confidence interval based on Cox Proportional Hazard models was presented along with the log rank test p-value. Kaplan-Meier plots were produced to evaluate the difference in overall survival (OS) between groups. Results: 1121 FL pts were enrolled in MER from 2002-2015, of which 117 were eligible. Median age at diagnosis was 60 years (range 35-83), and 61% were men. Median time to relapse of the 117 pts was 26 months (range 9-125). At a median follow-up from relapse of 69 months (range 0.23-179), 26 pts died. Pts completed a median of 3 imaging studies (range 0-15) during post-induction surveillance. 63 relapses (56%) were detected based on CS; 50 (44%) were detected by SI; and 4 were unknown. There was no difference in OS from relapse for those with relapse detected via CS vs. SI (HR = 0.98 [0.45,2.12], p = 0.96). Conclusions: Routine SI does not appear to improve survival outcomes in FL after achieving first remission, and its common practice should be questioned. Further investigation of prognostic markers to identify high-risk FL pts who may benefit from SI is needed.
Early progression of disease (POD24) as survival predictor in MALT lymphoma.
Authors: Conconi Annarita , Thieblemont Catherine , Cascione Luciano , Torri Valter , Kiesewetter Barbara , Margiotta-Casaluci Gloria , Gaidano Gianluca , Raderer Markus , Cavalli Franco , Lopez-Guillermo Armando , Johnson Peter W. M. , Zucca Emanuele ,   International Extranodal Lymphoma Study Group
Published: March 2020

7548 Background: Progression of disease within two years from start of therapy (POD24) is linked with poor outcome in follicular lymphoma. It is less clear whether POD24 affects overall survival (OS) also in extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma). Methods: We analyzed the dataset of the IELSG19 clinical trial (training set) to determine whether POD24 is associated with inferior OS. The study population included 401 EMZL patients (131 randomly assigned to chlorambucil treatment, 138 to rituximab and 132 to chlorambucil plus rituximab). Reproducibility was analyzed in an independent cohort (validation set) of 218 patients who received systemic treatment (chemotherapy, immunotherapy or both). In both, training and validation sets, we excluded from the analysis the patients who, within 24 months from treatment start, died without progression or were lost to follow-up without progression. Overall survival (OS) was calculated from disease progression in patients with POD24 and from 24 months after start of treatment in those without POD24 (reference group). Results: POD24 was observed in 69 of 401 patients of the IELSG19 study and 58 of 218 patients in the validation cohort. In the training set, the 10-year OS rates were 64% in the POD24 group and 85% in the reference group (HR = 2.42, 95%CI, 1.35-4.34; log-rank P = 0.002) and POD24 predicted poor outcome regardless of treatment type (multivariable Cox model, P = 0.003). The prognostic impact of POD24 was confirmed in the validation set, with 10-year OS rates of 48% in the POD24 group and 71% in the reference group (HR = 2.17, 95%CI, 1.20-3.93; log-rank P = 0.009). Conclusions: In patients with EMZL who received front-line systemic treatment, POD24 is associated with poorer survival and may represent a useful endpoint in future prospective clinical trial.
A phase Ib/II study of oral nanatinostat (N) and valganciclovir (VG) in subjects with Epstein-Barr virus (EBV)-associated lymphomas.
Authors: Porcu Pierluigi , Haverkos Bradley , Brem Elizabeth , Vallurupalli Anusha , Feldman Tatyana , Alpdogan Onder , Brammer Jonathan Edward , Bryan Locke Johnson , Barta Stefan K. , Obrzut Sebastian , Shen Hao , Rochford Rosemary , Baiocchi Robert A. , Casper Corey , Gutheil John , McRae Robert , Daniels Preston , Warren Marshelle Smith , Royston Ivor , Faller Douglas V. 
Published: March 2020

7551 Background: Nanatinostat (N; VRx-3996) is a Class I-selective oral hydroxamate histone deacetylase (HDAC) inhibitor active against HDAC 1-3, but not HDAC 6. N induces expression of EBV thymidine kinase (TK, BXLF1) and protein kinase (PK, BGLF4) in EBV+ lymphomas. This study examines if N+VG results in tumor sensitization to antivirals (i.e., VG) and impacts EBV-induced T-cell exhaustion. Methods: The study employs a 3+3 design with expansion in patients (pts) with relapsed/refractory EBV+ lymphomas (EBER-ISH). Objectives: Maximal Tolerated Dose (MTD), Recommended Phase 2 Dose (RP2D), and efficacy. Primary endpoint: safety. Secondary endpoints: PK, response rate. Exploratory endpoints: PBMC histone H3 acetylation (Ac), quantitative plasma EBV DNA (pEBVd), and immune biomarkers. Responses (investigator-assessed and centrally-reviewed) are based on the Lugano Classification. Early safety and efficacy data are reported. Results: As of 10-Jan-2019, 15 pts (4F/11M, median age 60 yrs [19-79]) were enrolled with a median of 2 prior therapies and various lymphoma subtypes. Cohort 1 (N 10 mg BID/VG 900 mg BID) exceeded MTD (DLTs: leukopenia, neutropenia and thrombocytopenia). PK demonstrated ~2-fold higher N exposure compared to a prior study. VG levels were consistent with published data. Doses were reduced in Cohort 2 (N 5 mg BID/VG 450 mg BID) with no DLTs to date and 3 active pts. Most non-hematologic treatment-related AEs (TRAEs) were G1-2. Most G3+ TRAEs were hematologic (neutropenia, leukopenia, thrombocytopenia). Increases in creatinine occurred early and responded to reductions in VG. Among 7 evaluable pts, 4 responses were seen (2 CR, 2 PR) in PTLD, DLBCL, AITL, and plasmablastic lymphoma. Two pts had SD, and 1 PD. Of 8 pts with detectable baseline pEBVd, 7 demonstrated a reduction (median -54% [17 to -83%]). PBMC H3 Ac levels, multi-cytokine expression panel, and functional assessments in CD8+ T cells are in progress. Conclusions: N+VG appears well-tolerated at 5 mg and 450 mg BID, respectively with hematologic DLTs in a higher dose cohort. Responses are observed at all doses in both B and T cell lymphomas, with reductions in pEBVd levels and changes in T cell functionality. A RP2D will be defined prior to dose expansion. Clinical trial information: NCT03397706.
Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results.
Authors: Moreau Philippe , Attal Michel , Hulin Cyrille , Béné Marie-Christine , Broijl Annemiek , Caillot Denis , Delforge Michel , Dejoie Thomas , Facon Thierry , Lambert Jérôme , Leleu Xavier , Macro Margaret , Perrot Aurore , Zweegman Sonja , Ahmadi Tahamtan , Chiu Christopher , Pei Lixia , Vermeulen Jessica , Avet-Loiseau Herve , Sonneveld Pieter ,   on behalf of IFM and HOVON
Published: March 2020

8003 Background: VTd is a standard of care (SoC) for TE NDMM. CD38 mAb DARA significantly reduced the risk of progression/death and improved CR and MRD-negative rates in relapsed refractory MM or transplant-ineligible NDMM in phase 3 studies. We report the primary and final analysis of Part 1 of CASSIOPEIA. Methods: In Part 1, TE NDMM pts 18-65 y were randomized 1:1 to VTd (6 28-day cycles [C; 4 pre-ASCT induction, 2 post-ASCT consolidation] of V 1.3 mg/m2 SC BIW Week [W] 1-2; T 100 mg PO QD; d 40-80 mg/week PO or IV W 1-4 C 1-2, W 1-3 C 3-6) ± DARA (16 mg/kg IV QW C 1-2, Q2W C 3-6). Melphalan 200 mg/m2 was pre-ASCT HDT. The primary endpoint, post-consolidation sCR rate, was assessed at Day [D] 100 post-ASCT. Part 2 (maintenance) is ongoing. Results: A cohort of 1085 pts (D-VTd, 543; VTd, 542) was randomized. The D 100 post-ASCT sCR rate was significantly higher for D-VTd vs VTd (28.9% vs 20.3%; P = 0.0010; Table). At 18.8-mo median follow-up, PFS from first randomization favored D-VTd with HR 0.47 (95% CI, 0.33-0.67; P <0.0001). With median PFS NR in either arm, 18-mo PFS rates were 92.7% vs 84.6% for D-VTd vs VTd. Rates of ≥CR, ≥VGPR, and MRD negativity supported sCR results (Table). OS is immature with 46 deaths on study (D-VTd, 14; VTd, 32; HR, 0.43; 95% CI, 0.23-0.80). The most common (≥10%) grade 3/4 TEAEs (D-VTd/VTd) were neutropenia (27.6%/14.7%), lymphopenia (17.0%/9.7%), stomatitis (12.7%/16.4%), and thrombocytopenia (11.0%/7.4%). In the D-VTd arm, infusion-related reactions occurred in 35.4% of pts. Conclusions: D-VTd in induction prior to and consolidation after ASCT improved depth of response (sCR, ≥CR, and MRD negativity) and PFS with acceptable safety. The favorable benefit-risk profile supports the use of D-VTd in TE NDMM. CASSIOPEIA is the first study to demonstrate clinical benefit of DARA + SoC in TE NDMM. Clinical trial information: NCT02541383. [Table: see text]
A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM).
Authors: Richardson Paul G. , Attal Michel , Rajkumar S. Vincent , San Miguel Jesus , Beksac Meral , Spicka Ivan , Leleu Xavier , Schjesvold Fredrik , Moreau Philippe , Dimopoulos Meletios A. , Huang Jeffrey SY. , Minarik Jiri , Cavo Michele , Prince H. Miles , Macé Sandrine , Corzo Kathryn Penkus , Campana Frank , Le-Guennec Solenn , Dubin Franck , Anderson Kenneth Carl ,   on behalf of the ICARIA-MM Study Group
Published: March 2020

8004 Background: The primary objective of this phase 3 trial was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti-CD38 monoclonal antibody, combined with pomalidomide (P)/dexamethasone (d) versus (vs) Pd. Methods: Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4mg PO days 1-21; 40mg [20mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity. Results: 307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36-86) yrs; median prior lines of therapy: 3 (2-11); estimated GFR: <60ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high-risk cytogenetics. At median follow-up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44-0.81), P=0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P<0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10-5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461-1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3h at 1st inf. and 2.8h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3-4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd. Conclusions: IsaPd significantly improved PFS and ORR vs Pd, with a manageable safety profile. IsaPd is an important new treatment option for the management of RRMM. Clinical trial information: NCT02990338.
Outcomes of patients with light chain amyloidosis who had autologous stem cell transplantation with three or more organs involved.
Authors: Al Saleh Abdullah , Sidiqi M Hasib , Dispenzieri Angela , Muchtar Eli , Buadi Francis , Dingli David , Lacy Martha , Warsame Rahma M. , Gonsalves Wilson I. , Kourelis Taxiarchis , Hogan William J. , Hayman Suzanne R. , Kapoor Prashant , Kumar Shaji , Gertz Morie A. 
Published: March 2020

8011 Background: Literature suggests that three or more organ involvement is a contraindication for autologous stem cell transplant (ASCT) in light chain amyloidosis (AL). Most centers limit transplantation to patients who have no more than two organs significantly involved. Methods: We retrospectively reviewed all patients with AL Amyloidosis involving three or more organs and who had ASCT between 1996-2015 at Mayo clinic, Rochester, Minnesota. Results: Seventy five patients underwent ASCT with three or more organs involved. Median age at diagnosis was 54 years and 67% were males. The heart was involved in 95%, followed by kidneys (84%). Thirty eight patients (51%) had no induction treatment prior to ASCT. Full dose melphalan (200mg/m2) was given in 45%, and the remaining received a reduced dose (140mg/m2). Overall response rate (hematological) was 75%. The median progression-free (PFS) and overall survival (OS) were 16.3 and 68.9 months, respectively. The 100-day mortality was 16% and overall forty four patients (59%) died during the follow up period. The most common causes of death were cardiovascular events (32%) and progressive amyloidosis (25%). On multivariable analysis, predictors for PFS were Mayo stage III/IV (RR 3.3, P = 0.0012) and hematological response (≥VGPR, RR 0.4, P = 0.012). An NT-ProBNP level of ≥2000 pg/ml was an independent predictor for shorter PFS (RR 2.6, P = 0.013). Predictors for OS included any hematological response (RR 0.1, P < 0.0001) and Mayo stage III/IV (RR 7, P < 0.0001). When looking at the NT-ProBNP, a level ≥2000 was prognostic (RR 5.5, P = 0.001). Number of organs involved (3 vs. 4-5) was not significant in either PFS or OS. Conclusions: We conclude that the high prevalence of cardiac involvement is the main driver for the poor outcome in patients who have three or more organs involved. Using selection criteria defined for safe transplantation in cardiac amyloidosis should result in low therapy-related mortality independent of the number of organs involved. The concept of considering patients with three organs involved ineligible for stem cell transplantation should be abandoned.