bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary results of earlier steroid use with axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL).
Authors: Topp Max S. , van Meerten Tom , Wermke Martin , Lugtenburg Elly J. , Minnema Monique C. , Song Kevin W. , Thieblemont Catherine , Jiang Yizhou , Plaks Vicki , Kerber Anne , Kersten Marie Jose 
Published: March 2020

7558 Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved in the EU and US for patients (pts) with R/R 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%. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 11% and 32% of pts, respectively; 26% of pts received steroids, and 43% received tocilizumab (Locke et al. Lancet Oncol. 2019). A safety expansion cohort was added to evaluate the effect of earlier steroid use on the rates of these adverse events (AEs). Methods: Eligible pts with R/R LBCL were leukapheresed and received conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. Pts in this cohort received early steroid intervention starting at Grade 1 NE and at Grade 1 CRS when no improvement was observed after 3 days of supportive care. The primary endpoint for this cohort was incidence and severity of CRS and NE. Results: As of 9/14/2018, 21 of 40 planned pts received axi-cel with a minimum follow-up of 1 mo (median, 2.6 mo). The median age was 63 y (range, 36 – 73), 67% were male, 81% had disease stage III-IV, 76% were R/R to ≥ second-line therapy, and 10% had relapsed post-autologous stem cell transplantation. Seventy-six percent of pts received steroids and 81% received tocilizumab. Most pts (81%) had Grade ≥ 3 AEs, most commonly neutrophil count decreased (33%), anemia (29%), and pyrexia (24%). Grade ≥ 3 NE occurred in 10% of pts; the most common symptoms were somnolence (10%) and confusional state (10%). Grade 1 and 2 NE occurred in 38% and 5% of pts, respectively. No pt had Grade ≥ 3 CRS; 33% of pts had Grade 1 CRS and 67% had Grade 2. There were no deaths due to AEs; 1 pt died due to disease progression. The ORR per investigator assessment was 76% with 48% of pts achieving a CR. Pharmacokinetic data will be presented. Conclusions: Early use of steroids may help in managing severe CRS and NE by potentially reducing their incidence in pts treated with CAR T cell therapy without affecting response rates. Optimizing AE management may help to further improve the benefit:risk profile of CAR T cell therapy. Clinical trial information: NCT02348216.
Association of high baseline metabolic tumor volume with response following axicabtagene ciloleucel in refractory large B-cell lymphoma.
Authors: Dean Erin , Lu Hong , Lazaryan Aleksandr , Krivenko Gabriel S , Bachmeier Christina A , Chavez Julio C. , Davila Marco L. , Khimani Farhad , Liu Hien D , Pinilla-Ibarz Javier , Shah Bijal D. , Jain Michael D. , Balagurunathan Yoganand , Locke Frederick Lundry 
Published: March 2020

7562 Background: Axicabtagene ciloleucel (axi-cel) is an anti-CD19 targeted Chimeric Antigen Receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). High tumor burden, by sum of the product of diameters (SPD) in ≥ 6 reference lesions, was associated with lower durable responses rates in the ZUMA-1 trial (Locke F.L. ASCO. 2018). Although metabolic tumor volume (MTV) predicts worse outcomes with chemotherapy in lymphoma (Guo B. PLoSOne. 2019), its prognostic significance remains unclear with axi-cel therapy. Methods: MTV was measured by MIM Software using a 41% SUVmax threshold with manual lesion contour adjustment and radiologist review. Low and high MTV groups were defined based on median cutoff value. Cytokine release syndrome (CRS) was graded by Lee et al. ( Blood. 2014). Neurotoxicity (NT) was graded by CTCAEv4. Toxicities, overall response rate (ORR), and complete response rate (CR) were evaluated via Fisher’s test; PFS and OS via Kaplan-Meier and log-rank test. Results: 48 patients with LBCL, or its variants, that received axi-cel at Moffitt from June 2015 to October 2018 were included. 31 were male, and median age was 63 years (range, 28-76). CRS occurred in 43/47 (91.5%) and NT in 32/47 (68.1%) patients. Grade 3-4 CRS in 2/47 (4.3%) and NT in 12/47 (25.5%). Median follow up for survivors was 8.9 months (range, 1.4- 36.8 months). CR was achieved in 31/48 (64.6 %) and ORR in 39/48 (81.3%). Median for the low MTV group was 35.1 mL (range, 4.24-132.8 mL), and for the high MTV group 455.5 mL (range, 162.2-1221.4 mL). High MTV was not predictive of G1-4 NT or G3-4 NT (OR = 1.14, P = 0.99; OR = 1.66, P = 0.52). Similarly, high MTV was not predictive of G1-4 CRS or G3-4 CRS (OR = 0.29, P = 0.348; OR = 1.05, P = 0.99). Low MTV was predictive of ORR (OR = 11.50, P = 0.026) and CR (OR = 9.8, P = 0.002). Patients with high MTV had inferior PFS (HR = 3.296, 95% CI 1.42-7.64, P = 0.008) and OS (HR = 6.68, 95% CI 2.56-17.32, P = 0.003). Conclusions: High baseline MTV is associated with decreased and less durable response following axi-cel. As survival data mature, future analyses will aim to assess the role of MTV as an independent prognostic tool in axi-cel recipients with LBCL.
A phase I study of a selective PI3Kδ inhibitor YY-20394 in patients with relapsed or refractory B-cell malignancies.
Authors: Qiu Lugui , Qi Junyuan , Song Yuqin , Jiang Bo , Tu Meifeng , Ping Lingyan , Li Zengjun , Zhu Jun , Xu Yuanyuan , Bao Hanying , Xu Zusheng 
Published: March 2020

7563 Background: YY-20394, an oral highly selective PI3Kδ inhibitor was studied in a phase I trial for patients with relapse or refractory B-cell malignancies. We characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary efficacy of YY-20394. Methods: YY-20394 was given orally once daily (QD) in 28 days cycle until disease progression, unacceptable toxicity, or withdrawal from the study. Only 1 subject was treated with starting dose 20 mg once daily, then subsequent cohorts used a 3+3 design and evaluated doses of 40, 80, 140 and 200 mg QD. Once a recommended Phase II (RP2D) dose is determined, a separate dose expansion part will enroll up to 12 patients at the RP2D. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Efficacy was assessed according to IWG-NHL and CLL consensus response criteria. Results: 22 patients were enrolled as of Jan 14th 2019. The patients including diffuse large B-cell lymphoma (DLBCL), n=2; follicular lymphoma (FL), n=8; follicular lymphoma with diffuse large B-cell lymphoma (FL/DLBCL), n=3; mantle cell lymphoma (MCL), n=3; lymphoplasmacytic lymphoma (LPL), n=1; marginalzone B-cell lymphoma (MZBL), n=1 and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), n=4, received YY-20394 20 mg (n=1), 40 mg (n=3),80 mg (n=11),140 mg/day (n=3) or 200 mg/day (n=4) respectively. All the patients had heavy treatment and had received an average of 3.5 lines of therapy before participating in the current study including BTK inhibitor therapy and CAR-T treatment. All the patient have completed cycle 1 safety observation and no dose-limiting toxicities occurred. The most common nonhematologic TEAEs (all grades/grade≥3) were LDH elevation (36.4%/0%), pneumonia (18.2%/18.2%) and hyperuricemia (13.6%/4.5%). Gr≥3 hematologic TEAEs were neutropenia (13.6%), lymphocythaemia (9.1%), leukocytosis (4.5%) and leukopenia (4.5%). Of 19 patients evaluable for response, the overall objective response rate was 68% ((4CR + 9 PR)/19), with 86% ((3CR + 3PR)/7) in FL. The median duration of response is not available so far, the treatment for 11 subjects was still ongoing. The duration of response in 4 subjects with ongoing treatment has already over 8 months. PK parameters AUC0-24h and Cmax were dose proportional with median Tmax 2 hours. Conclusions: YY-20394 is well tolerated and with promised objective response rates in patients with relapsed or refractory B-cell malignancies. Clinical trial information: NCT03757000.
Effect of epigenetic modifier-based combinations on efficacy in patients with peripheral T-cell lymphoma (PTCL): Deciphering impact of mutations in epigenetic operations on response.
Authors: O'Connor Owen A. , Sokol Lubomir , Shustov Andrei R. , Falchi Lorenzo , Lue Jennifer Kimberly , Montanari Francesca , Amengual Jennifer , Sawas Ahmed , Deng Chanchung , Khan Karen , Jacobs Alice , Rada Aishling , Kim Hye A. , Soderquist Craig R. , Park David , Menezes Daniel 
Published: March 2020

7565 Background: Recurring mutations in epigenetic functions in PTCL, coupled with marked activity of epigenetic drugs, raises a question regarding whether these mutations might portend greater vulnerability to one drug over another. For example, do mutations in genes governing DNA methylation suggest these patients might benefit from a hypomethylating (HMA) agent? Preclinical data from our group suggests marked synergism between histone deacetylase inhibitors (HDACi) and HMA, as well as HDACi and pralatrexate (PDX), irrespective of mutations in epigenetic genes. Phase 1 studies (romidepsin [R] plus PDX or R plus 5-azacytidine [Aza]) are completed, and the Phase 2 studies are near completion. This clinical trial scenario affords a unique opportunity to decipher the impact of a HMA on response as a function of TET2, IDH2, DNMT3 and other mutations in PTCL. Methods: Patients with R/R lymphoma were eligible for the phase 1, whereas the phase 2 only enrolled patients with PTCL, either R/R or treatment-naïve individuals. Exploratory endpoints included next generation sequencing (NGS) and methylation arrays. Results: In toto, 89 patients have been enrolled on both trials across all histology’s, 58 have PTCL. NGS and efficacy data is available for the majority of patients, with some from the PDX + R study in process. The ORR among the PTCL patients for PDX+R and Aza+R has been 71% and 73% respectively. Eight of 9 angioimmunoblastic TCL patients responded. Among those with TET2 mutations, 7 of 8 responded to the Aza based treatment, while only 3 of 6 (50%) who were TET2 negative responded. Similarly, of 3 patients with DNMT3 treated with Aza based therapy, all 3 responded. Remarkably one patient with a TET2 mutation experienced progression to PDX+R, and CR to Aza+R. Among the PTCL patients treated with Aza, the global demethylation score (GDMS) demonstrated marked demethylation among all patients, with no correlation between the score and likelihood of response. Conclusions: We will share the completely annotated analysis correlating clinical metrics to the spectrum of epigenetic mutations and GDMS and across all histology’s and treatments. Clinical trial information: NCT01998035; NCT01947140.
Outcomes of patients with t(11;14) multiple myeloma: An International Myeloma Working Group (IMWG) multicenter study.
Authors: Durie Brian G. , Goldschmidt Hartmut , Mateos Maria-Victoria , Gonzalez Veronica , Du Juan , Kim Kihyun , Merlini Giampaolo , Mangiacavalli Silvia , Min Chang Ki , Dimopoulos Meletios A. , Kastritis Efstathios , Ludwig Heinz , Esteves Graca , Handa Hiroshi , Escalante Fernando , Fernández de Larrea Rodríguez Carlos , Delforge Michel , Cameron Chris , Rajkumar S. Vincent , Kumar Shaji 
Published: March 2020

8015 Background: Multiple myeloma (MM) is a heterogeneous disease with varying survival outcomes depending on the presence of certain genetic abnormalities. Common abnormalities include trisomies, translocations involving chromosome 14, and amplifications or deletions of chromosomes 1, 13, and 17. t(11;14), occurring in approx. 15% of patients (pts) with MM, is considered a standard risk abnormality, but recent data suggest that the prognosis may be inferior to what had been expected. This is of particular relevance as new therapeutic options such as the BCL-2 inhibitor venetoclax has been shown to be effective in t(11;14) pts. Methods: This was a multicenter study designed and conducted by the IMWG, to identify the outcomes of pts with t(11;14) using a retrospective cohort of pts. Pts with MM diagnosed between 2005 and 2015 with t(11;14) identified on FISH performed within six months (mos) of diagnosis, and with treatment details available and if alive, a minimum of 12 mos of follow up, were enrolled. Results: The current analysis includes 848 pts with a median age of 64.4 years; 60.0% are male. The median follow-up from diagnosis for the entire cohort was 45.7 mos; 84.7% of the pts were alive at the last follow up. ISS stage distribution included: Stage 1 (35.3%), Stage II (38.9%) and stage III (25.8%). The distribution of FISH abnormalities included: del 13q (14.5%), 1q amp (12.1%), del 17p or monosomy 17 (6.1%). Pts received initial therapy with different regimens: IMiD-24.3%, PI-41.0%, both-20.8% and 13.8% had no novel agent. The drug classes by line of therapy are shown in table. An early stem cell transplant (SCT) was used in 40.8% of pts. The median time to next treatment (TTNT) after initial treatment was 15.0 (95% CI: 12.2 to 17.7) mos. The median overall survival from diagnosis for the entire cohort was 82.5 (95% CI: 73.5 to 95.8) mos. Conclusions: This is the first study to examine the outcomes of a large group of myeloma pts with t(11;14) abnormality. Pts receiving a combination if a PI and an IMiD appear to have the best survival outcomes and thse receiving an early SCT appear to have excellent survival with median OS approaching 10 years. Additional pts are being accrued to this study and additional analysis examining the variables affecting response duration and survival will be presented. [Table: see text]
Ixazomib, lenalidomide, and dexamethasone for patients with POEMS syndrome.
Authors: Dispenzieri Angela , Lacy Martha , Mauermann Michelle , LaPlant Betsy , Go Ronald S. , Kapoor Prashant , Leung Nelson , Hwa Yi Lisa , Fonder Amy , Buadi Francis , Hayman Suzanne R. , Lust John Anthony , Dingli David , Gonsalves Wilson I. , Kourelis Taxiarchis , Warsame Rahma M. , Rajkumar S. Vincent , Kumar Shaji , Gertz Morie A. 
Published: March 2020

8019 Background: POEMS syndrome is a rare paraneoplastic syndrome caused by an underlying plasma cell disorder. Most of the information regarding treatment has been gleaned from retrospective data. The combination of a proteasome inhibitor, an IMiD and corticosteroid is known to be highly effective among patients with myeloma. Methods: We designed a pilot using a 28-day oral regimen of ixazomib (4 mg days 1, 8, 15), lenalidomide (25 mg days 1-21), and dexamethasone (20 mg days 1, 8, 15, 22). Aspirin and acyclovir were used for prophylaxis. Eligibility included a diagnosis of POEMS syndrome, a plasma VEGF > 200 pg/ml, a PS < 3. There were two groups [gp] (intended enrollment 15 per gp): Gp A, 13 cycles for patients (pts) who had relapsed or refractory disease; Gp B, 3 cycles for pts destined for high-dose chemotherapy with stem cell transplant. Primary endpoint was VEGF complete response (CR = normalization) after 3 cycles. Secondary endpoints included safety, hematologic response, and overall survival at 3 and 12 months. Other domains including PET response, clinical responses including neurologic response were also studied. To date, 13 pts enrolled since 10/31/2016—4 to Gp A and 9 to Gp B. 11 pts were analyzed (2 dropped out before receiving any therapy). Data were frozen as of 1/21/2019. Results: Median age was 55; 73% were male. So far, overall 64% met primary endpoint of VEGF CR (Table). The median follow-up of survivors is 12.4 mo (6, 24). 1 pt came off study for non-responsive disease and died thereafter. 38% of patients had grade 3+hematologic AE; 72% had grade 3-4 non-hematologic AE. These included: rash, respiratory infection and hypotension in 2 each; atrial fibrillation, diarrhea, edema, dyspnea, and thromboembolism in 1 each. 4 pts had non-objective worsening of their neuropathy. Conclusions: These preliminary results suggest that Ixa-Len-Dex is an effective and tolerable regimen for patients with POEMS syndrome. Clinical trial information: NCT02921893. [Table: see text]
Pharmacokinetics, pharmacodynamics, safety, and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.
Authors: Elassaiss-Schaap Jeroen , van Zandvoort Peter , Lo Jeannette , Nair Nitya , Walling Jackie , Hari Parameswaran , Bensinger William 
Published: March 2020

8022 Background: APRIL (“a proliferation-inducing ligand”) levels are elevated in the serum of patients diagnosed with multiple myeloma (MM) and is correlated to promotion of malignancy, chemo- and immune-resistance. BION-1301 (BION) is a recombinant, humanized monoclonal antibody against APRIL. We report on the initial pharmacokinetic/ pharmacodynamic (PK-PD) profile, safety, and tolerability of BION in adults with relapsed or refractory MM. Methods: Adults with MM and disease progression after ≥3 systemic therapies were recruited for the study. BION was administered every 14 days through intravenous infusion. This ongoing Phase 1/2, open-label, multicenter study is evaluating 6 cohorts with increasing BION dose levels of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Serum was analyzed for BION, anti-drug antibodies (ADA), and free APRIL (fAPRIL) at baseline and upon treatment, and evaluated by PK-PD modeling. Results: As of 7Dec2018 reporting through the first 4 cohorts, 15 patients were enrolled in the study (N = 3-4 per cohort). BION has been well-tolerated to date. While exposure increased dose-proportionally from 50 to 1350 mg, half-life and clearance did not significantly differ between 50 and 1350 mg. APRIL serum levels decreased with increasing BION doses. To date no DLT was observed. Non-neutralizing ADA were detected in 1 of the 15 patients. BION transiently reduced fAPRIL levels starting at a dose of 50 mg. A prolonged reduction was seen at higher doses, and at 450 mg, reduction was maintained in 2 patients on treatment for 6 cycles (5.5 months). The area under the normalized fAPRIL curve (Days 1-15) decreased 5-fold from 50 to 1350 mg. Data fit well in an exploratory PK-PD model, with kinetic binding of BION and fAPRIL according to in vitro parameters, and peripheral compartments for both entities. While at 450 mg, 95% target engagement (TG) was achieved around peak exposure levels, at 1350 mg this 95% TG was maintained throughout the dosing interval of 3 doses. Conclusions: BION dose-dependently inhibits serum levels of fAPRIL between 50 to 1350 mg dose levels. Exposure was approximately dose-linear over the dose range evaluated, with a low incidence of ADA. Promising TG was obtained at prolonged dosing of 450 mg Q2W. A favorable safety profile supports continued dose escalation and more frequent dosing regimens based on PK-PD modeling. The study is ongoing with subjects exposed to higher and/or more frequent doses anticipated to result in accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.
Effect of iFISH defined 1q21 amplification/gain in multiple myeloma patients treated on total therapy protocols.
Authors: Zangari Maurizio , Mohan Meera , Weinhold Niels , Rasche Leo , Sawyer Jeffrey , Van Rhee Frits , Thanendrarajan Sharmilan , Schinke Carolina D. , Davies Faith , Tian Erming 
Published: March 2020

8023 Background: The amplification of the proximal 1q21 region has been reported by interphase FISH (iFISH) in about 40% of newly diagnosed patients, and in 70% of MM patients at relapse. We hereby report the prognostic value of 1q21 amplification/gain by iFISH at enrollment in subjects treated on total therapy (TT) 4, 5 and 6 protocols. Methods: TT4 protocol enrolled newly diagnosed patients with LR disease as defined GEP 70 model ≤ 0.66. TT5 was designed for newly diagnosed patients with HR MM.TT6 enrolled previously treated patients with both HR and LR disease. iFISH was performed on bone marrow samples obtained at the time of study enrollment. FISH probes were generated from specific BAC DNA clone for CKS1B gene locus (1q21) gene locus. MM cells were identified post hybridization using isotype specific antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) to stain Ig-Kappa or Ig-Lambda light chain in cytoplasm (cIg) of MM cells. The iFISH signals in 100 of MM cells were recorded. A 20% cutoff point was used for detection of significant abnormalities i.e. gain of 1q21 (≥ 3 copies). Results: 607 patients were included in this analysis. With a median age of 61 years, 39% had high risk and 88% low risk disease. 1q21 abnormalities were present in 55% of patients at enrollment. 591 patients (97%) received at least one HDT ASCT. The analysis included 382 TT4 patients with a median PFS of 7.2 years and OS not yet reached. 75 patients enrolled on TT5 protocol experienced median PFS of 2.2 years and median OS of 5.6 years.150 TT6 enrolled patients experienced median PFS of 4.1 years and median OS of 7.5 years. Statistically significant difference in PFS (p < 0.0001) and OS (p < 0.0001) was observed between 1q21 defined groups (figure 1). No differences in survival were observed based on the 1q21 copy number > 3. Conclusions: This retrospective analysis clearly showed that 1q21 amplification/gain detected by interphase iFISH in different stages of disease can identify patients with significant shorter progressive free and overall survival even if exposed to total therapy regimens. Clinical trial information: NCT00734877, NCT00869232.
Correlation of minimal residual disease negativity (MRD-) with prognosis in high-risk myeloma (HRM).
Authors: Kunacheewa Chutima , Patel Krina K. , Lee Hans Chulhee , Thomas Sheeba K. , Amini Behrang , Srour Samer , Bashir Qaiser , Qazilbash Muzaffar H. , Weber Donna M. , Neelapu Sattva Swarup , Orlowski Robert Z. , Feng Lei , Lin Pei , Manasanch Elisabet Esteve 
Published: March 2020

8024 Background: MRD is a standard measurement for response assessment in MM. Despite new treatments, HRM patients continue to have poor prognosis. We evaluated the impact of MRD- in high vs standard (SRM) risk patients. Methods: We retrospectively evaluated all consecutive MM/plasma cell leukemia patients who had routine MRD testing by 1-tube 8-color advanced flow cytometry with 2,000,000 events and sensitivity level 10-5 at our center from 2015-2018 after initial therapy. Kaplan-Meier and log-rank test were used to assess survival estimates and differences between study groups. Results: 136 patients with MRD testing after initial therapy/autologous transplant (ASCT) were identified. Patient and disease characteristics are included in Table. At a median follow-up of 14 months (1-36), PFS and OS were significantly worse in HRM vs SRM. During the study period, 50% of HRM had progressed (relapse and/or death) vs 20% in SRM (p=0.0006). No patients with SRM died, but 4 (14%) in the HRM group did (p=0.0007). Regardless of MRD status, HRM patients had statistically significant worse PFS than SRM; at median f/u 10% SRM MRD-; 20% SRM MRD+; 40%HRM MRD-; 45% HRM MRD+ had either relapsed or died (p=0.0041). MRD status did not impact OS in either group (p=0.0914), however longer follow up is needed to assess survival. Conclusions: Genetic abnormalities (FISH/GEP) remain a powerful prognostic indicator for myeloma regardless of MRD status. For newly diagnosed myeloma patients treated with novel triple initial therapy and frontline ASCT, achieving MRD negative status didn’t mitigate the poor prognosis outcomes of HRM. [Table: see text]