bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I trial using CD19 CAR-T expressing PD-1/CD28 chimeric switch-receptor for refractory or relapsed B-cell lymphoma.
Authors: Liu Hui , Lei Wen , Zhang Chaoting , Yang Chunmei , Wei Juying , Guo Qunyi , Guo Xiaojun , Chen Zhilu , Lu Ying , Lu Zheming , Qian Wenbin 
Published: March 2020

7557 Background: The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has established efficacy in the treatment of refractory or relapsed (R/R) B-cell lymphoma. However, the existence of different immunosuppressive pathways such PD-1/PD-L1 pathway can restrict the full potential of CAR-T therapy. A recent study demonstrates that a novel PD-1/CD28 chimeric switch-receptor, comprising the extracellular domain of PD-1 and the transmembrane and cytoplasmic signaling domains of CD28, can be used a modality for augmenting antitumor activity of mesothelin- and prostate specific cancer antigen-specific CAR-T cells in either pleural mesothelioma or prostate cancer xenograft model. Here, we describe the first human trial of CD19-PD-1/CD28-CAR-T cells (a CD19-specific CAR-T expressing PD-1/CD28 chimeric switch-receptor) to evaluate safety and efficacy. Methods: This phase I, single-arm, open-label, multicenter trial enrolled patients (18-75 years) with R/R large B-cell lymphoma. PD-L1 expression was confirmed by immunohistochemistry using an anti-PD-L1 mAb (SP142), and confirmed by the review committee with a central evaluation. Seventeen patients received conditioning chemotherapy (cyclophosphamide [500 mg/m2] and fludarabine [30 mg/m2] on days -5, -4 and -3) and followed by CD19-PD-1/CD28-CART cells infusion at doses ranging 0.5 to 4 × 106 CAR+ T cells/kg on day 0. Response was assessed by F-FDG PET/CT at month 3 after CAR-T infusion, according to the International Working Group Response Criteria for Malignant Lymphoma, and duration of response was evaluated by ultrasonic and computed tomography every three months from month 3 to month 12. Results: At data cutoff, 17 patients had received CD19-PD-1/CD28-CART cells. Overall PD-L1 positivity was 15/17 (88.2%) and the mean percentage of PD-L1 positivity was 19.7% (range, 5-50%). Fourteen patients (82.35%) developed cytokine release syndrome (grade ≤ 2) and four (23.53%) developed neurotoxicity (grade = 1), which was reversible in all. The overall response rate was 58.8% (10/17) and complete remission rate was 41.2% (7/17). At a median follow-up 5 months, median overall survival for all patients was not reached. Conclusions: This trial showed the feasibility, controllable toxicities, and effective activity of CD19-PD-1/CD28-CART cells for treating patients with R/R B-cell lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the PD-1/PD-L1 pathway in lymphoma in the clinical setting. Clinical trial information: NCT03258047.
Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma.
Authors: Lin John , Muffly Lori S. , Spinner Michael Alexander , Barnes James I , Owens Douglas K. , Goldhaber-Fiebert Jeremy D 
Published: March 2020

7561 Background: Two anti-CD19 chimeric antigen receptor T-cell therapies are approved for large B-cell lymphoma (DLBCL): axicabtagene ciloleucel (axi-cel) and tisagenlecleucel. Each costs $373,000 (wholesale acquisition). We evaluated each therapy’s cost-effectiveness. Methods: A decision analytic Markov model evaluated axi-cel and tisagenlecleucel in multiply relapsed/refractory adult DLBCL from a US health-payer perspective over a lifetime horizon. The model was informed by recent multi-center, single-arm clinical trials. Under a range of plausible long-term effectiveness assumptions, axi-cel and tisagenlecleucel were each compared with salvage chemoimmunotherapy regimens and stem-cell transplantation. Main outcomes were un-discounted life-years, discounted lifetime costs, discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (3% discount rate). Sensitivity analyses explored uncertainty. Results: In an optimistic scenario, assuming 40% five-year progression-free survival (PFS), axi-cel increased life-expectancy by 8.15 years at $129,000/QALY (95% UI: $90,000-215,000/QALY) gained. At 30% five-year PFS, improvements in life-expectancy were more modest (6.4 years) and expensive ($159,000/QALY [$107,000-281,000/QALY] gained). In an optimistic scenario, assuming 35% five-year PFS, tisagenlecleucel increased life-expectancy by 4.6 years at $168,000/QALY ($104,000-453,000/QALY) gained. At 25% five-year PFS, improvements in life-expectancies were more modest (3.4 years) and expensive ($224,000/QALY [$124,000-1,190,000/QALY] gained). Administering CAR-T to all indicated patients would increase US healthcare costs by $10 billion over 5 years. Price reductions to $250,000 or payment only for initial CR or 90-day CR/PR (at current prices) would allow both therapies to cost < $150,000/QALY down to 25% PFS. Conclusions: At current prices, it is possible that each CAR-T therapy may meet a < $150,000/QALY threshold; this is dependent on long-term benefit compared with chemoimmunotherapy and SCT, which is uncertain. Widespread adoption would increase non-Hodgkin lymphoma healthcare costs substantially. Price reductions or payment for initial CR or 90-day CR/PR would favorably influence cost-effectiveness even if long-term outcomes are modest.
Updated risk stratification model for smoldering multiple myeloma (SMM) incorporating the revised IMWG diagnostic criteria.
Authors: San Miguel Jesus , Mateos Maria-Victoria , Gonzalez Veronica , Dimopoulos Meletios A. , Kastritis Efstathios , Hajek Roman , Fernández de Larrea Rodríguez Carlos , Morgan Gareth John , Merlini Giampaolo , Mangiacavalli Silvia , Goldschmidt Hartmut , Cavo Michele , Kyriakou Charalampia , Qi Ming , Ukropec Jon , Weiss Brendan M. , Cameron Chris , Rajkumar S. Vincent , Durie Brian G. , Kumar Shaji 
Published: March 2020

8000 Background: The diagnostic criteria for MM were revised in 2014, recategorizing ultra-high risk (i.e., 80% at two years) as active myeloma requiring therapy. The removal of patients at the highest risk of progression from the smoldering group requires reassessment of current risk stratification models. Methods: We designed a multicenter, retrospective study of SMM patients to develop a risk stratification model. Patients diagnosed with SMM on/after January 1, 2004 were included if they had no disease progression within 6 months, had baseline data from diagnosis (+/- 3 months), had a follow up of ≥1 year, and did not participate in a therapeutic trial of SMM. Various clinical and laboratory factors were explored to identify factors that predicted progression at 2 years. Univariate Cox regressions were run for each factor. For factors with p-values ≤ 0.25, optimal cut points were identified using Youden’s index. Binary factors were used in stepwise regression to fit multivariable Cox model and significant risk factors were determined (F-test). Results: Overall, 2004 patients were included (ages 26-93, 51% female). Factors independently associated with progression (optimal cutoffs) included: Serum M protein (2 g/dL), involved to uninvolved serum-free light chain ratio (20), and marrow plasma cell % (20%). Patients were stratified using the risk factors: Low- (0 factors), Intermediate- (1), and High-Risk (≥2). Previously used high risk markers such as Bence Jones proteinuria (≥500 mg/24 hours) and severe immunoparesis (50% decrease in uninvolved immunoglobulin levels) were both significant in univariate analysis, but were eliminated on step wise selection. Compared to the low risk group, intermediate- and high-risk groups had significantly higher rate of progression (Table). Within the high-risk group, having all 3 risk factors (n=61) versus 2 did not add to the model, with insufficient separation between 2 and 3 factors. Conclusions: We have developed a risk stratification model for SMM that incorporates revised cutoffs for previously used parameters (20/2/20) that can be universally applied. Additonal analysis are being conducted to develop models that utilize common cytogenetic abnormalities, as well as those without FLC given lack of availability of all tests across the world. [Table: see text]
Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: Results from the FORTE trial.
Authors: Gay Francesca , Cerrato Chiara , Petrucci Maria Teresa , Zambello Renato , Gamberi Barbara , Ballanti Stelvio , Omedè Paola , Palmieri Salvatore , Troia Rossella , Spada Stefano , Gozzetti Alessandro , Caravita Tommaso , Spadano Antonio , Palumbo Antonio , Montefusco Vittorio , Musto Pellegrino , Cavo Michele , Boccadoro Mario 
Published: March 2020

8002 Background: High and comparable rates of MRD negativity were seen in NDMM pts after 4 28-day induction cycles with KRd followed by ASCT and 4 KRd consolidation (KRd_ASCT_KRd) and after 12 KRd cycles (KRd12), showing the superiority of both regimens over KCd induction-ASCT-KCd consolidation (KCd-ASCT-KCd) (Gay F ASH 2018). Here we evaluated the benefit of KRd_ASCT_KRd vs KRd12 in specific subgroups of pts. Methods: 474 NDMM pts ≤65 years were randomized to KRd_ASCT_KRd or KRd12 or KCd_ASCT_KCd. We compared rate of ≥VGPR, ≥CR, sCR, MRD negativity (centralized, second generation flow cytometry, sensitivity 10-5) after consolidation with KRd_ASCT_KRd vs KRd12 in patients with R-ISS 1 and R-ISS 2/3. Since high-risk pts may sometimes respond rapidly, but then relapse early, we also analyzed the rate of early relapse (<18 months from randomization). We performed a multivariate logistic regression analysis to evaluate factors predictive of early relapse. Results: Median follow-up was 25 months. Rates of ≥VGPR, ≥CR, sCR, MRD negativity were comparable between KRd_ASCT_KRd and KRd12 overall, in pts with R-ISS Stage 1 and with R-ISS Stage 2/3 (Table). A significantly lower number of pts experienced early relapse with KRd_ASCT_KRd vs KRd12 (12 pts [8%] vs 26 pts [17%]; P=0.015). This difference was mainly related to a significantly lower rate of early relapse in R-ISS Stage 2/3 pts receiving KRd_ASCT_KRd vs KRd12 (11 pts [12%] vs 22 pts [23%]; P=0.05); no difference was seen in R-ISS 1 (0 vs 2 pts). In multivariate regression analysis, KRd_ASCT_KRd vs KRd12 reduced the risk of early progression (OR 0.42; P=0.021); R-ISS Stage 2 (OR 3.6; P=0.001) and R-ISS Stage 3 (OR 4.85; P=0.003) increased the risk compared with R-ISS 1. Conclusions: KRd-ASCT-KRd and KRd12 were equally effective in inducing high-quality responses, with about 50% of high-risk pts achieving MRD negativity. In high-risk pts ASCT reduced the risk of early relapse. Clinical trial information: NCT02203643. [Table: see text]
First clinical (phase 1b/2a) study of iberdomide (CC-220; IBER), a CELMoD, in combination with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Authors: Lonial Sagar , van de Donk Niels W.C.J. , Popat Rakesh , Zonder Jeffrey A. , Minnema Monique C. , Larsen Jeremy , Nguyen Tuong Vi , Chen Min S. , Bensmaine Amine , Cota Mariana , Sonneveld Pieter 
Published: March 2020

8006 Background: IBER is a novel cereblon E3 ligase modulator (CELMoD) with enhanced tumoricidal and immunostimulatory activities. Preclinically, IBER overcomes immunomodulatory drug (IMiD) resistance and has synergy with daratumumab (DARA), bortezomib (BORT), and DEX. Methods: A phase 1b/2a multicenter, open-label, dose-escalation study evaluated the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and preliminary efficacy of IBER. Eligible pts had RRMM and must have received ≥ 2 prior regimens including lenalidomide (LEN) and/or pomalidomide (POM), and a proteasome inhibitor (PI). All pts had progressed on or within 60 days of last MM therapy. Escalating doses of IBER were given on days 1–21, in combination with DEX 40 mg (20 mg in pts age > 75 years) on days 1, 8, 15, and 22, of each 28-day cycle. Dose escalation was reviewed by a dose escalation committee. Results: As of Jan 2019,58 pts received IBER + DEX. Median age was 64.5 years (range 33–79), and median number of prior regimens was 5 (2–12). Prior therapies included autologous stem cell transplant (79%), LEN (100%), POM (69%), PIs (100%), and DARA (66%). IBER dose ranged from 0.3 to 1.2 mg; MTD/RP2D was not reached. Median duration of therapy was 12+ weeks (range 4–109). Grade 3–4 adverse events (AEs) were reported in 41 (72%) pts and were not related to dose. Grade 3–4 neutropenia, thrombocytopenia, neuropathy, and fatigue occurred in 26%, 11%, 2%, and 0% pts, respectively. Three pts discontinued treatment due to AEs. Clinical activity occurred early and was observed across all dose levels (Table); 20 of 51 pts remain on treatment (2–27+ cycles). Conclusions: IBER + DEX showed favorable efficacy and safety in heavily pretreated pts with RRMM who failed multiple prior therapies. This study is ongoing, including combinations of IBER with DARA or BORT. Clinical trial information: NCT02773030. [Table: see text]
Safety and tolerability of BION-1301 in adults with relapsed or refractory multiple myeloma.
Authors: Bensinger William , Raptis Anastasios , Berenson James R. , Spira Alexander I. , Nooka Ajay K. , Chaudhry Maria , van Zandvoort Peter , Nair Nitya , Lo Jeannette , Elassaiss-Schaap Jeroen , Walling Jackie , Hari Parameswaran 
Published: March 2020

8012 Background: BION-1301 (BION) is first in class humanized monoclonal antibody directed against a proliferation-inducing ligand (APRIL) for treatment of relapsed/refractory (R/R) multiple myeloma (MM). APRIL secreted by cells in the bone marrow (BM) niche binds to BCMA (B-Cell maturation antigen) and TACI (transmembrane activator and CAML interactor) expressed on human MM cells to drive their proliferation and survival. In patients (pts) with MM, serum APRIL levels are elevated and are correlated with promotion of malignancy, chemo- and immune-resistance. This study evaluated tolerability and clinical activity of BION monotherapy in R/R MM pts. Methods: Adults with MM, progression after ≥3 systemic therapies, and ECOG 0-1 were enrolled in this phase 1/2, open-label study. The phase 1 study is evaluating 6 cohorts with increasing BION doses of 50, 150, 450, 1350, and 2700 mg administered Q2W intravenously (cohort 6 - 1350 mg dose given QW and Q2W). Response was assessed by investigators Q4W. Serum was analyzed for BION, anti-drug antibodies (ADA), and soluble unbound “free APRIL” (fAPRIL) and evaluated by PK-PD modeling. Results: As of 7Dec2018, 15 pts were enrolled in 4 cohorts at doses between 50-1350 mg given Q2W. 5/15 (33%) had ECOG 0 and pts received median of 6 prior systemic therapies (range: 4-17). Related treatment emergent adverse events (TEAE) were reported in 8/15 (36%); most common related TEAE included anemia (n=3), arthralgia (n=2), and dysgeusia (n=2). 1 subject receiving 4th dose of BION experienced grade 3 wheezing considered infusion-related and serious. No dose-limiting toxicities were observed. Of 14/15 evaluable for response, no objective response was observed and 5/14 (36%) had stable disease. Median time on treatment was 2 months (range: 0.9-4.9+) and median of 3 doses of BION (range: 2-11) were administered. BION exposure increased dose proportionally from 50-1350 mg, and half-life (T1/2) and clearance (CL) did not differ significantly (median T1/2 = 9.0 days [range: 3.9-20], median CL = 0.52 L/day [range: 0.32-0.72]). Levels of fAPRIL in serum and BM decreased with increasing BION doses. By 450 mg, 95% target engagement (TG) was achieved around peak exposure levels. Non-neutralizing ADA was detected in 1/15 pts. Conclusions: BION, at doses 50-1350 mg given Q2W, was well-tolerated and dose-dependently reduces serum levels of fAPRIL. To date, objective responses have not been observed. The study is ongoing with pts exposed to higher and/or more frequent doses with the objective of achieving accelerated and sustained APRIL TG. Clinical trial information: NCT03340883.
Multimorbidity patterns and their association with survival in a large national cohort of older veterans with multiple myeloma.
Authors: Fillmore Nathanael , DuMontier Clark , Cheng David , Cirstea Diana , Yellapragada Sarvari , Pyarajan Saiju , Do Nhan , Kim Dae , Abel Gregory A. , Brophy Mary T. , Driver Jane A. , Munshi Nikhil C. 
Published: March 2020

8033 Background: The majority of older adults carry two or more chronic conditions (multimorbidity). Although comorbidity in multiple myeloma (MM) has often been described with comorbidity counts, the impact of multimorbidity clusters has yet to be investigated. Methods: In a national cohort of 7815 patients aged ≥60 years diagnosed with and treated for MM in Veterans Affairs Healthcare System, we extracted 53 chronic conditions from claims in the 3 years preceding diagnosis using the Centers of Medicare and Medicaid Services-defined chronic and disabling conditions. We performed latent class analysis to identify patterns of multimorbidity that coexisted with MM at diagnosis. We then assessed whether these multimorbidity patterns were associated with survival in 5992 non-transplanted patients initially treated with either doublet or triplet chemotherapy regimens, adjusting for MM stage, sociodemographic factors, and prognostic lab values. Results: Mean follow up time was 3.1 years (SD, 2.6). We identified 6 multimorbidity clusters at the time of MM diagnosis: minimal disease (1302 patients, 16.7%), cardiovascular disease (2011, 25.7%), diabetes and complications (1820, 23.3%), psychiatric and substance use disorders (931, 11.9%), chronic lung disease (759, 9.7%), and multisystem impairment (992, 12.7%). In patients initially treated with doublet or triplet chemotherapy, survival varied across multimorbidity patterns (p < 0.001); patients with minimal disease had the best survival (median survival [MS] = 4.5 years, 5-year survival = 47.5%), and patients with multisystem impairment had the worst (MS = 2.4 years, 5-year survival = 24.3%). After adjustment for covariates, patients with clusters of chronic lung disease (HR = 1.40 [1.22-1.60]), psychiatric and substance use (HR = 1.57 [1.37-1.79]), and multisystem impairment (HR = 1.71 [1.50-1.94]) had higher hazards of death than patients with minimal disease. Conclusions: We found higher-impact and lower-impact multimorbidity clusters among older veterans with newly-diagnosed MM treated with chemotherapy. Unique combinations of chronic diseases may interact with MM itself to drive differences in mortality.
Impact of age on efficacy and safety of daratumumab in combination with lenalidomide and dexamethasone (D-Rd) in patients (pts) with transplant-ineligible newly diagnosed multiple myeloma (NDMM): MAIA.
Authors: Usmani Saad Zafar , Facon Thierry , Kumar Shaji , Plesner Torben , Moreau Philippe , Basu Supratik , Nahi Hareth , Macro Margaret , Quach Hang , Perrot Aurore , Venner Chris , Weisel Katja , Raje Noopur S. , Attal Michel , Leleu Xavier , Krevvata Maria , Wang Jianping , Kobos Rachel , Hulin Cyrille 
Published: March 2020

8035 Background: D-Rd significantly reduced the risk of progression/death by 44% in transplant-ineligible NDMM pts vs Rd in the phase 3 MAIA study. To examine the impact of age on efficacy/safety of D-Rd vs Rd in this population, a subgroup analysis was conducted in pts <75 and ≥75 y of age. Methods: Transplant-ineligible NDMM pts were randomized 1:1 to Rd ± DARA; stratification was based on age (<75 vs ≥75 y), ISS (I, II, III), and region (North America vs Other). Pts received 28-day cycles of either R 25 or 10 mg (based on renal function) PO QD on Days 1-21 and either d 40 or 20 mg (based on age or BMI) PO/IV weekly until progression. In the D-Rd arm, pts received daratumumab 16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W thereafter until progression. PFS is the primary endpoint. Results: Among 737 randomized pts (D-Rd, n=368; Rd, n=369), 321 (44%) were ≥75 y of age. For D-Rd vs Rd, relative median dose intensity for R was 79% vs 93% for <75 y subgroup and 66% vs 89% for ≥75 y subgroup, respectively. After median follow-up of 28 mo, significant PFS benefit of D-Rd vs Rd was maintained in both <75 and ≥75 y subgroups (Table). Deeper responses and MRD-negative rate (10-5 threshold) remained higher with D-Rd vs Rd in both subgroups (Table). Most common (≥10%; D-Rd/Rd) grade 3/4 TEAEs in ≥75 y pts were neutropenia (60%/41%), lymphopenia (19%/12%), anemia (16%/22%), pneumonia (15%/10%), leukopenia (12%/6%), and thrombocytopenia (8%/11%). Fewer pts receiving D-Rd vs Rd discontinued treatment due to TEAEs (<75 y: 5% vs 12%; ≥75 y: 10% vs 21%). Conclusions: D-Rd pts received less R vs Rd group regardless of age. Efficacy of D-Rd in <75 and ≥75 y pts was consistent with the ITT population, and D-Rd demonstrated acceptable tolerability regardless of age. Together with the phase 3 ALCYONE study, these studies confirm clinical benefit of daratumumab plus standard-of-care in transplant-ineligible NDMM pts ≥75 y of age. Clinical trial information: NCT02252172. [Table: see text]
Analysis of time to next treatment (TTNT) in melflufen and dexamethasone-treated patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Authors: Bringhen Sara , Richardson Paul G. , Voorhees Peter Michael , Plesner Torben , Mellqvist Ulf-Henrik , Zonder Jeffrey A. , Reeves Brandi Nikcole , Zavisic Stojan , Harmenberg Johan , Obermüller Jakob , Sonneveld Pieter 
Published: March 2020

8043 Background: Melflufen is a novel peptide-conjugated alkylator potentiated by intracellular aminopeptidases, which are markedly overexpressed in MM. Melflufen + dex had encouraging activity in pts with RRMM and ≥2 prior lines of therapy in the phase 1/2 O-12-M1 study (overall response rate 31%; median overall survival of 20.7 mo; Richardson et al. ASH 2017. Abs. 3150). TTNT is used in Real World Evidence (RWE) to assist treatment decisions and support economic reimbursement modeling. We report TTNT after melflufen + dex in O-12-M1. Methods: Pts with RRMM and ≥2 prior lines of therapy, including bortezomib and lenalidomide (len) received 40 mg IV melflufen on d 1 of each 28-d cycle + 40 mg weekly dex until progressive disease (PD)/unacceptable toxicity. Pts were followed up for 2 y after PD, and TTNT was retrospectively reviewed for subsequent therapy. Results: As of 9 Nov 2017, 45 pts were treated: median age, 66 y (47-78); ISS stage II/III, 60%; high-risk cytogenetics, 44%. Pts had 4 median prior lines of therapy; 87% were refractory to last line of therapy including alkylators (24%), proteasome inhibitors (PIs; 27%), IMiDs (56%), and monoclonal antibodies (mAbs, 9%); 11% were last-line double refractory. At data cutoff, 44 pts (98%) discontinued melflufen + dex, mainly due to adverse events (40%) and PD (29%). 26 pts received subsequent therapy. Median time from start of melflufen + dex to first subsequent therapy or death, whichever occurred first, (TTNT) was 7.9 mo (95% CI: 5.7-11.0); next therapy included alkylators (27%), PIs (38%), IMiDs (58%), and mAbs (8%). Conclusions: Types of subsequent salvage therapy used after melflufen + dex were similar to studies of approved agents in RRMM; TTNT was also similar (Table). Further trials are ongoing, including melflufen + dex vs pomalidomide (pom) + dex in pts with RRMM refractory to len (Phase 3 OCEAN study; NCT03151811). Clinical trial information: NCT01897714. [Table: see text]