bluuebunny/crossref_metadata_2025 huggingface dataset:
Interim analysis of ZUMA-5: A phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL).
Authors: Jacobson Caron A. , Chavez Julio C. , Sehgal Alison R. , William Basem M. , Munoz Javier , Salles Gilles A. , Casulo Carla , Munshi Pashna N. , Maloney David G. , De Vos Sven , Reshef Ran , Leslie Lori A. , Yakoub-Agha Ibrahim , Oluwole Olalekan O. , Fung Henry C. , Plaks Vicki , Yang Yin , Lee Jennifer , Avanzi Mauro P. , Neelapu Sattva Swarup
Published: May 2020

8008

Background: Advanced stage iNHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), is considered incurable as most pts experience multiple relapses (Wang, et al. Ther Adv Hematol. 2017), highlighting a need for novel therapies. Here, we present interim results from ZUMA-5, a Phase 2, multicenter study of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in pts with R/R iNHL. Methods: Adults with R/R FL (Grades 1-3a) or MZL (nodal or extranodal) after ≥ 2 lines of therapy (including an anti-CD20 monoclonal antibody [mAb] with an alkylating agent), and an ECOG of 0 – 1 were eligible. Pts were leukapheresed and received conditioning chemotherapy followed by axi-cel infusion at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and blood levels of cytokines and CAR T cells. Results: As of 8/20/19, 94 pts (80 FL; 14 MZL) received axi-cel with a median follow-up of 11.5 mo (range, 4.2 – 24.9). Median age was 63 y (range, 34 – 79), 47% of pts were male, 52% had stage IV disease, 51% had ≥ 3 FLIPI, and 59% had high tumor bulk (GELF). Pts had a median 3 prior lines of therapy, 66% progressed < 2 y after initial anti-CD20 mAb-containing therapy (POD24), and 73% were refractory to the last prior treatment. Of 87 pts evaluable for efficacy, ORR was 94% (79% complete response [CR] rate). Pts with FL (n = 80) had an ORR of 95% (80% CR rate). Pts with MZL (n = 7) had an ORR of 86% (71% CR rate). Overall, 68% of pts had ongoing responses as of the data cutoff. Updated data, including DOR, PFS, and OS with longer follow-up, will be included in the presentation. Of 94 pts evaluable for safety, 83% experienced Grade ≥ 3 adverse events (AEs), most commonly neutropenia (33%) and anemia (28%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al, Blood 2014) and neurologic events (NEs; per CTCAE v4.03) occurred in 11% and 19% of pts, respectively. Median times to onset of CRS and NEs were 4 and 7 d, with median durations of 6 and 14.5 d. There were 2 Grade 5 AEs: multisystem organ failure in the context of CRS (related to axi-cel) and aortic dissection (unrelated to axi-cel). Median peak and AUC0-28 CAR T cell levels were 44 cells/µL and 490 cells/µL × d, respectively. Conclusions: Axi-cel demonstrated significant and durable clinical benefit, with high rates of ORR and CR, and a manageable safety profile in pts with R/R iNHL. Clinical trial information: NCT03105336 .
Effect of adding ublituximab to ibrutinib on PFS, ORR, and MRD negativity in previously treated high-risk chronic lymphocytic leukemia: Final results of the GENUINE phase III study.
Authors: Sharman Jeff P. , Brander Danielle M. , Mato Anthony R. , Ghosh Nilanjan , Schuster Stephen J. , Kambhampati Suman , Burke John M. , Lansigan Frederick , Schreeder Marshall T. , Lunin Scott D , Zweibach Alexander , Shtivelband Mikhail , Travis Patrick M. , Chandler Jason Claud , Kolibaba Kathryn S. , Sportelli Peter , Miskin Hari P. , Weiss Michael S. , Flinn Ian
Published: May 2020

8022

Background: The BTK inhibitor ibrutinib (IB) has advanced the treatment for patients (pts) with CLL, however, among pts with high-risk CLL, disease control with IB is less durable. Ublituximab (UTX) is a glycoengineered mAb with enhanced ADCC. The GENUINE study evaluated the addition of UTX to IB vs. IB alone in high-risk rel/ref CLL. With a median follow up now 3.5+ yrs, we present the final results. Methods: Eligible pts having rel/ref CLL with centrally confirmed del17p, del11q, and/or a TP53 mutation, were randomized 1:1 to IB (420 mg QD) alone or with UTX (900 mg on D1, 8, 15 of Cy 1, D1 of Cy 2-6, and Q3 Cy thereafter). No limit on # of prior Tx; prior IB excluded. Primary endpoint was overall response rate (ORR) by iwCLL 2008 (excludes PR-L); secondary endpoints were CR rate, peripheral blood MRD negativity (analyzed centrally), PFS, and safety. Response was by blinded independent review. Results: 117 pts were treated (59 in UTX + IB arm; 58 in IB arm). Med age was 66 yrs and med # of prior Tx was 1 (range 1-5) for each arm. Baseline features were relatively balanced including ECOG, gender, and med time since diagnosis (6+ yrs). 17p del was greater in the IB arm (50% vs 44%); bulky disease was greater in UTX + IB arm (47% vs 28%); IGHV-unmut was 83% for both arms. At data-cutoff of Sep 1, 2019, AEs were comparable between the arms, except infusion reactions (UTX + IB: All G 53% / G 3/4 3%) and neutropenia (All G 36% vs 21%, G 3/4 19% vs. 12%) which were higher for UTX + IB. At a med follow up of 42 mos, all efficacy endpoints were in favor of UTX + IB (see Table). Conclusions: In contrast to prior studies adding rituximab to IB, GENUINE is the first randomized trial to demonstrate a PFS benefit with the addition of an anti-CD20 to IB. Increasing depth of response (CR rate, MRD-neg) post first year of Tx supports maintenance therapy with UTX. Clinical trial information: NCT02301156 . [Table: see text]
Gls-010, a novel anti-PD-1 mAb in Chinese patients with relapsed or refractory classical Hodgkin lymphoma: Preliminary impressive result of a phase II clinical trial.
Authors: Song Yuqin , Zhu Jun , Lin Ningjing , Zhang Mingzhi , Bai Hai , Liu Hui , Cui Jie , Ke Xiaoyan , Zhang Huilai , Liu Lihong , Yan Dongmei , Jiang Yongsheng , Zang Aimin , Qi Junyuan , Wang Li , Liu Zhuogang , Xu Bing , Zhang Ying , Zhang Zhihui , Meng Haijin
Published: May 2020

8033

Background: classical Hodgkin lymphoma (cHL) are characterized by genetic alterations at the 9p24·1 locus and PD-L1 ligand overexpression. GLS-010 is a novel fully human anti-PD-1 mAb and exhibited favorable result in previous Phase I study. This multi-center, single-arm Phase II clinical trial is aimed to further evaluate the safety and efficacy profile of GLS-010 in Chinese patients (pts) with relapsed or refractory cHL. Methods: All pts enrolled received GLS-010 240mg every 2 weeks until disease progression, death, unacceptable toxicity or withdraw from the study. The primary endpoint was objective response rate (ORR) by independent review committee (IRC) per Lugona 2014. Adverse events (AEs) were graded by NCI CTCAE v4.03. Results: 85 pts with relapsed or refractory cHL who had received at least 2 lines of prior systemic chemotherapies were enrolled and treated. As of August 2 2019, data cutoff, pts received a median of 8 treatment cycles (1 cycle include 2 injections), with 12 pts discontinued and 73 pts were still in treatment. At a median follow-up of 6.57 months, an ORR was reported in 78 of 85 patients (91.76%, 95%CI, 83.77-96.62), by an IRC assessment, including 30(35.3%) pts with a complete response (CR) and 48 pts (56.5%) with a partial response (PR). Median duration of response (DoR) and progression free survival (PFS) were not reached yet. Treatment-related adverse events (TRAEs) of any grade occurred in 77 (90.6%) of 85 patients, most of which were Grade 1-2.The most common TRAEs were fever (26/85, 30.6%), neutrophil count decreased (16/85, 18.82%), white blood cell count decreased (15/85, 17.65%). ≥ Grade 3 TRAEs occurred in 23 (27.06%) pts, most commonly, hepatic function abnormal (5/85, 5.88%), hyperuricaemia (4/85, 4.71%). Conclusions: GLS-010 showed impressive anti-tumor activity (ORR = 91.96%) and manageable safety profile in Chinese patients with relapsed or refractory cHL, which could be a new safe and effective treatment option in this setting. Clinical trial information: NCT03655483 .
Sintilimab for relapsed/refractory classical Hodgkin’s lymphoma: Long-term follow-up on the multicenter, single-arm phase II ORIENT-1 study.
Authors: Su Hang , Song Yongping , Jiang Wenqi , Sun Xiuhua , Qian Wenbin , Zhang Wei , Gao Yuhuan , Jin Zhengming , Zhou Jianfeng , Jin Chuan , Zou Liqun , Qiu Lugui , Li Wei , Yang Jianmin , Hou Ming , Zeng Shan , Liu Peng , Shi Yuankai , Zhou Hui , Zuo Hongli
Published: May 2020

8034

Background: Sintilimab, a programmed death-1 checkpoint inhibitor, has demonstrated efficacy in relapsed/refractory cHL after the primary analysis of the ORIENT-1 study. Here, we report the updated safety and efficacy profile after long-term follow-up. Methods: ORIENT-1 is a multicenter, single-arm, phase II study in China. Classical Hodgkin’s lymphoma patients who had failed ≥2 lines of systemic therapy, including autologous hematopoietic stem cell transplantation (HSCT) were enrolled. Sintilimab, 200 mg IV was given every 3 weeks, until disease progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint objective response rate (ORR) by an independent radiological review committee (IRRC) per IWG 2007 has been reported before. The progression free survival (PFS) by IRRC follow-up data are reported herein. Results: 96 patients were treated. As of the data cutoff on 30 Sep, 2019, 57.3 % patients complete two-year treatment, with a median follow-up of 26.7 months. The median duration of treatment was 24.1 months (range: 0.7 to 24.8). Of 49 patients with progressive disease (PD) by investigator, 39/49 (79.6%) patients received treatment beyond PD, with a median treatment duration after PD of 8.0 months (range: 1.4 to 20.8). The median PFS was 18.6 months (95%CI: 14.4 to 22.3). Median overall survival has not been reached. Two-year OS rate was 96.3% (95%CI: 88.9% to 98.8%). The treatment-related adverse event (TRAE) was reported in 92/96 (95.8%) patients, most (71/96, 74.0%) of which were grade 1-2. The most common grade 3 or 4 TRAEs were pyrexia (3/96, 3.1%), lipase increased (3/96, 3.1%) and lymphocyte decreased (3/96, 3.1%). Conclusions: The results from long-term follow-up showed that, in addition to a high rate of response, sintilimab also demonstrated durable efficacy and favorable long-term safety profile. Considering the high rate (nearly 80%) of treatment beyond PD, IWG 2007 which was used to evaluate PFS may not be a suitable criteria for evaluating the efficacy of anti-PD-1 antibody in cHL. Further investigation and analysis are required. Clinical trial information: NCT03114683 .
Outpatient treatment with lisocabtagene maraleucel (liso-cel) across a variety of clinical sites from three ongoing clinical studies in relapsed/refractory (R/R) large B-cell lymphoma (LBCL).
Authors: Bachier Carlos R. , Godwin John E. , Andreadis Charalambos , Palomba Maria Lia , Abramson Jeremy S. , Sehgal Alison R. , Hildebrandt Gerhard , Stevens Don A. , Hoda Daanish , Licitra Edward J. , Siddiqi Tanya , Farazi Thalia Andrea , Kostic Ana , Trede Nikolaus S. , Wang Lei , Lymp James , Maloney David G.
Published: May 2020

8037

Background: Currently approved CAR T cell therapies are generally administered as inpatient (inpt) treatment at university medical centers due to concerns about frequency, onset, severity, and management of AEs, including cytokine release syndrome (CRS) and neurologic events (NEs). We sought to characterize whether patients (pts) could be safely monitored in the outpatient (outpt) setting after receiving liso-cel, an investigational, CD19-directed CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells, across university and non-university sites in TRANSCEND NHL 001 (NCT02631044), OUTREACH (NCT03744676), and PILOT (NCT03483103). Methods: Eligible pts had R/R LBCL after systemic chemoimmunotherapy; moderately impaired organ function was allowed. For outpt infusion of liso-cel, pts were required to receive safety monitoring education, have a caregiver and stay within 1 h travel to site of care for 30 d post-treatment. All study sites had a multidisciplinary CAR T cell team and standard operating procedures for toxicity monitoring and management. Results: At data cutoff, 53 pts had received liso-cel on Study Day 1 and were monitored as outpts (university, n = 33; non-university, n = 20), including pts ≥65 y of age (n = 23) and with high tumor burden (SPD ≥50 cm2; n = 16). Any grade CRS and NEs were reported in 18 (34%) and 14 pts (26%), respectively. Severe CRS and/or NEs occurred in only 2 pts (4%) and were reversible. Median (range) time to onset of CRS and NEs was 5 (2–9) and 8.5 (3–22) d, respectively. Tocilizumab and/or corticosteroids for treatment of CRS and/or NEs were required in 8 pts (15%). Overall, 30 pts (57%) required hospitalization post-treatment, with a median (range) time to hospitalization post-treatment of 5.5 (2–22) d; 9 pts (17%) were hospitalized Study Day 4 or earlier. Two pts required ICU-level care. There were no grade 5 treatment-emergent AEs. Safety in pts monitored as outpts was comparable across types of sites. Overall response rate was 81% (95% CI, 68–91). Safety and efficacy were consistent with data from inpts across the 3 studies (N = 270). Conclusions: Pts with R/R LBCL were successfully treated with liso-cel and monitored for CAR T cell-related toxicity in the outpt setting across different types of sites. Incidences of severe CRS, NEs, and early hospitalization were low; 43% of pts did not require hospitalization. A larger dataset will be presented, including comparisons of outpts vs inpts and sites of care. Clinical trial information: NCT02631044 (TRANSCEND NHL 001), NCT03744676 (OUTREACH), NCT03483103 (PILOT) .
Myeloablative versus non-myeloablative consolidative chemotherapy for newly diagnosed primary central nervous system lymphoma: Results of induction therapy in Alliance 51101.
Authors: Batchelor Tracy , Giri Sharmila , Ruppert Amy S. , Bartlett Nancy L. , Hsi Eric D. , Cheson Bruce D. , Nayak Lakshmi , Leonard John Paul , Rubenstein James L.
Published: May 2020

8042

Background: Optimal consolidative therapy for primary central nervous system lymphoma (PCNSL) is not defined. Avoidance of whole brain radiation may reduce risk of neurotoxicity. Non-radiation consolidative options include myeloablative chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) or non-myeloablative chemotherapy. Methods: This is a randomized phase 2, National Clinical Trials Network study of induction methotrexate (MTX) (8 g/m2days 1, 15), temozolomide (TMZ) (150-200 mg/m2 D7-11), and rituximab (RTX) (C1 D3, 10, 17, 24 and C2 D3, 10) in four 28-day cycles followed by one cycle of cytarabine (ARA-C) (2 g/m2 BID, D1, 2) (MTRA). Following induction, patients (pts) received consolidation with thiotepa (5 mg/kg BID, D -5, -4) plus carmustine (400 mg/m2, day -6) and ASCT (Arm A) or one cycle of ARA-C (2 g/m2 BID, D1-4) plus infusional etoposide (40 mg/kg over 96h) (Arm B). The primary endpoint was median progression-free survival (PFS), designed to compare consolidation regimens. This report describes the results of the 5 cycles of induction therapy. Results: 113 pts (median age 61 years, range 33-75) were randomized (Arm A: 57, Arm B: 56) across 27 centers. 108 eligible pts who received induction therapy were evaluated. 36 pts (33.3%) did not proceed to consolidation, mainly due to disease progression (17), pt withdrawal (8), or adverse events including death (6). Grade 3 or 4 febrile neutropenia occurred in 12 pts (11.1%) during induction. Dose modifications of MTX were required in 75% of pts and 63.3% of cycles, mainly due to renal adjustments. Dose delays of MTX were required in 52.8% of pts and 22.2% of cycles. Overall response rate (CR, CRu, PR) at the end of induction was 65.7% (95% CI, 56%, 74.6%). Conclusions: While MTRA is feasible and active a significant proportion of pts did not receive consolidation, supporting the need to develop more effective induction strategies. Clinical trial information: NCT01511562 .
Treatment stratification in B-cell PTLD after solid organ transplantation (SOT) by international prognostic index (IPI) and response to rituximab: Interim results from the PTLD-2 trial.
Authors: Trappe Ralf Ulrich , Koenecke Christian , Dreyling Martin H. , Pott Christiane , Duehrsen Ulrich , Meidenbauer Norbert , Hahn Dennis , Heuser Michael , Schmidt Christian , Ritgen Matthias , Siebert Reiner , Oschlies Ilske , Anagnostopoulos Ioannis , Zimmermann Heiner ,   DPTLDSG and GLA
Published: May 2020

8045

Background: The PTLD-1 trials have established risk-stratified sequential treatment of B-cell PTLD. After rituximab induction, patients (pts) in complete remission (25 %) received rituximab consolidation, while all others received R-CHOP. The PTLD-2 trial tests modified risk-stratification including clinical risk factors. These are the results of the 2nd scheduled interim analysis (40/60 planned pts). Methods: The prospective, multicenter phase II PTLD-2 trial (NCT02042391) enrols treatment-naïve adult SOT recipients with CD20-positive PTLD. Key exclusion criteria are CNS involvement, ECOG > 2, pregnancy, and severe organ dysfunction or severe, active infection. Treatment consists of rituximab (1400 mg SC; first application 375 mg/m2 IV) on days 1, 8, 15 and 22. After restaging, pts in CR as well as those in PR with ≤ 2 IPI risk factors at diagnosis (low-risk group) continue with four three-weekly courses of rituximab. Most other pts (high-risk group) receive 4 cycles of R-CHOP-21, while thoracic SOT recipients who progress under rituximab (very-high-risk group) receive six cycles of alternating R-CHOP-21 and R-DHAOx. The primary endpoint (event-free survival in the low-risk group) is not analyzed here. Secondary endpoints presented here are response and overall response (ORR) by computed tomography, overall survival (OS), time to progression (TTP) and treatment-related mortality (TRM) overall and by risk group. Results: 40 pts were recruited at 12 centers (2015 – 2019). 21/40 were kidney, 11 lung, 4 liver, 3 heart, and 1 liver/kidney transplant recipients. Median age was 54 years. 38/40 PTLD were monomorphic and 15/40 EBV-associated. 38 pts were evaluated for response at interim staging: 13 were allocated to the low-risk, 17 to the high-risk and 8 to the very-high-risk group. ORR was 28/30 (93 %, CR: 16/30 [53 %]). With a median follow-up of 1.9 years, the 1-year/3-year Kaplan-Meier (KM) estimates of TTP and OS in the intention-to-treat population (40 pts) were 85 %/80 % and 70 %/70 %, respectively. In the low-risk group, the 2-year KM estimate of OS was 100 %. The frequency of infections (all grades) was 50 %, and TRM occurred in 3/40 pts (8 %). Conclusions: One third of enrolled pts were treated in the low-risk group and the recruitment goal for evaluation of the primary endpoint will likely be reached. Interim efficacy and toxicity data with rituximab SC and modified risk-stratification are encouraging despite the inclusion of 35 % thoracic SOT recipients. Clinical trial information: NCT02042391 .
Sintilimab for relapsed/refractory (r/r) extranodal NK/T cell lymphoma (ENKTL): Extended follow-up on the multicenter, single-arm phase II trail (ORIENT-4).
Authors: Li Jianyong , Tao Rong , Fan Lei , Song Yongping , Hu Yu , Zhang Wei , Wang Yafei , Xu Linxinyu , Sun Xing , Zhou Hui
Published: May 2020

8050

Background: Patients with r/r ENKTL have a poor prognosis after failing an asparaginase-based regimen. The overexpression of PD-L1 induced by EBV infection is a potential mechanism for ENKTL to avert immune surveillance. Sintilimab, a fully human anti-PD-1 monoclonal antibody, has demonstrated efficacy in r/r ENKTL after the primary analysis of the ORIENT-4 study. Here, we report the updated efficacy and safety results with extended follow-up. Methods: Patients with pathologically confirmed r/r ENKTL were enrolled. Sintilimab was given 200 mg IV Q3W, until PD, death, unacceptable toxicity, or withdrawal from the study. Treatment beyond PD is allowed. Tumor response evaluation was performed by both PET-CT and CT/MRI with contrast. The primary endpoint was objective response rate per Lugano 2014. Data cut-off date for this analysis was Jan 17, 2020. Results: A total of 28 patient were enrolled and treated. With a median follow-up of 26.9 months (range, 23.3 to 28.6), the median treatment duration was 24.15 months (range, 1.4 to 28.7). Of 20 patients with progressive disease (PD) by investigator per Lugano 2014 criteria, 19/20 (95%) patients received treatment beyond PD. The median OS has not been reached and 24-month OS rate was 78.6% (95% CI, 58.4% to 89.8%). ORR was 67.9% (95% CI, 47.6% to 84.1%), including 4 pts who experienced PD prior to having a response. DCR was 85.7%, including 5 pts who experienced PD before SD or response. Median duration of response was 4.1 months (range, 1.9 to 15.2+). After treatment, the mean EQ-5D-5L VAS Score (from 79.3 to 90.8), EQ-5D-5L Index Value (from 0.8 to 0.9) and EORTC QLQ-C30 (from 70.5 to 87.3) were all increased. The Treatment-related adverse events (TRAEs) of any grade occurred in 28 (100%) pts; grade 3 occurred in 11 (39.4%) pts, most commonly, decreased lymphocyte count (2 [7.1%]) and diabetes (2 [7.1%]); no grade 4-5 TRAE. Conclusions: In addition to an encourage response, sintilimab also demonstrated long-term clinical benefit, with 78.6% of 24-month OS rate, and favorable long-term safety profile after extended follow-up. Considering the high rate (95%) of treatment beyond PD, Lugano 2014 may not be a suitable criteria for evaluating the efficacy of anti-PD-1 antibody in r/r ENKTL. Clinical trial information: NCT03228836 .
Prognostic relevance of CD4+ T-cells in the microenvironment of newly diagnosed follicular lymphoma (FL) patients is independent of the tumor gene expression profile.
Authors: Mondello Patrizia , Fama Angelo , Larson Melissa C. , Feldman Andew L. , Yang Zhi-Zhang J , Villasboas Jose Caetano , Huet Sarah , Tesson Bruno , Slager Susan L. , Link Brian K. , Syrbu Sergei , Novak Anne , Habermann Thomas Matthew , Witzig Thomas E. , Nowakowski Grzegorz S. , Salles Gilles A. , Cerhan James Robert , Ansell Stephen M.
Published: May 2020

8052

Background: A significant proportion of patients with FL experience an early relapse and a subsequent poor outcome. While several prognostic indices have been developed, none were designed to predict early failure. Recently, we established that lack of intrafollicular CD4+ T-cell expression predicted risk of early failure, and integrating this microenvironment biomarker with the Follicular Lymphoma International Prognostic Index, termed BioFLIPI, further improved identification of FL patients at risk of early failure ( Blood 2019;134(suppl1):121). However, the microenvironment may be influenced by the genetic composition of tumor. We investigated whether the CD4 biomarker and BioFLIPI were impacted by genetic features of the tumor as assessed by a 23-gene expression prognostic score ( Lancet Oncol 2018;19:549-61). Methods: Of the 186 cases with FL grade 1-3A treated with immunochemotherapy (IC) in our prior study, 152 had digital expression quantification of 23 selected genes (23-GEP score), which used RNA from formalin-fixed, paraffin-embedded samples. Event-free survival (EFS) was defined as time from diagnosis to progression, relapse, retreatment, or death. Early failure was defined as failing to achieve EFS at 24 months. Risk of early failure was estimated using odds ratios (ORs) and 95% confidence intervals from logistic regression models. We also used Cox regression to assess associations with continuous EFS and overall survival (OS). Results: 28% of patients failed to achieve EFS24. Lack of CD4+ intrafollicular expression (38% of patients, OR = 2.33, p = 0.024) and high risk 23-GEP score (26% of patients, OR = 3.52, p = 0.001) each predicted early failure, and in a multivariable model that included FLIPI, both CD4+ (OR = 2.26, p = 0.046) and 23-GEP score (OR = 2.26, p = 0.0.057) remained predictors. Similarly, BioFLIPI modeled as a continuous score (1-4, OR per one point increase = 2.31, p < 0.001) predicted early failure, and the association remained (OR = 2.14, p < 0.001) when the high risk 23-GEP score (OR = 2.79, p = 0.013) was included in the model. When stratified on 23-GEP score, BioFLIPI was a stronger predictor of early failure in low risk (74%, OR = 2.51, p = 0.002) relative to high risk (26%, OR = 1.55, p = 0.27) patients. Similar patterns were observed for EFS and OS. Conclusions: CD4+ T-cell infiltrate and tumor gene expression appear to be independently predictive of early failure in newly diagnosed FL patients treated with IC. Future studies should integrate and validate these measures.
Identification of predicted neoantigen vaccine candidates in follicular lymphoma patients.
Authors: Ramirez Cody , Frenkel Felix , Plotnikova Olga , Belousov Vladislav , Bagaev Alexander , Ocheredko Elena , Kiwala Susanna , Hundal Jasreet , Skidmore Zach L , Watkins Marcus , Becker-Hapak Michelle , Fronick Catrina , Fulton Robert , Schreiber Robert , Bartlett Nancy L. , Kahl Brad S. , Ataullakhanov Ravshan , Griffith Malachi , Griffith Obi , Fehniger Todd A.
Published: May 2020

8054

Background: Follicular lymphoma (FL) is incurable with conventional therapies and poorly responsive to immune checkpoint blockade. There is a need for new therapies without long-term complications of chemotherapy and with curative potential. We hypothesize that FL contains tumor-specific mutant antigens (TSMAs) that can be targeted by the immune system by vaccination. Recent reports have highlighted the potential for unique immunoglobulin peptides to elicit immune response in lymphomas. We utilized whole exome sequencing (WES) and RNA sequencing (RNA-Seq) of FL patient samples to infer HLA genotype, and predict TSMAs with the goal of designing a personalized cancer vaccine, supported by recent reports of this approach in solid cancers. Methods: DNA and RNA from 58 patients’ FL biopsies underwent WES and RNA-Seq. pVACtools and MiXCR predicted potential somatic and B-cell clonotype neoantigens, which were filtered to identify high quality TSMAs. B-cell oligoclonality was determined by comparison to B-cell receptor (BCR) repertoire profiling of healthy individual lymph nodes. RNA-seq data allowed us to identify expressed TSMAs. Complementary in silico analysis based on mRNA-based peptide reconstruction and custom HLA affinity binding predictions were performed. Results: An average of 52 somatic mutations per patient (range: 2-172) were identified. At least one high quality TSMA was predicted for 57 of 58 patients. Five or more TSMA candidates were identified for 52 (90%) patients with a mean of 17 predicted peptides per patient (range: 0-45). 81% (813/1,004) of the total predicted TSMA peptides arose from missense mutations, 9% (94/1,004) from indels, and 10% (97/1,004) from BCR. 78% (45/58) of patients have both somatic and BCR vaccine candidates, while 21% (12/58) of patients had only somatic vaccine candidates. Predicted TSMAs were identified in multiple genes recurrently mutated in lymphoma (e.g., BCL2). There was a high prediction concordance with the orthogonal BostonGene Vaccine Module V1 pipeline. These pre-clinical results led to a first-in-human pilot trial of personalized TSMA vaccine combined with anti-PD-1 mAb for rel/ref FL patients (NCT03121677), with one response observed within 4 patients evaluable for response to date. Conclusions: TSMA peptides suitable for cancer vaccines were identified for most FL patients via next-generation sequencing, MiXCR and pVACtools. This pre-clinical study suggests that FL patients will be candidates for TSMA vaccine clinical trials and pilot clinical results provide proof of concept for this approach.
REFLECT real-world evidence (RWE) prospective study update: Efficacy and safety results of Sandoz biosimilar rituximab (SDZ-RTX) for the treatment of diffuse large B-cell lymphoma (DLBCL).
Authors: Welslau Manfred , Marschner Norbert Walter , Otremba Burkhard Joerg , Topaly Julian , Bittencourt da Silva Larissa
Published: May 2020

8060

Background: SDZ-RTX (Rixathon) is approved in more than 20 countries and regions, including highly regulated markets e.g. Europe, Japan and Switzerland for all labeled indications of reference rituximab. REFLECT is the first prospective post-approval study to evaluate a rituximab biosimilar as a curative therapy in untreated pts with CD20+ DLBCL. This interim analysis adds up efficacy and additional safety results on the previously presented data (Welslau et al, ASCO and EHA 2019). Methods: Adult patients (pts) were treated with SDZ-RTX and cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) according to the product label. The primary endpoint is to evaluate the effectiveness of Rixathon measured by complete response (CR) rate at the end of treatment. Secondary endpoints are overall response rate (ORR), progression-free survival at 24 months and adverse events (AEs). Data were collected at baseline and all scheduled treatment and follow-up visits, which is still ongoing. No imputation was made for missing values, and endpoints are summarized descriptively. Results: As of Sep 30, 2019, 170 pts were enrolled, and R-CHOP treatment was close to completion. The median age of pts was 70 years, and 52% were women. Overall, 38% of pts completed the first 12-month observation period, 41% were ongoing, while 21% of pts discontinued. Most of the pts (~80%) had an ECOG score of 0 (35%) or 1 (46%). Early staging (I–II2), low to intermediate disease risk (IPI 0-2), and known B symptoms were reported for 55%, 50%, and 30% of pts, respectively. CR rate at the end of treatment was 57% (defined as the revised response criteria for malignant lymphoma by Cheson et al, 2007 that excludes complete remission/unconfirmed [CRu]). Summary of efficacy is reported in the Table. Overall, 83% of pts experienced AEs, the most common being anemia (23%), fatigue (21%), and polyneuropathy (15%). Treatment-related AEs were reported for 28% of pts. Rates of any serious AEs (SAEs) and treatment-related SAEs were 37% and 6.5%, respectively. On-treatment deaths and all deaths were reported in 2.4% and 4.7% of pts, respectively. Conclusions: REFLECT is the first prospective post-approval study to evaluate a rituximab biosimilar as a curative therapy in untreated pts with DLBCL. This interim analysis results re-confirms the expected safety and efficacy profile for DLBCL patients treated with R-CHOP. [Table: see text]
Idecabtagene vicleucel (ide-cel; bb2121), a BCMA-targeted CAR T-cell therapy, in patients with relapsed and refractory multiple myeloma (RRMM): Initial KarMMa results.
Authors: Munshi Nikhil C. , Anderson, Jr Larry D. , Shah Nina , Jagannath Sundar , Berdeja Jesus G. , Lonial Sagar , Raje Noopur S. , Siegel David Samuel DiCapua , Lin Yi , Oriol Albert , Moreau Philippe , Yakoub-Agha Ibrahim , Delforge Michel , Petrocca Fabio , Connarn Jamie , Patel Payal , Huang Liping , Campbell Timothy Brandon , Hege Kristen , San Miguel Jesus ,   on behalf of the KarMMa Study Investigators
Published: May 2020

8503

Background: Outcomes are poor in triple-class exposed RRMM patients (pts) who progress on immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and CD38 antibodies (mAbs). Ide-cel, a BCMA targeted CAR T cell therapy, showed promising tolerability and efficacy in RRMM pts in the phase I CRB-401 study ( NEJM2019;380:1726). We present primary efficacy and safety data from the pivotal phase II KarMMa trial of ide-cel in RRMM (NCT03361748). Methods: Enrolled pts had ≥3 prior regimens (including IMiD, PI, and CD38 mAb) and were refractory to their last regimen per IMWG criteria. After lymphodepletion (cyclophosphamide 300 mg/m2+ fludarabine 30 mg/m2 x 3), pts received 150─450 × 106 CAR+ T cells (target dose range). Endpoints included overall response rate (ORR; primary), complete response (CR) rate, duration of response (DoR), and PFS. Results: Of 140 pts enrolled, 128 received ide-cel. Median age was 61 y; median no. of prior regimens was 6; 84% were triple- and 26% were penta-refractory. Most pts (88%) had bridging therapy. At data cutoff (16 Oct 2019), median follow up was 11.3 mo. ORR was 73% and median PFS was 8.6 mo; both increased with higher dose (Table). All subgroups had an ORR ≥50%, including older and high-risk pts. Most common any-grade (Gr) toxicities were cytopenias (97%) and cytokine release syndrome (CRS; 84%). CRS was mainly Gr 1/2; 5 pts (5%) had Gr 3, 1 had Gr 4, and 1 had Gr 5 (at 300 × 106). Neurotoxicity developed in 23 pts (18%); 4 (3%) Gr 3 and 0 Gr ≥4. Median peak CAR+ T cell expansion occurred at 11 d. Expansion was higher in responders and parameters (AUC0−28d, Cmax) increased with higher dose, with exposure overlap across doses. Persistence was durable, with CAR+ T cells detected in 29/49 (59%) and 4/11 pts (36%) at 6 and 12 mo. Conclusions: Ide-cel demonstrated deep, durable responses in heavily pretreated RRMM pts. Efficacy and safety reflected prior reports and support a favorable ide-cel clinical benefit-risk profile across the target dose range. Clinical trial information: NCT03361748 . [Table: see text]
Depth of response prior to autologous stem cell transplantation to predict survival in light chain amyloidosis.
Authors: Vaxman Iuliana , Sidiqi M Hasib , Al Saleh Abdullah S. , Kumar Shaji , Muchtar Eli , Dispenzieri Angela , Buadi Francis , Dingli David , Lacy Martha , Hayman Suzanne R. , Leung Nelson , Gonsalves Wilson I. , Kourelis Taxiarchis , Warsame Rahma M. , Hogan William J. , Gertz Morie A.
Published: May 2020

8516

Background: The role of induction therapy prior to autologous stem cell transplant (ASCT) in immunoglobulin light chain (AL) amyloidosis remains controversial. Data on the prognostic impact of response to induction in a transplanted cohort are lacking. The aim of this study was to assess the impact of response to induction therapy on survival in patients undergoing ASCT for AL amyloidosis. Methods: We conducted a retrospective study of all newly diagnosed AL amyloidosis patients who received induction prior to ASCT between January 2007 and August 2017 at Mayo Clinic, Rochester, Minnesota. Patients receiving only corticosteroids prior to transplant were excluded as were those with an involved light chain of less than 5 mg/dL (not measurable for response). Results: 134 patients met inclusion criteria. The median age at diagnosis was 60 (range 36-74) and 85 (63%) were men. The most commonly used induction regimen was proteasome inhibitor-based (73.1%, n=98). The overall response rate to induction was 83% (complete response 17%, very good partial response 30% and partial response 36%). With a median follow up of 56.5 months, the median PFS and OS was 48.5 months and not reached, respectively. Response depth to induction therapy was associated with improved PFS and OS and was independent of the bone marrow plasma cell percentage. The median PFS was not reached for patients achieving ≥VGPR prior to ASCT and 33.8 months for patient achieving PR or less (P=0.001). The median OS was longer in patients with deeper responses (not reached for patients achieving ≥VGPR vs. 128 months for patients achieving PR or less (P=0.02). On multivariable analysis, independent predictors of OS were melphalan conditioning dose (RR= 0.38; P=0.018) and depth of response prior to transplant (RR 2.52; P=0.039). Conclusions: Hematologic response prior to transplant predicts post-transplant outcomes in patients with AL amyloidosis. [Table: see text]
Ixazomib vs placebo maintenance for newly diagnosed multiple myeloma (NDMM) patients not undergoing autologous stem cell transplant (ASCT): The phase III TOURMALINE-MM4 trial.
Authors: Dimopoulos Meletios A. , Spicka Ivan , Quach Hang , Oriol Albert , Hajek Roman , Garg Mamta , Beksac Meral , Bringhen Sara , Katodritou Eirini , Chng Wee Joo , Leleu Xavier , Iida Shinsuke , Mateos Maria-Victoria , Morgan Gareth , Vorog Alexander , Labotka Richard , Wang Bingxia , Palumbo Antonio , Lonial Sagar
Published: May 2020

8527

Background: Maintenance therapy delays disease progression in non-ASCT NDMM patients. However, in practice, currently used maintenance therapies may be limited to fixed duration due to toxicity and route of administration; additional options are needed. Methods: 706 non-ASCT NDMM patients who received 6–12 months of standard-of-care induction therapy and achieved at least a partial response (≥PR) were randomized 3:2, double-blind, to the oral proteasome inhibitor (PI) ixazomib (n = 425; 3 mg, cycles 1–4, then, if tolerated, 4 mg, cycle 5 onwards) vs placebo (n = 281) on days 1, 8, and 15 of 28-day cycles for ≤2 yrs. Patients were stratified by prior PI exposure (yes vs no), pre-induction International Staging System (ISS) disease stage (I/II vs III), age ( < 75 vs ≥75 yrs), and post-induction best response (complete or very good partial response [CR/VGPR] vs PR). Primary endpoint was progression-free survival (PFS). Results: Baseline characteristics were well balanced. Overall median age was 73 yrs, 38% of patients were aged ≥75 yrs, 35% were ISS stage III, and 22%/40%/38% had CR/VGPR/PR post induction. Overall, 82% of patients received a PI and 33% an immunomodulatory drug as part of their induction regimen. At a median follow-up of 21.1 months, median PFS was 17.4 months with ixazomib vs 9.4 months with placebo (hazard ratio [HR] 0.659, 95% confidence interval [CI] 0.542–0.801, p < 0.001). Significant (p < 0.001) PFS benefit was seen in patients who achieved CR/VGPR post induction (Table). Overall survival data are not yet mature (19% of events); follow-up is ongoing. Treatment-emergent adverse events (TEAEs) were mostly grade 1–2 (37% vs 23% of patients had grade ≥3 TEAEs with ixazomib vs placebo). Common TEAEs for ixazomib vs placebo included nausea (27% vs 8%), vomiting (24% vs 4%), and diarrhea (23% vs 12%); 5% vs 6% of patients had new primary malignancies. No cumulative toxicities were observed. Conclusions: Ixazomib maintenance therapy in non-ASCT NDMM patients showed a clinically meaningful 34% reduction in the risk of progression or death, with a well-tolerated safety profile. Ixazomib is the first oral PI maintenance option for non-ASCT NDMM patients. Clinical trial information: NCT02312258 . [Table: see text]
Multiple myeloma (MM) vaccination (influenza, FV and pneumococcal, PV) rates worldwide and impact on infection, hospitalization, and death.
Authors: Thompson Michael A. , Costello Caitlin , Berdeja Jesus G. , Davies Faith , Zonder Jeffrey A. , Lee Hans Chulhee , Omel Jim , Spencer Andrew , Terpos Evangelos , Hungria Vania , Puig Noemi , Fu Cheng-Cheng , Skacel Tomas , Ferrari Renda H. , Ren Kaili , Stull Dawn Marie , Chari Ajai
Published: May 2020

8528

Background: MM is a cancer of the immune system. Infections are common reasons for hospitalization and death in MM. As MM patients (pts) are living longer, with prolonged exposure to systemic therapy, there is a need to vaccinate pts and to determine the effectiveness of these vaccines. Vaccination in MM pts is underutilized, based on a study of vaccination patterns in a large health system (Alemu JPCRR 2017) and data collected via a pt self-report online portal (Thompson ASCO 2020). We analyzed FV and PV patterns and associated outcomes in INSIGHT MM, the largest global, prospective, observational study in MM to date. Methods: INSIGHT MM aims to understand MM pt and disease characteristics at diagnosis and relapse, treatment patterns, clinical outcomes, and treatment-associated tolerability, effectiveness, quality of life, and healthcare resource utilization. INSIGHT MM has enrolled 4318 MM pts from 15 countries worldwide; pts are being followed up prospectively for ≥5 yrs. Vaccine status is collected at study entry and yearly. We analyzed FV and PV patterns and associated outcomes of pts enrolled in July 2016–2019. Results: At data cutoff (Sep 1, 2019), 2562/2523 pts had study entry data on FV/PV status. Overall vaccination rates were low (FV 40%, PV 30%) and varied by region: FV 56%/38%/27%/4% and PV 43%/28%/21%/5% in US/Europe/Latin America/Asia. In evaluable pts, lack of vaccination was associated with higher infection and hospitalization rates for FV, and with increased risk of death (univariate analysis) for both FV and PV (Table; multivariate analysis underway). Infections, including influenza and pneumonia, were the cause of death in 19% (43/226) / 8% (9/108) (P = 0.018) of pts who did not receive FV / received it in the past 2 yrs and 19% (46/236) / 9% (9/100) (P = 0.027) of pts who did not receive PV / received it in the past 5 yrs, and in 7%/15%/20%/40% of pts who died in US/ Europe/Latin America/Asia (P < 0.0001). Conclusions: Global vaccination rates in MM pts were low and varied by region. Lack of vaccination correlated with rates of infection (FV), hospitalization (FV), and death (FV and PV). Further MM datasets should be analyzed to confirm the findings. Vaccination data should be collected in prospective clinical trials as it may affect survival. Vaccination is important in MM and should be encouraged. Clinical trial information: NCT02761187 . [Table: see text]
Updates from a phase Ib study of isatuximab (Isa), bortezomib (V) and dexamethasone (D) plus cyclophosphamide (C) or lenalidomide (R) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM).
Authors: Ocio Enrique M. , Rodríguez Otero Paula , Bringhen Sara , Oliva Stefania , Nogai Axel , Attal Michel , Moreau Philippe , Martinez-Lopez Joaquin , Le Roux Nadia , Macé Sandrine , Rouchon Marie-Claude , Wang Qiuyan , Mateos Maria-Victoria
Published: May 2020

8529

Background: We report updated data from a Phase Ib study of Isa, a CD38 monoclonal antibody, plus VCd or VRd in transplant ineligible patients (pts) with NDMM (NCT02513186). Methods: Isa-VCd: Isa (10 or 20 mg/kg; weekly [QW] cycle 1 [C1], then Q2W), V (1.3 mg/m2; twice weekly C1, then QW), C (300 mg/m2; QW C1, then Days [D] 1, 8, 15 to C12), d (20 mg; twice weekly C1, then D1, 2, 8, 9, 15, 16, 22, 23 to C12). Isa-VRd: Isa (10 mg/kg), V and d as described above; R (25 mg/day; D1–14 and D22–35). Efficacy and safety were evaluated. Conventional (M-protein levels) and minimal residual disease (MRD) IMWG response assessments were compared. MRD negativity was assessed at 10−5 by next-generation sequencing and flow. Mass Spectrometry (MS) negativity (no detectable serum M-protein) was assessed for 13 pts by Immuno-Capture and Liquid Chromatography coupled to High Resolution MS. Results: As of Nov 18, 2019, 17 pts were treated with Isa-VCd (10 mg/kg, n = 13; 20 mg/kg, n = 4), 27 with Isa-VRd; 53% and 63% remained on treatment, respectively. Infusion reactions were seen in 53% of Isa-VCd and 63% of Isa-VRd pts; Grade ≥3 infections in 23% and 37%; serious adverse events in 47% and 52%. See table for efficacy. 3 MRD positive pts were MS positive with persistent detectable M-protein ( > 10 µg/mL). 8/10 MRD negative pts were MS positive (4 at 5-10 µg/mL; 4 at > 10 µg/mL) and 2/10 were MS negative ( < 5 µg/mL). Stable residual M-protein was observed by MS up to 23 months post-MRD negativity. All pts tested by MS are still progression-free. Conclusions: Isa-VCd/VRd shows encouraging efficacy and tolerability in NDMM. MS seems to be more sensitive than MRD; low levels of M-protein were detectable even in MRD negative pts. Clinical trial information: NCT02513186 . [Table: see text]
A phase Ib study of TAK-079, an investigational anti-CD38 monoclonal antibody (mAb) in patients with relapsed/ refractory multiple myeloma (RRMM): Preliminary results.
Authors: Krishnan Amrita Y. , Patel Krina K. , Hari Parameswaran , Jagannath Sundar , Niesvizky Ruben , Silbermann Rebecca Wang , Berg Deborah T. , Li Qing , Allikmets Kristina , Stockerl-Goldstein Keith
Published: May 2020

8539

Background: TAK-079 is a subcutaneously (SC) administered mAb with multiple modes of action for killing target cells. Here we report data from an ongoing dose finding study of TAK-079 monotherapy in patients with RRMM (NCT03439280). Methods: Pt were eligible after ≥ 3 lines of therapy and previous exposure to immunomodulatory drug (IMiD), proteasome inhibitor (PI), alkylating agent, and corticosteroid; prior anti-CD38 therapy allowed. Patients were refractory or intolerant to at least 1 PI and 1 IMiD. TAK-079 given as a SC injection weekly for 8 doses, every other week for 8 doses, then monthly until disease progression (PD) or unacceptable toxicity. SC injection was 2 mL administered in ≤ 1 minute. Results: 34 patients were enrolled across 5 fixed dose cohorts (TAK-079 45-135-300-600-1200 mg SC) as of 09 December 2019. Median age was 65 (50–81) years. At study entry, 65% were refractory to both an IMiD and PI; 82% refractory to last line of therapy, 21% of patients were previously exposed to at least 1 anti-CD38 monoclonal antibody. Median number of prior therapies was 4 (2,12). No ≥ Grade 1 early or late systemic infusion reactions (IRR) reported. Three ( < 1%) injection site reactions described in > 1200 injections administered; 2 mild pruritis and 1 moderate swelling. Drug related adverse events (AEs), any grade, occurring in at least 10% of patients were: fatigue (21%), anemia (18%), neutropenia (18%), leukopenia (15%). Neutropenia was the only drug related grade 3 AEs in 2 or more patients (n = 2); only drug related SAE was 1 Grade 3 diverticulitis. No drug-related grade 4 AEs, AEs leading to study discontinuation, or on-study deaths reported. Recommended phase 2 dose (RP2) is to be 600 mg based on no reported DLTs, no MTD identified, and preliminary efficacy (PFS and response [ORR]). At the RP2 dose, 9 patients received at least 6 cycles of therapy by the data cutoff; their ORR was 33%, median duration of response was not estimable. The clinical benefit rate (minimal response or better) in all 12 patients enrolled at the RP2 dose was 67%. At a median follow-up of 7.5 months, PFS not estimable at the RP2 dose. Conclusions: TAK-079 monotherapy is safe, generally well tolerated, and active in patients with RRMM through tested doses. Clinical activity occurred early and was durable. With no MTD identified, no IRRs, no significant hematologic toxicity, the RP2 dose is 600 mg. PFS, with a median FU of 7.5 months at the data-cut off, is not estimable at the RP2 dose. Updated safety and efficacy data will be presented. Clinical trial information: NCT03439280 .