bluuebunny/crossref_metadata_2025 huggingface dataset:
Features of HPV+ OPSCC predictive of recurrence identified by transcriptional profiling of a case-control cohort.
Authors: Basu Devraj , Sannigrahi Malay Kumar , Raghav Lovely , Sun Lova , Cohen Roger B. , Gimotty Phyllis A. , Jalaly Jalal , Pearson Alexander T.
Published: June 2024

6055

Background: De-escalating therapy for HPV+ oropharyngeal cancers (OPSCCs) is hampered by poor ability to predict recurrence, and limited insight into the biologic traits predisposing to recurrence impedes personalizing therapy. We aimed to (1) define biologic features underlying therapy resistance by transcriptional profiling and (2) evaluate the features for prognostic utility. Methods: A single institution cohort of 851 HPV+ OPSCC patients undergoing transoral robotic surgery during 2007-2020 was used to identify 50 cases that recurred locoregionally in the adjuvant RT field (n=14) and/or at distant sites (n=43). As controls, we used 49 recurrence-free patients with long-term follow up and similar stage, smoking history, and adjuvant therapy. RNAseq of pretreatment tumors was used to compare individual gene expression and Hallmark/Kegg pathway activity between cases and controls using unpaired t-test (p<.05) and Gene Set Enrichment Analysis (p-adj<.05), respectively. Activity of the significant pathways was quantified in individual tumors using Gene Set Variation Analysis (GSVA), and a regression-based composite of GSVA scores was developed to distinguish cases from controls by ROC analysis. The composite score was used to test for stratification of recurrence free survival (RFS) in external cohorts using Youden Index and logrank test. Results: The21 Hallmark/Kegg pathways downregulated in cases indicated suppression of anti-tumor immunity, and the 20 upregulated ones revealed increased biosynthetic function and tumor cell proliferation. The 1472 upregulated mRNAs contained several components of the ATR-chk1 DNA repair pathway and trans-lesion synthesis polymerases, suggesting that mitigation of DNA replication stress enhanced tumor growth. The 958 downregulated mRNAs suggested reductions in the cytoplasmic dsDNA sensing and downstream NF-kB signals that lead to replication stress-driven anti-tumor immunity. Two GSVA scores were created to quantify the key tumor-intrinsic and immune suppressive features separately in each tumor. The scores correlated with each other (R=0.6, p<.001), and a regression-based combination of them distinguished cases from controls (AUC=.76, p<.001). This composite score also stratified RFS in three external cohorts: TCGA (n=52, p<0.001) and two single institution cohorts containing both surgical and nonsurgical cases (n=46, p=.002; n=81, p<0.001). Conclusions: HPV+ OPSCCs failing primary surgical therapy show evidence of reduced replication stress mediating tumor progression and low anti-tumor immunity. These features appear generalizable to heterogeneously treated external cohorts, where they predicted recurrence. Our results provide a new basis for creating transcriptomic predictors of treatment response and suggest targetable molecular mechanisms to overcome therapy resistance.
Can TTMV clearance predict recurrence in HPV HNSCC?
Authors: Misiukiewicz Krzysztof , Worona Leslie Anne , Ramos Emily J , Bakst Richard Lorne , Sindhu Kunal K. , Westra William , Roof Scott , Genden Eric Michael , Posner Marshall R.
Published: June 2024

6066

Background: Patients with locally advanced (LA) HPV HNSCC are treated with various types of induction chemotherapy (IC) followed by standard (sd) or reduced (rd) chemoradiation (CRT). Tumor tissue-modified viral HPV DNA (TTMV) pairs with PET-CT in predicting an early detection of treatment failure in HPV-related HNSCC. Mid-treatment TTMV assessment in HPV-related HNSCC can help identify patients who are eligible to receive a lower dose of IC and/or CRT or those who may require close follow-up. Methods: Patients with LA HPV+ HNSCC with high-risk features (radiographic ECE, T4 primary, >N2c) and <20 pack-year (py) smoking history were treated with IC followed by rdCRT (56 Gy); sdCRT (70 Gy) was used in non-responders. 16/23 received IC with TPF, 1/23 TP, and 6/23 TP-PD1, and all patients received carboplatin weekly with their CRT. Regeneron trial patients who received TP-Cemiplimab (PD1) IC followed by sdCRT are also continuing adjuvant Cemiplimab alone for 6 months (NCT05376553). PET-CT-confirmed residual, recurrent, or metastatic diseases were defined as treatment failures; TTMV + patients only if PET-CT confirmed. Results: 23 subjects treated with IC followed by CRT between 2/4/21-1/26/24, who had pre- and post-treatment TTMV were included in our analysis. The median pre-IC TTMV was 8082 (27 – 90770). The median follow-up time from treatment start was 21 months. 9/23 patients had full clearance TTMV after 1 cycle of IC defined as rapid responders (RR). 11/23 patients still had positive TTMV after 1st cycle of IC were defined as slow responders (SR). 1 patient had no TTMV done after 1 cycle of IC but was elevated after 2nd IC; he was defined as SR. 2 patients had a positive pre-IC TTMV, but no TTMV was drawn during IC to see if RR. 1 of 2 patients was TTMV negative prior to CRT, and 2/2 had a 1st post IC negative TTMV done 1 week after CRT started. They were both included in the analysis but defined as unknown response status. TTMV testing was done for all 23 subjects after CRT; all were negative. All subjects have TTMV testing done during their surveillance visits. Among 9/23 RR, none developed a failure. Among 12/23 SR, 3 patients developed a failure: 1/3 was TTMV+ but PET-, being followed with TTMV and PET-CT; and 2/3 were confirmed failures, TTMV+ and PET+; 1 locoregional, 1 metastatic. 2 patients were not known to be a SR or RR and had no recurrence. Among 23 patients, NPV of TTMV to detect failure was 100%, but PPV was 96% (1/23). Conclusions: IC followed in rapid clearance of TTMV in 39% of patients, and all remained disease-free. 3/11 (27%) with persistently elevated TTMV after cycle 1 relapsed as of this time point. This small study was not large enough to be practice-changing. However, this is significantly hypothesis-generating and should be tested in a larger trial to help identify patients for de-escalation (RR) or closer surveillance (SR).
Evaluating perceived barriers to optimal care in head and neck cancer: A mixed-methods study.
Authors: Powell Steven Francis , Beadle Beth Michelle , Watts Tammara L , Maxwell Jessica H. , Hutkin-Slade Linda , Haynes-Lewis Hilda , Demirhan Kimberly , Plotkin Elana , Rush Angie , Dibble Jacqueline , Kim Joseph
Published: June 2024

6079

Background: Head and neck cancer (HNC) is a complex disease that requires multidisciplinary care and poses significant challenges for patients and healthcare providers. Despite the availability of evidence-based guidelines, achieving optimal HNC care faces many barriers. This mixed-methods study explores the perceived barriers by patients and clinicians to optimal HNC care. Methods: The Association of Cancer Care Centers (ACCC) collaborated with the Head and Neck Cancer Alliance and the American Society for Radiation Oncology (ASTRO), along with an expert steering committee of multidisciplinary roles representing diverse cancer care centers, to evaluate the current landscape of HNC care delivery. Using an explanatory sequential design, ACCC conducted patient (n= 247) and provider (n=206) surveys and four focus groups which included patients with HNC and clinicians to capture barriers to optimal HNC care. Results: Barriers were classified as patient-related, provider-related, and system-related factors. Survey highlights include: 32% of patients received multimodal treatment including surgery, radiation, and medications; 50% of clinicians were at centers that utilized multidisciplinary clinics for HNC; 60% of patients “strongly agreed” they were satisfied with their care; 48% of patients felt members of their treatment team communicated and coordinated care “very well”; and 56% of patients “strongly agreed” clinicians explained their diagnosis comprehensibly. Clinicians and patients differed in their perspectives on how care was delivered in a few areas: 52% of clinicians vs. 40% of patients agreed that side effects of treatment were explained in ways that patients could understand; 29% of clinicians vs. 21% of patients felt that emotional concerns and mental health needs were addressed. Clinicians identified key areas that needed improvement to provide more effective care: financial resources (62%), dedicated navigation (45%), and coordination across members of the care team (45%). Qualitative analysis of focus group responses identified travel logistics to care centers, inadequate health insurance coverage, and lack of dental insurance delaying care as major systems-related barriers to optimal HNC care. Conclusions: This study revealed insights into the delivery of optimal care in HNC in the US, including being a high-volume center, having dedicated HNC nurse navigators, and multidisciplinary meetings for care coordination. Multifactorial barriers to optimal HNC care were also identified and will be used to inform future educational programming and the development of interventions to improve care.
Induction chemotherapy followed by concurrent chemoradiotherapy combined with toripalimab and Endostar in high-risk locally advanced nasopharyngeal carcinoma: A multicenter, randomized, phase 2 trial.
Authors: Kang Min , Yang Kunyu , Lu Ying , Yu Jinming , Ma Daiyuan , Tang Shuang , Gao Jianquan , Zhang Tingting , Yang Zhendong , Lv Jun , Qin Yutao , Wu Fang , Ruan Lin , Liu Kang , Dong Huan , Meng Zhen , Qin Yating , Wang Rensheng
Published: June 2024

6086

Background: Even though induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) can improve the survival rate of patients with locally advanced nasopharyngeal carcinoma (LA-NPC), the recurrence and/or metastasis rates for patients with stage IV (T4 and/or N3) diseases remain high. This study investigates the efficacy and safety of adding Toripalimab (PD-1 inhibitor) and Endostar (recombinant human endostatin) to IC-CCRT in patients with high-risk LA-NPC. Methods: High-risk LA-NPC patients were randomly divided (1:1) into either the IC-CCRT+TE group (gemcitabine and cisplatin induction chemotherapy followed by concurrent chemoradiotherapy combined with Toripalimab and Endostar) or the IC-CCRT group (gemcitabine and cisplatin induction chemotherapy followed by concurrent chemoradiotherapy). Toripalimab (240mg, d1) was administered intravenously every 3 weeks for up to 12 cycles (3 induction, 2 concurrent, and 7 adjuvant). Endostar (7.5mg/m2, d1-10) was continuously injected intravenously every 3 weeks for a total of 5 cycles (3 induction and 2 concurrent). The primary endpoint was 3-year progression-free survival (PFS), and the secondary endpoints included 3-year overall survival (OS), 3-year locoregional relapse-free survival (LRFS), 3-year distant metastasis-free survival (DMFS), objective response rate (ORR) and safety. Results: From September 7, 2020, to August 23, 2022, a total of 106 eligible patients were randomly assigned to the IC-CCRT+TE group (n = 53) and IC-CCRT group (n = 53). At a median follow-up of 25 months, the PFS was significantly improved in the IC-CCRT+TE group compared to the IC-CCRT group (HR=0.36, p=0.041). 28 patients (52.8%) in the IC-CCRT+TE group and 5 patients (9.4%) in the IC-CCRT group achieved complete response (CR) after induction chemotherapy, and the difference was statistically significant (P < 0.001). The incidence of grade ≥3 acute adverse events in the IC-CCRT+TE group and IC-CCRT group was 66.0% and 62.3%, respectively. The incidence of grade ≥3 late adverse events in two groups was 5.8% and 5.7%, respectively. The incidence of grade ≥3 immune-related adverse events was only 4.7%. Conclusions: IC-CCRT combined with Toripalimab and Endostar significantly improved PFS in patients with high-risk locally advanced nasopharyngeal carcinoma, and the adverse events are manageable. Clinical trial information: NCT04447326 .
Survey of long term survivors of oral cancer: Looking beyond cancer biology.
Authors: Nair Sudhir Vasudevan Vasudevan , Bavaskar Manasi , Singhavi Hitesh , Shetty Rathan , Singh Arjun
Published: June 2024

6087

Background: While surgery is the main stay of treatment for early stage oral cancers, advanced stages require adjuvant treatments in the form of radiotherapy or concurrent radiotherapy. Yet, the effectiveness of these interventions is not solely determined by clinical measures but also by personal factors such as individual motivation, support from loved ones, and financial security. These aspects might explain the survival rate variations among patients who, despite having similar prognostic categories and stages of disease, show differing outcomes. The role of social determinants in influencing patient survival, apart from the acknowledged impact of disease biology, is not well understood. Methods: All treatment-naive oral cavity cancer patients who underwent definitive treatment during 2014 to 2018 at our institute and are alive for more than five years were selected for this study. A custom investigator-administered questionnaire was developed and it had 32 questions under six domains- personal, habit history, financial, social, functional, and emotional. The study was approved by the institutional ethics committee. Of the 1787 potential participants, we found that 219 had expired, only 442 patients agreed to answer the questionnaire, while 45 refused to participate. The rest of the patients were not reachable telephonically. Results: This survey had 442 patients, of which 90% were males, with a mean age of 52.1 years. The most common site of the presentation was buccal mucosa (60%), and 59% presented in the locally advanced stage. Post-operatively, 71% received adjuvant therapy. All patients were motivated to undergo the radical treatments and had their family support. However, post-treatment, about 10% of individuals experienced a change in marital status. Financial constraints did affect 20% of patients during and after treatment, and more than 70% had their out-of-pocket expenditure above 50% of the total cost. While 80% did not have trouble attending social functions, 46% reported trouble eating socially. However, this was more common for patients who received adjuvant treatment (p < 0.001). About 21% reported shoulder dysfunction and body discomfort. However, no statistically significant associations could be drawn for any of the domains of the questionnaire when compared to patients between the early and late stages. Shoulder discomfort was experienced more by patients who were treated for tongue cancer (p-value 0.010). Conclusions: The results of this study shed light on the challenges faced by long-term survivors of oral cancer following radical treatment regimens. More than half of patients reported that out-of-pocket expenses constituted more than half of their total treatment costs. A notable minority of people suffer from shoulder dysfunction, suggesting there is a clear opportunity for advancements in reconstruction and rehabilitation.
Validation of a prognostic nomogram for locally advanced oropharyngeal carcinoma (OPC) treated with intensity modulated radiation therapy (IMRT) ± systemic therapy (ST).
Authors: Bossi Paolo , Gili Riccardo , Calza Stefano , Licitra Lisa F. , Maddalo Marta , Bacigalupo Almalina , Belgioia Liliana , Cacicedo Jon , Facchinetti Nadia , Garcia Almudena , Oliva Marc , Bonomo Pierluigi , Sanguineti Giuseppe , Franco Pierfrancesco , Argiris Athanassios , Psyrri Amanda , Orlandi Ester
Published: June 2024

6088

Background: The interplay among prognosticators in OPC patients (pts) may be influenced by sociodemographic, geographic, epidemiologic and genetic features. We aimed to validate an existing prognostic nomogram (PN) (Fakhry et al 2017) in a large, independent, geographically homogeneous pt cohort. Methods: We retrospectively collected data on consecutive OPC pts treated with definitive IMRT (66-72 Gy) ± systemic therapy (ST) in 14 South-European Centres from 2007 to 2019. We analysed the role of the nomogram prognostic factors (PF) (T and N stage, age, p16 status, smoking, performance status, weight loss, anemia, education, and marital status) with respect to overall survival (OS) and progression-free survival (PFS), and we also evaluated alcohol abuse, comorbidities according to ACE-27 and the presence of a caregiver as added PF. The PN was evaluated in terms of discrimination performance (Harrel C-index) and calibration (ratio O/E and calibration line). Model was recalibrated evaluated via optimism adjusted C-index. Results: We considered 786 pts, with a median follow-up of 63 months (0-189). The table reports pts characteristics. The PN showed a good discrimination for OS and PFS both at 2- and 5-years, not dissimilar from original external validation, with a C-index of 0.75 (CI 95% 0.70-0.79,) and 0.68 (0.64-0.72), respectively. Adding alcohol abuse, comorbidities and caregiver presence did not change the PN. Regarding OS, the model estimated risk was slightly higher than the observed, with an O/E ratio of 0.73 (CI 95% 0.57-0.93) and 0.60 (0.49-0.74) at 2- and 5- years and calibration slope of 1.07 (0.83-1.31). For PFS, the O/E ratio was 0.48 (0.40-0.58) at 2 years and 0.50 (0.42-0.58) at 5 years, and a calibration slope of 0.89 (0.66-1.12). Both for OS and PFS rescaling of baseline hazard and model coefficients resulted in a better calibrated model. Model was validated also after missing data imputation, via MCE (m=5) showing consistent estimates. Conclusions: We validated the prognostic nomogram developed by Fakhry et al. in a large independent European cohort, demonstrating its applicability. These real-life data may represent the benchmark for the design of new prospective clinical trials.[Table: see text]
Mosunetuzumab with polatuzumab vedotin: Subgroup analyses in patients (pts) with primary refractory or early relapsed large B-cell lymphoma (LBCL).
Authors: Assouline Sarit , Budde Lihua Elizabeth , Chavez Julio C. , Diefenbach Catherine S. , Dorritie Kathleen Anne , Ghosh Nilanjan , Olszewski Adam J , Lossos Izidore S. , Mehta Amitkumar , Modi Dipenkumar , Naik Seema , Smith Stephen Douglas , Makadia Sneha , Pham Song , Wu Hao , Batlevi Connie Lee , To Iris , Wei Michael C. , Kamdar Manali
Published: June 2024

7021

Background: The primary analysis of mosunetuzumab with polatuzumab vedotin (mosun-pola) in the Phase Ib/II study (NCT03671018) demonstrated durable responses and manageable safety in pts with relapsed or refractory (R/R), transplant-ineligible LBCL (Budde et al. Nat Med 2023). Here, we present results for primary refractory (refr) or early relapse (rel) subgroups from this study after a median follow-up of 23.9 months. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [NOS], high-grade B-cell lymphoma [HGBCL], transformed follicular lymphoma (FL), and FL grade 3b) and who received ≥1 prior line of therapy (including an anti-CD20 antibody) were treated with mosun-pola. Refr was defined as SD, PD, PR, or CR with relapse <3 months after first-line (1L) therapy. Rel was defined as CR with relapse ≥3 and ≤12 months after 1L therapy. The primary endpoint was best overall response rate (ORR) by IRC using Lugano 2014 response criteria. Key secondary endpoints included CR rate, duration of response (DOR), duration of CR (DOCR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 6, 2023, of the 98 pts in the overall population, 45 (46%) and 27 (28%) pts had refr or rel LBCL, respectively. At baseline, the median age in the refr and rel subgroups was 68 and 70 years respectively; 23/45 pts (51%) and 6/27 pts (22%) were treated with mosun-pola as second-line, respectively. The majority of refr/rel pts had DLBCL NOS (71%; 78%) or HGBCL (24%; 19%), Ann Arbor stage III/IV (80%; 89%), elevated LDH (55%; 48%), and extranodal involvement (67%; 59%). In refr pts, the ORR was 49%, which was generally consistent with the overall population (59%); although the sample size was limited, higher responses (ORR: 74%) were observed in rel pts. Additional clinical outcomes are reported (Table). The safety profile was consistent with the overall population. Grade 3 CRS occurred in one pt in each subgroup. Treatment-related ICANS-like events occurred in 2/45 pts (4%; refr) and 3/27 pts (11%; rel). Conclusions: Mosun-pola demonstrated durable benefits in ORR and CR rates irrespective of a poor response to 1L treatment. Outcomes for pts with refr or rel LBCL are encouraging. Clinical trial information: NCT03671018 . [Table: see text]
Carfilzomib plus rituximab, ifosfamide, carboplatin and etoposide (C-RICE) led to higher response, OS, and PFS in patients with transplant-eligible relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
Authors: Amin Mody , Niu Alex , Attwood Kristopher , George Anthony , Azad Farhan , Wong Jerry , Schofield Grant , Pan Dorothy C. , Sait Sheila N. J. , Block Anne Marie W. , Przespolewski Eugene , Connors Carolyn , Demarco Joseph , Gauch Keryn , Gjorgievski Nikolina , Johnson Michael , Manth Linda , McWhite Kenneth , Cortese Matthew Joseph , Hernandez-Ilizaliturri Francisco J.
Published: June 2024

7042

Background: The CORAL study highlighted the need to develop novel salvage regimens for R/Rr/r DLBCL previously treated with R+CHOP. Overall response rate (ORR) to second line immuno-chemotherapy was 51% with a 3-year progression free survival (PFS) of 30% following high-dose chemotherapy and autologous stem cell support (HDC-ASCS). Optimal disease control (complete remission [CR] or partial remission [PR]) prior to HDC-ADCS and more recently to chimeric antigen receptor T-cell therapy (CAR T), correlates with improved outcomes. Dysregulation of Bcl-2 family members has been associated with acquired resistance to rituximab and chemotherapy which we have previously shown may be mitigated by co-treatment with proteasome inhibition in pre-clinical model. Subsequently, we conducted a Phase I/II clinical trial evaluating the safety and efficacy of CRICE as salvage therapy for R/R DLBCL (Blood Adv. 2023 7:1146-1155). Methods: Here we retrospectively compared the clinical outcomes of R/R DLBCL patients treated with CRICE (N=28) versus RICE (N=38) on our prior clinical trial (NCT01959698). Demographic, clinical, and pathological characteristics were collected for both groups (Table). Study endpoints consisted of differences in overall response rate (ORR), CR/PR rates, median progression free survival (PFS) and overall survival (OS) between the two cohorts. Results: The addition of Carfilzomib to RICE resulted in improved clinical outcomes. A higher ORR (92.9 vs 76.3, P=0.073) and CR rates (82.1 vs. 44.7, P=0.002) were observed in CRICE vs. RICE treated patients. Multivariate analysis confirmed the higher CR rates in CRICE vs. RICE when adjusted by DLBCL subtype (GCB vs. nNon-GCB, P=0.003). More CRICE patients proceeded to HDC-ASCS (52.6% vs. 47.4%, P=0.618). The 3yr PFS rate was higher in CRICE (54%, 32-72%) vs. RICE treated patients (35%, 19-51%). While the median PFS was longer in CRICE treated patients 36.8m (0.8, 73.2) vs. 3.2m (0.5, 54.2) (RICE), it did not reach statistical significance (P=0.714). No differences in OS were observed between CRICE & RICE patients, median OS 67.3m vs. 71.8m. Conclusions: The CRICE outcomes were more striking in patients with non-GCB r/r DLBCL (ORR 85%, mPFS and OS not reached). CRICE led to high CR rates and longer PFS among r/r DLBCL patients, especially in non-GCB DLBCL patients. CRICE could be an attractive regimen to achieve disease control in r/r DLBCL patients undergoing consolidation therapy with HDC-ASCT or CAR T-cell therapy. [Table: see text]
Real world incidence, prevention, and management of tumor lysis syndrome in patients with chronic lymphocytic leukemia treated with venetoclax in the inpatient and outpatient settings.
Authors: Valtis Yannis , Nemirovsky David , Derkach Andriy , Roeker Lindsey Elizabeth , Sharan Saumya , Kabel Charlene , Ortiz Ricardo , Geyer Mark Blaine
Published: June 2024

7045

Background: Venetoclax (ven) is a BCL2 inhibitor used for the treatment (tx) of chronic lymphocytic leukemia (CLL) which can cause clinical or laboratory (lab) tumor lysis syndrome (TLS). A dose ramp-up schedule and prophylaxis strategies are incorporated into NCCN guidelines and prescribing information. Prior reports have of TLS focused mostly on patients (pts) with relapsed/refractory CLL receiving ven as monotherapy. Methods: We included pts >18y who were diagnosed with CLL or small lymphocytic lymphoma (SLL) and received tx with commercial ven in any line of therapy at our institution from 1/1/2016 to 12/31/2020. TLS was defined using the modified Cairo Bishop Criteria. TLS risk was based on the size of the largest lymph node (LN) on imaging or examination and the absolute lymphocyte count (ALC) as defined by ven prescribing information. Results: We included 616 ven escalations among 136 pts with CLL. Median age was 70 years and 86% were white. Ven was part of first line of tx for 48 pts (35%). 11% had high TLS risk at baseline; 37% among those escalated exclusively inpatient (IP) and 2% among those escalated exclusively outpatient (OP). Among those treated with ven, 47 pts (35%) received ven monotherapy. 74 (54%) of pts were escalated exclusively OP, 35 (26%) had at least one prophylactic hospitalization and 27 (20%) were escalated exclusively IP. During ven initiation, 86% of pts received allopurinol, 71% intravenous hydration, 18% phosphate binders, and 10% prophylactic rasburicase. Among the entire cohort, 8 pts (5.9%) developed lab TLS and zero developed clinical TLS. There were 11 TLS events; 2 pts developed TLS in more than one escalation. Incidence of TLS was 15% for those escalated exclusively IP, 5.7% for those with any prophylactic hospitalization and 2.7% for those escalated exclusively OP. Those who developed TLS were more likely to have a higher TLS risk at baseline, preceding isolated hyperuricemia, or CrCl measurement < 60 mL/min (Table). Conclusions: In this single institution retrospective cohort study, lab TLS was observed, though clinical TLS was not. Baseline hyperuricemia and impaired renal function were more common among those who developed lab TLS compared to those who did not. Prophylactic measures, including use of IV hydration, may have contributed to low rates of observed TLS in the outpatient setting. [Table: see text]
Comparative efficacy of Bruton tyrosine kinase inhibitors in the treatment of relapsed/refractory chronic lymphocytic leukemia: A network meta-analysis (NMA).
Authors: Shadman Mazyar , Brown Jennifer R. , Mohseninejad Leyla , Yang Keri , Burnett Heather , Neupane Binod , Williams Rhys , Lamanna Nicole , O'Brien Susan M. , Tedeschi Alessandra , Tam Constantine S.
Published: June 2024

7048

Background: Next-generation Bruton’s tyrosine kinase inhibitors (BTKis) have led to changes in the treatment algorithm for patients with high-risk relapsed/refractory (R/R) CLL; defined based on the presence of genetic mutations and a high unmet need. Given the lack of head-to-head trials comparing these treatments in R/R CLL, a NMA was performed to estimate the relative efficacy of BTKis used to treat high-risk patients. Methods: Randomized controlled trials ALPINE (zanubrutinib vs. ibrutinib), ELEVATE-RR (acalabrutinib vs. ibrutinib), and ASCEND (acalabrutinib vs. bendamustine + rituximab/idelalisib + rituximab [BR/IR]) were included in the NMA. High-risk populations were defined based on the pre-specified subgroups within each trial, including patients with del17p and/or TP53 mutations in ALPINE (zanubrutinib: 75/327 and ibrutinib: 75/325), ASCEND (acalabrutinib: 44/155 and BR/IR: 42/155), and del17p/del11q in ELEVATE-RR (acalabrutinib: 268/268 and ibrutinib: 265/265). Bayesian NMAs were used to estimate hazard ratios (HRs) or odds ratios (ORs) with 95% credible intervals (CrIs), and probability better (PB) for zanubrutinib versus all other treatments. Outcomes analysed included investigator-assessed progression-free survival (PFS), overall survival (OS), overall response (ORR), and complete response (CR). Given the timing of the included trials in relation to the COVID-19 pandemic, ALPINE data were analyzed with and without adjustment for COVID-19 related deaths. Results: The NMA found a statistically significant improvement in PFS for zanubrutinib over acalabrutinib in high-risk patients and a trend towards improvement in OS, ORR, and CR (Table). Zanubrutinib led to statistically significant improvements in PFS versus ibrutinib (HR [95% CrI]: 0.49 [0.30, 0.78], PB: 99.9%) and BR/IR (0.12 [0.05, 0.26], PB: 100.0%). For OS, zanubrutinib showed a trend towards improvement versus ibrutinib (0.59 [0.31, 1.12] PB: 94.8%) and BR/IR (0.64 [0.24, 1.74] PB: 80.7%). Conclusions: This NMA found zanubrutinib to be the most efficacious BTKi for patients with high-risk R/R CLL, offering significantly delayed disease progression, and favourable survival and response vs. alternative BTKi treatments. [Table: see text]
Frontline treatment with zanubrutinib plus rituximab (ZR) followed by short course R-DHAOx in patients with mantle cell lymphoma (MCL): Results of the phase II CHESS clinical trial.
Authors: Cai Qingqing , Xia Yi , Huang Huiqiang , Li Zhiming , Huang He , Li Guowei , Zhang Yuchen , Cao Yi , Gao Yan , Liu PanPan , Fang Xiaojie , Mie Man , Tian Xiaopeng , Sun Xiuhua , Pan Xueyi
Published: June 2024

7062

Background: Combining Bruton’s tyrosine kinase (BTK) inhibitor and rituximab showed favourable efficacy as first-line therapy for mantle cell lymphoma (MCL). Zanubrutinib, a next-generation, highly-selective BTK inhibitor, achieved promising antitumor activity in MCL. In this multicenter phase II trial (CHESS - chemo-less), we aimed to investigate the efficacy and toxicity of zanubrutinib plus rituximab (ZR) combination, followed by short course cytarabine-based chemotherapy, then zanubrutinib maintenance as frontline therapy for MCL (NCT04624958). Methods: Previously untreated MCL patients enrolled and received induction therapy of ZR until complete response (CR) or to a maximum of 12 cycles, and followed by 4 cycles of R-DHAOx regimen (rituximab, dexamethasone, cytarabine and oxaliplatin). Patients achieving CR after chemotherapy would receive maintenance therapy with zanubrutinib for a maximum of 1 year. The primary endpoint was CR rate after induction therapy with ZR regimen. Minimal residual disease (MRD) of bone marrow and peripheral blood were evaluated by flow cytometry. Results: From Oct 2020 to Nov 2023, a total of 42 patients were enrolled and the enrollment was finished. The median age was 57 years (IQR, 51-64). Stage III-IV accounted for 92.8%, and 42.8% were intermediate or high risk simplified MIPI. Thirty-four patients (81.0%) were classic histological subtype. The median cycle of ZR was 4 (range, 2-6). As of Jan 2024, among 37/42 patients with post-treatment PET evaluation, the best CR rate of ZR regimen was 91.9% (34/37), and 94.1% (32/34) obtained CR after 2-4 cycles. The bone marrow MRD negative CR rate was 92.0% (23/25). The other 5/42 patients were still receiving ZR treatment, and PET evaluation would be performed subsequently. Among 27 patients who finished chemotherapy and were evaluable for response, only one patient experienced disease progression. With a median follow up of 11.6 months, the 1-year progression-free survival and overall survival was 90.1% and 96.7%, respectively. Two patients died due to lymphoma (n=1) and COVID-19 (n=1). Grade 3-4 adverse events on ZR regimen were neutropenia (n=3), fatigue (n=2), and aminotransferase (n=1). During chemotherapy, grade 3-4 thrombocytopenia was observed in 75.8% of patients. Conclusions: Induction treatment with ZR followed by short-course R-DHAOx chemotherapy yielded promising antitumor efficacy. This strategy might reduce the toxicity of cytarabine-based chemotherapy without weakening the therapeutic efficacy. Clinical trial information: NCT04624958 . [Table: see text]
A phase 1 study of SHR-A1912, a CD79b targeted antibody-drug conjugate (ADC), in patients (pts) with B-cell non-Hodgkin lymphoma (B-NHL).
Authors: Li Zengjun , Xie Yang , Ni Shuqin , Zhou Hui , Chen Junmin , Huang Pinfang , Yang Wei , Zheng Li , Zou Liqun , Wang Yike , Liu Yiming , Ma Dahua , Mao Wenjun , Zhu Jun , Song Yuqin
Published: June 2024

7064

Background: CD79b is an attractive therapeutic target for B-NHL. SHR-A1912 is a novel ADC containing an anti-CD79b monoclonal antibody conjugated to the DNA topoisomerase I inhibitor. Here, we present results of the dose-escalation (D-ESC) and dose-expansion (D-EXP) parts of a first-in-human phase 1 study of SHR-A1912 in B-NHL. Methods: Pts with histologically confirmed B-NHL that had failed to respond to or had progressed after ≥1 prior anti-cancer therapy were enrolled. The D-ESC part commenced with accelerated titration at 0.1 and 0.3 mg/kg and then switched to an i3+3 scheme at escalated doses starting from 0.6 mg/kg (Q3W, IV). In the D-EXP part, additional pts were enrolled to selected doses (approximately 10–12 pts in total per dose level). Primary objectives were to assess the safety and tolerability of SHR-A1912 and determine the RP2D. Results: As of Nov 7, 2023, 49 pts were enrolled (n=1, 1, 7, 3, 13, 13, and 11 in the 0.1, 0.3, 0.6, 1.2, 1.8, 2.7, and 3.6 mg/kg dose cohorts), including 33 pts with diffuse large B-cell lymphoma (DLBCL), 12 with follicular lymphoma (FL), and 4 with marginal zone lymphoma (MZL). Pts had received a median of 2 lines of prior treatment (range, 1–9). DLTs occurred in 3 pts during D-ESC (grade 4 decreased neutrophil count lasting ≥3 days in 0.6 and 3.6 mg/kg cohorts, 1 pt for each; grade 3 pneumonia in 2.7 mg/kg cohort, 1 pt). The 1.8, 2.7, and 3.6 mg/kg cohorts were expanded. Overall, grade ≥3 treatment-related adverse events occurred in 20 (40.8%) pts, with the most common (≥20%) being decreased neutrophil count. 41 pts with baseline target lesions had at least one post-baseline assessment; ORR was 56.1% (95% CI, 39.8–71.5), and 6-mo DoR rate was 62.7% (95% CI, 26.7–84.8). As for subtypes, ORR was 51.9% in pts with DLBCL (57.1% and 77.8% in the 2.7 and 3.6 mg/kg cohorts, respectively), 63.6% in pts with FL, and 66.7% in pts with MZL (Table). The mean half-life of conjugated antibody ranged from 4.7 to 5.3 days for pts in the 1.8–3.6 mg/kg cohorts, with volume of distribution close to human plasma volume. The plasma exposure of free toxin was low, with the molar ratio of toxin/conjugated-antibody <1%, and no accumulation was observed. Conclusions: SHR-A1912 was tolerable up to 3.6 mg/kg and had promising anti-tumor activity in pts with previously treated B-NHL, supporting further investigations of SHR-A1912. Clinical trial information: NCT05113069 . [Table: see text]
Incidence of central nervous system relapse in primary mediastinal B-cell lymphoma: Implications for central nervous system prophylaxis.
Authors: Okcu Izel , Zhou Jihao , Wang Yucai , Bock Allison Marie , Alhaj Moustafa Muhamad , Baidoun Firas , Tun Han W. , Rosenthal Allison Claire , Johnston Patrick B. , Kabat Brian , Rimsza Lisa M. , Habermann Thomas Matthew , Nowakowski Grzegorz S.
Published: June 2024

7080

Background: Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of aggressive B-cell non-Hodgkin lymphoma. PMBCL has distinct clinicopathologic features compared to diffuse large B-cell lymphoma but shares some clinical and biologic features with nodular sclerosis classic Hodgkin lymphoma (cHL). Central nervous system (CNS) relapse is exceedingly rare in cHL, therefore one may expect that CNS relapse in PMBCL is also uncommon. Herein, we examined the incidence of CNS relapse in patients with PMBCL. Methods: Patients with newly diagnosed PMBCL seen at Mayo Clinic between 1/2002 and 4/2023 were identified from the Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from medical records. The CNS relapse rate was calculated using a competing risk model, with death considered as a competing risk. Results: A total of 154 PMBCL cases were identified. The median age at diagnosis was 38 years (range 18-77) and 60.4% were female. The distribution of CNS-IPI was low-risk in 80 (51.9%) patients, intermediate-risk in 43 (27.9%), and high-risk in 3 (1.9%), and data were missing for 28 patients (18.2%). 78 patients (50.6%) received R-CHOP and 76 patients (49.4%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 5 patients (all treated with R-CHOP). 20 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis (4 with R-CHOP [1 received HD-MTX too],16 with R-DA-EPOCH). The median follow-up was 39 months (95% CI 28.2-49.8). Only 3 patients had CNS relapse, all associated with systemic relapse (1 concurrent, 1 had CNS relapse 8.8 months after systemic relapse, 1 had CNS relapse 2 months before systemic relapse). The cumulative incidence of CNS relapse for the entire cohort was 1.43% (95% CI 0.3%-4.6%) at 1 year and 2.21% (95% CI 0.6%-5.8%) at both 2 and 5 years. For those who did not receive CNS prophylaxis (n=130), the incidence was 0.86% (95% CI 0.1%-4.3%) at 1 year and 1.82% (95% CI 0.4%-5.8%) at both 2 and 5 years. All 3 patients who experienced CNS relapse had R-CHOP as frontline therapy; two patients did not receive any CNS prophylaxis, while 1 patient received IT CNS prophylaxis. Conclusions: The risk of isolated CNS relapse in PMBCL appears to be very low, even in patients who did not receive CNS prophylaxis. While some patients may experience CNS relapse associated with systemic relapse, the overall incidence was low (1.43% at 1 year and 2.21% at 2 and 5 years). The rarity of isolated CNS relapse in PMBCL suggests that routine CNS prophylaxis may not be necessary as part of initial therapy.
Outcomes and prognostic factors of patients diagnosed with relapsed/refractory primary B-cell lymphoma: A retrospective study.
Authors: Dumke Henry , Phillips Tycel Jovelle , Kaminski Mark S , Carty Shannon , Wilcox Ryan A. , Sano Dahlia , Kandarpa Malathi , Polk Avery , Karimi Yasmin
Published: June 2024

7081

Background: PMBCL is an aggressive form of large B-cell lymphoma (LBCL) but has a unique gene expression profiling signature that more closely resembles Hodgkin’s lymphoma. Treatment of R/R PMBCL is largely extrapolated from trials in LBCL with few PMBCL patients included. Randomized trials leading to use of CART as second line treatment for patients with primary refractory or early relapsed LBCL enrolled ≤ 10% PMBCL patients (ZUMA-7 and TRANSFORM). In the rituximab era, there is a paucity of data on the efficacy and outcomes of salvage therapy followed by high-dose chemotherapy and autologous stem cell transplant (HDT/ASCT) in PMBCL. Methods: We conducted a retrospective study of patients with PMBCL, histologically confirmed at the University of Michigan, diagnosed between 2001 and 2023. Results: 70 patients were included with a median age of diagnosis of 31.5 years and 57% female. R-DA-EPOCH was the most commonly used first line therapy (FLT) in 58 patients (83%). 10 patients (14%) were treated with R-CHOP with or without consolidative radiation. 65 patients had end of treatment (EOT) PET/CT: 45 (69%) patients achieved a Deauville (D) 1-3 response, 15 (23%) had D4 response, 5 (8%) had D5 response. 4 (26%) of patients with D4 response and all patients with D5 response ultimately developed R/R disease. 5 had EOT response assessed by CT and all deemed to have complete response. 16 patients (23%) developed R/R disease with a median time to relapse of 8.3 months. All relapses occurred within 2 years: 5 patients with primary refractory disease, 10 patients with relapse <12 months and only 1 patient with relapse >12 months. Platinum based chemotherapy with RICE, RDHAP or RGemOx were the most common salvage regimens (N=11) with ORR 60% among evaluable patients. 5 patients received HDT/ASCT with ORR of 80% and CR rate of 80%. Only 1 patient progressed following ASCT, who had relapsed >12 months after FLT. 9 patients (13%) had high-risk extranodal disease (EN) such as renal, adrenal or breast sites with 2 patients (11%) developing CNS relapse. At a median follow up time of 6.5 years, 5-year PFS and OS for the entire cohort was 76% and 96%, respectively. For patients with R/R disease, 5-year PFS and OS was 49% and 84%, respectively. Conclusions: We report high response rates to platinum-based salvage chemotherapy in the rituximab era, even with primary refractory or early relapsed disease. Higher PFS and OS suggests improved outcomes with HDT/ASCT compared to historical outcomes in R/R LBCL (SCHOLAR-1). Larger prospective studies are needed to determine whether HDT/ASCT or CART is the optimal approach in R/R PMBCL. [Table: see text]
Outcomes of patients who received CAR T cell therapy and developed IEC-HS treated with cytokine directed therapy.
Authors: Leung Nelson , Alkhateeb Hassan B. , Atallah-Yunes Suheil Albert , Durani Urshila , Gallo De Moraes Alice , Gupta Supriya , Hayman Suzanne R. , Herrmann Joerg , Johnston Patrick B. , Kenderian Saad , Khurana Arushi , Puttkammer Jenna R , Rees Matthew J. , Sandahl Tyler B , Vergidis Paschalis , Warsame Rahma M. , Wolf Robert C. , Lin Yi
Published: June 2024

7516

Background: Immune effector cell hemophagocytic lymphohistiocytosis IEC-HS is a complication of CAR T cell therapy (CART). This study aims to look at the outcomes of CART patients who develop IEC-HS. Methods: Patients who developed IEC-HS after receiving CART and patients who developed IEC-HS without (nonCART) between December 2020 and March 2022 were included. Results: The 20 CART patients were older than the 25 nonCART patients. Peak ferritin, fibrinogen, CRP, serum creatinine and transaminases were similar between the 2 group. CART patients had lower white blood cell count and platelets and bilirubin than the nonCART patients. CART patients were more like to have markedly elevated IL-6 levels (> 315 mg/ml), higher IL-18, higher MCP-1, and suppressed IL-1β and GMCSF than nonCART patients (Table). Treatment of IEC-HS included tocilizumab (n = 19), anakinra (n = 18) siltuximab (n = 4) and basiliximab (n = 4), dexamethasone (n = 18) methylprednisolone (n = 6), etoposide (n = 1) and ruxolitinib (n = 1). A significant response defined by a 90% reduction or normalization of the cytokine was observed with IL-10 and IFN-ϒ in 92.3% and 84.6% of the CART patients respectively. An intermediate response was noted with TNF, IL-6, MCP-1 and MIP-1 in 38.4%, 30.8% and 61.6% and 38.5% of the patients respectively. No patient had a significant response in IL-2Rα or IL-1β and only 7.7% had a significant response in IL-18. Of the 5 patients who had a MIP-1 response, 4 were on basiliximab +/- high flow continuous venovenous hemofiltration and the only patient that had an IL-18 response was on both modalities. The 100-day mortality after IEC-HS in the CART patients was 40% and was associated with higher peak and lower best ferritin but not the percentage reduction (Table). Higher TNF (90.3 pg/ml vs 37.2 pg/ml, p = 0.05), markedly elevated levels of IL-6 (92% vs 50%, p = 0.03) and IL-10 (33% vs 0%) and an IL-6 response (44.4% vs 0%) were associated with survival at day 100. IL-6 responders had lower peak ferritin vs IL-6 nonresponders (14066 mcg/L vs 45051 mcg/L, p = 0.08). Enterococcus faecium bacteremia developed in 75% of the nonsurvivors vs 16.6% of the 100-day survivors (p = 0.009). Survivors cleared the enterococcus bacteremia within days while nonsurvivors had protracted bacteremia. Conclusions: IEC-HS is devastating complication of CART. Anti-cytokine therapy can reduce some cytokines and ferritin but overimmunosuppression may lead infectious complication, in particular with E. faecium. Better biomarkers are needed to finetune immunosuppressive therapy in order to avoid over-immunosuppression. [Table: see text]
Real world outcome of patients with multiple myeloma who received bispecific antibodies after CAR-T therapy.
Authors: Bansal Radhika , De Menezes Silva Corraes Andre , Brunaldi Larissa , Sandahl Tyler B , Rees Matthew J. , Hayman Suzanne R. , Binder Moritz , Abdallah Nadine , Dingli David , Cook Joselle , Gertz Morie A. , Kapoor Prashant , Kourelis Taxiarchis , Warsame Rahma M. , Kumar Shaji , Lin Yi
Published: June 2024

7520

Background: There are 2 CAR-T products and 3 bispecific antibodies (BsAbs) that are FDA-approved for patients (pts) with relapsed, refractory multiple myeloma (MM). Clinical trials experience to date suggests that clinical response of BsAb is less impacted after CAR-T therapy. We examined the outcome of pts who received BsAb in standard-of-care (SOC) practice at Mayo Clinic Rochester. Methods: Retrospective analysis of MM patients who received FDA-approved BsAb at Mayo Clinic, Rochester between 12/2022- 1/2024. IMWG criteria was used for clinical response. Results: Sixty-two patients received BsAbs: 77% (48/62) received teclistamab, and 23% (14/62) received talquetamab. Median age was 62 years (range: 33-81), 60% (37/62) were males, and 45% (28/62) received prior CAR-T. Patients who had prior CAR-T therapy had more prior lines of therapy compared to those who did not. Overall, ORR to teclistamab was 61%, which is comparable to previous studies and other real-world reports. ORR and ≥CR rates were comparable between patients with and without prior CAR-T (Table). Of the 28 pts who received CAR-T before BsAbs, 61% (17/28) received idecabtagene vicleucel, 10% (3/28) were ciltacabtagene autoleucel, and 29% (8/28) on clinical trial. We then compared outcome of BsAb between pts who had relapsed from CAR-T within 1 year (n=21, median PFS: 8.84 months (range, 1.12, 10.84)) or after 1 year (n=7, median PFS: 16.62 months (range, 13.30, 36.20)). At the time of BsAb infusion, pts with who relapsed < 1 year vs ≥1 year post CAR-T had comparable blood counts, ALC, M-protein and involved FLC levels, CRP, ferritin and LDH. BsAb CR/sCR rate was significantly higher in pts with disease relapse ≥1 year compared to <1 year post CAR-T (57% vs 14%, p=0.02). Conclusions: Irrespective of prior CAR-T exposure, BsAb have clinical activity in SOC practice in pts with MM. Our preliminary data suggest that responses to BsAbs are better in pts with late compared to early relapse post CAR-T. Longer follow-up is needed to understand the duration of response. Larger, multi-center studies with longer follow-up will help identify factors that impact BsAb response post CAR-T.[Table: see text]