bluuebunny/crossref_metadata_2025 huggingface dataset:
External validation of the Molecular International Prognostic Scoring System (IPSS-M) for myelodysplastic syndromes.
Authors: Chernak Brian , Ali Abdullah , Jan Amna , Mukherjee Sanjay , Jurcic Joseph G. , Raza Azra
Published: June 2023

7056

Background: Myelodysplastic Syndromes (MDS) comprise of a group of clonal diseases characterized by dysplastic hematopoietic progenitor cells, leading to cytopenias and in select cases transformation to acute myeloid leukemia (AML). In June 2022 the Molecular International Prognostic Scoring System (IPSS-M) was developed to build on the traditional IPSS-R and is reported to be prognostic even with incomplete molecular data. We aimed to validate this scoring system with an external dataset, and utilize a patient population which typically does not contain complete molecular testing at diagnosis. Methods: This single center study at a tertiary medical center in New York, NY was conducted as an external validation of the IPSS-M. Patients with MDS who had documented peripheral blood counts, bone marrow biopsies, and cytogenetic data were identified in the institutional tissue bank. After eliminating repetitive patient samples, 405 patient entries, collected between July 7, 2010 and March 29, 2022 were included in this study. 392 patients had previously been categorized by IPSS-R score. 332 patients had at least one subsequent follow-up event. 94 patients had bone marrow biopsies that were peri-diagnostic (within 12 months of diagnosis). Results: Patients in the entire cohort had a median age of 74 years (range, 30-96). The median follow-up duration was 1.5 years (range 0.0-9.9 years). Nearly all patients had at least partial molecular diagnostic data. Other than PRPF8 mutations (0%), all other mutations included in the IPSS-M scoring system were tested in a subset of the study population. The most common mutations in the patient population were SF3B1 (20.4%), ASXL1 (17.6%), and SRSF2 (15.9%); 12.2% of patients had the del5q cytogenetic abnormality, and 5.6% were found to have at least one TP53 mutation; 2.7% were TP53 (multi-hit). 29% of all patients were up-staged from IPSS-R to IPSS-M score, while 12% were down-staged. At the time of study evaluation, there were 84 events; 61.3% of patients were alive at the time of analysis. The median overall survival was 3.6 years (25-75% range: 2.75-5.50 years). When limited to patients with peri-diagnostic bone marrow biopsies, there were statistically significant differences in overall survival between IPSS-M categories (p<0.000001) as well as IPSS-R categories (p<0.00001). There was no statistical difference in survival between IPSS-M categories (p=0.6) or IPSS-R categories (p = 0.2) if scores were calculated at any time point in the patient’s disease course. Conclusions: This study validates the utility of both the IPSS-M and the IPSS-R scoring systems, and notably retains important risk stratification with incomplete diagnostic data. Importantly, the scoring systems are not effectively prognostic as the disease progresses, and thus should only be utilized at or near the time of diagnosis.
Hematologic and transfusion outcomes in patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS) receiving luspatercept: Real-world assessment in the community practice setting.
Authors: Mukherjee Sudipto , Brown-Bickerstaff Cherrishe , Falkenstein Angelica , Makinde Adeola Y. , Bland Emily , Laney JaLyna , Garretson Marné , McBride Ali
Published: June 2023

7057

Background: Erythropoiesis-stimulating agents (ESAs) are used as first-line (1L) treatment (tx) for the management of symptomatic anemia in LR-MDS. Luspatercept is approved for pts with LR-MDS with ring sideroblasts (RS) who experience ESA failure and are transfusion dependent. We assessed clinical outcomes of pts with LR-MDS with RS, or MDS/myeloproliferative neoplasms with RS and thrombocytosis, treated with luspatercept in US community practices. Methods: This retrospective, observational cohort study used physician-abstracted chart data from community oncology clinics and included adults diagnosed with LR-MDS (including Very low- to Intermediate-risk IPSS-R status) on/after Jan 1, 2015 who received luspatercept for ≥ 3 months (mos) with ≥ 3 mos of follow-up. Transfusion burden (TB) was defined by number of sessions (ses) received in the 8 weeks (wks) prior to luspatercept tx (baseline) and the lowest number for any consecutive period ≥ 8 wks during wks 1–24 of tx: transfusion independent (TI); low TB (LTB), 1–3 ses; and moderate TB (MTB), 4–5 ses. Results: Of 253 pts, 219 (87%) had 1 tx prior to luspatercept tx and 31 (12%) received ≥ 2. ESAs were used as 1L tx in 210 pts (83%). Median follow-up was 5.7 mos. The most common reason for discontinuing initial MDS tx among patients who received ≥ 1 tx prior to luspatercept was lack of anemia improvement (133/250). At baseline, 21 (8%) pts were TI, 208 (82%) had LTB, and 24 (10%) MTB. Median duration of luspatercept tx was 10.8 mos. During wks 1–24, 20/21 (95%) pts remained TI and 201/232 (87%) pts with LTB/MTB at baseline achieved TI for ≥ 8 wks. The Table shows changes in median hemoglobin (Hb), absolute neutrophil count (ANC), and platelet (plt) count. Conclusions: Most pts with LR-MDS received 1L ESAs and over half discontinued the first tx prior to luspatercept due to lack of anemia improvement, highlighting the need for alternative options to improve clinical outcomes. Consistent with data from the MEDALIST trial, 87% of pts with LTB/MTB who received luspatercept achieved TI for ≥ 8 wks, supporting its clinical benefit in routine clinical practice. [Table: see text]
Selinexor (SEL) plus ruxolitinib (RUX) in JAK inhibitor (JAKi) treatment-naïve patients with myelofibrosis: Updated results from XPORT-MF-034.
Authors: Ali Haris , Kishtagari Ashwin , Maher Keri Renee , Mohan Sanjay , Prchal Josef T. , Wang Xulong , Chamoun Kamal , Tantravahi Srinivas Kiran
Published: June 2023

7063

Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, high symptom burden, and poor prognosis. Activity has been shown with the combination of SEL + the JAKi RUX in preclinical studies. Specific subgroups with lower response rates to RUX monotherapy, such as males vs females (25% vs 59%) and those with a lower (≤15 mg vs 20 mg) RUX starting dose (22-27% vs 43%), highlight unmet need in specific groups (grps). Methods: XPORT-MF-034 is a Phase 1/2, open-label study evaluating safety and efficacy of SEL at 40 mg and 60 mg once-weekly plus RUX per standard of care in 28-day cycles. Assessments included safety, spleen/symptom response, survival, and hemoglobin levels. The primary analysis population included those who had baseline assessment and were treated to at least Week 24 (W24) or discontinued before W24. Two pts with baseline total symptom score (TSS) = 0 were excluded from analysis of TSS reduction of ≥50% (TSS50). Results: As of Dec 21, 2022, 10 participants received 40 mg and 14 participants received 60 mg SEL; 22 of the 24 pts enrolled had reached at least W24 and were included in the efficacy analysis. The median duration of treatment was 28 wks overall, 33 wks for 60 mg and 22.5 wks for 40 mg grps. Most common adverse events (AEs) by dose (60/40 mg) were nausea (79%/70%; majority grade 1-2), anemia (79%/50%), and fatigue (57%/60%). Most common Grade ≥3 AEs were anemia (50%/40%), thrombocytopenia (29%/10%), and neutropenia (7%/20%). AEs were reversible with dose modifications. Two patients discontinued treatment due to treatment-related AEs (thrombocytopenia and neuropathy); 3 deaths have occurred in the study, none related to SEL. Overall, 64% (14/22) achieved SVR35 at W24, with 79% [11/14] vs 38% [3/8], in the 60 mg vs 40 mg grp, respectively. The 60 mg grp achieved a deeper median SVR response vs the 40 mg grp at W24 (49% vs 31%). At W24, TSS50 was achieved by 45% (9/20) overall, 58% [7/12] of the 60 mg, and 25% [2/8] of the 40 mg grp. Among 11 pts with baseline hemoglobin < 10 g/dL, median hemoglobin decreased by 0.5 g/dL from baseline to W12 and increased by 0.8 g/dL from baseline to W24. Similar efficacy was observed across all subgrps with 60 mg. Reduction of variant allele frequency from baseline to W24 was > 10% in 50% (4/8) and > 20% in 25% (2/8) of evaluable pts for 60 mg grp. Conclusions: Encouraging activity with 60mg SEL + RUX combination were observed in TSS50, SVR and hemoglobin levels overall, as well as in key subgroups including males, in pts started on low dose RUX (≤15 mg), and pts with larger baselines spleen size. Updated data will be available for presentation. Clinical trial information: NCT04562389 . [Table: see text]
Impact of transfusion burden on health-related quality of life (HRQOL) and functioning in patients (pts) with myelofibrosis (MF): Post hoc analysis of SIMPLIFY-1 (S1) and -2 (S2).
Authors: Mesa Ruben A. , Palandri Francesca , Verstovsek Srdan , Masarova Lucia , Harrison Claire , Mazerolle Flora , Gorsh Boris , M'Hari Manal , Wang Zhaohui , Ellis Catherine Elizabeth , Deheshi Samineh , Kawashima Jun , Von Maltzahn Robyn , Regnault Antoine
Published: June 2023

7066

Background: MF is associated with substantial symptom burden that can negatively impact pt quality of life (QOL). Transfusions may reduce anemia-associated symptoms, but can be burdensome and carry complications that may affect social, emotional, and general health; thus, QOL may be further negatively affected in transfusion-dependent (TD) pts. To characterize the relationship between transfusion burden and pt-reported outcomes (PROs), we report an exploratory post hoc analysis of the phase 3 S1 and S2 trials of the JAK1/JAK2/ACVR1 inhibitor momelotinib (MMB) in pts with MF. Methods: The pooled analysis set comprised both arms of the intent-to-treat populations of S1 (JAK inhibitor naive, MMB vs ruxolitinib [RUX]; N = 432) and S2 (JAK inhibitor exposed, MMB vs best available therapy [88% RUX]; N = 156). Transfusion independent (TI): no transfusions and hemoglobin (Hb) ≥8 g/dL in 12 wk; TD: ≥4 units transfused or Hb < 8 g/dL in 8 wk; transfusion requiring (TR): not meeting TI or TD criteria. PRO assessment: SF-36v2 (physical functioning [PF], role-physical [RP], general health [GH], vitality [VT], social functioning [SF], and mental health [MH] domains; norm-based scores [NBS] range from 11.6 to 70.4 based on domain). PROs by transfusion status were described over the 24-wk randomized period. Results: SF-36v2 NBS were available from 503/588 pts in the pooled analysis set at baseline (BL); mean NBS in all domains were lower than the general population mean per the SF-36v2 Manual (50; SD, 10): PF, 39.6; RP, 39.0; GH, 39.8; VT, 43.6; SF, 43.2; MH, 46.3. Within the pooled analysis set, mean NBS in all domains at BL and week 24 (W24) were lower in TD vs TI pts. Among BL TD pts (n = 150) at W24, 75 remained TD (TD-TD), 40 became TI (TD-TI), 21 became TR, and 14 had no data. Pts who became TI experienced greater improvement (positive mean change from BL) in most domains vs pts who remained TD (Table). Conclusions: Among pts with MF in S1 and S2, TD pts had lower functioning and HRQOL than TI pts across SF-36v2 domains, suggesting that transfusion dependence has detrimental effects on multiple aspects of QOL. Among BL TD pts, those who became TI at W24 had greater improvement across most domains than those who remained TD, with mean changes for TD-TI pts near or above the minimally important difference (2 or 3, based on domain) for groups with low BL NBS. These analyses highlight transfusion dependence as a key pt-centered outcome and support further research into the impact of transfusions on QOL in MF. Clinical trial information: NCT01969838 ; NCT02101268 . [Table: see text]
Longitudinal assessment of cardiac involvement in Erdheim-Chester disease using cardiac magnetic resonance imaging.
Authors: Azoulay Levi-Dan , Bravetti Marine , Cohen-Aubart Fleur , Amoura Zahir , Spano Jean-Philippe , Cluzel Philippe , Haroche Julien
Published: June 2023

7067

Background: Erdheim-Chester disease (ECD) is a rare multi-systemic non-Langerhans cell histiocytosis that affects the heart in nearly half of patients. Atrial infiltration and pericardial effusion are the hallmarks of cardiac involvement and can lead to clinical complications (conduction disorders, coronary artery stenosis, tamponade, constrictive pericarditis). Evolution under treatment is poorly studied. We aimed to investigate the evolution of cardiac involvement in ECD using cardiac magnetic resonance (CMR) imaging. Methods: All ECD patients with a CMR imaging disclosing a cardiac involvement and who underwent at least one follow-up CMR imaging between 2005 and 2020 at a French tertiary center were retrospectively included. First and last CMR imaging were compared. Multivariable analysis was performed to search for independent predictors of cardiac involvement resolution. Variables were included in the model if their P-value was < 0.1 on univariable analysis. Results: Overall, 46 patients were included. Median age at first imaging was 63 years [53-69]. Median delay between the first and the last imaging was 4 years [2-7]. BRAFV600E mutation was present in 43 patients (94%). Patients received a median of 2 [1-3] treatments. All patients (100%) had cardiac involvement at baseline. Right atrio-ventricular sulcus (RAVS) was infiltrated in 38 patients (83%) and was the main cardiac feature.Overall, complete regression was observed in 6 patients (13%), partial regression in 26 patients (56%), stable imaging in 12 patients (26%), and worsening in 2 patients (5%). In patients with RAVS infiltration, complete regression was observed in 5 patients (16%) and partial regression was seen 22 patients (58%) regression. On univariable analysis, patients with regression of their infiltration had a lower rate of death (16% versus 64%, P= 0.002), a higher rate of atrial infiltration late gadolinium enhancement (LGE) (97% versus 71%, P= 0.01), a higher rate of hydronephrosis (50% versus 14%, P= 0.03) and a lower rate of interferon prescription (69% versus 100%, P= 0.02). A similar rate of vemurafenib use was observed in both groups (69% versus 54%, P= 0.3). On multivariable analysis, death remained significantly associated with follow-up imaging status (ß = -2.3 P= 0.01), while atrial infiltration LGE (ß = 2.7, P= 0.06), hydronephrosis (ß = 1.6, P= 0.1) and treatment with interferon (ß = -16, P= 1) were no longer significantly associated with imaging status. Conclusions: Partial or complete resolution of cardiac involvement was observed in 69% of patients with ECD and was significantly associated with a lower rate of death on multivariable analysis.
Consistency of pacritinib for spleen and symptom reduction in patients with myelofibrosis regardless of cytopenias.
Authors: Bose Prithviraj , Gagelmann Nico , Gupta Vikas , McLornan Donal P. , Vachhani Pankit , Al-Ali Haifa Kathrin , Ali Haris , Treskes Philipp , Buckley Sarah , Roman-Torres Karisse , Scott Bart L.
Published: June 2023

7068

Background: In patients with myelofibrosis (MF), JAK inhibitor therapy can improve both splenomegaly and disease symptoms. Unfortunately, dosing – and thus efficacy – of available current JAK1/2 inhibitors is frequently limited in patients with cytopenic MF due to drug-induced exacerbation of cytopenias. Pacritinib is a novel JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that has been studied at full dose in patients with MF regardless of cytopenias. Here, we present data on spleen and symptom benefit in pacritinib-treated patients across the cytopenic spectrum, stratified by both baseline platelet (PLT) count and hemoglobin (HB) level. Methods: Evaluable patients treated with pacritinib in the PERSIST-1 and PERSIST-2 studies were analyzed, stratified by baseline PLT (<100, ≥100x109/L) and HB (<8, 8 to <10, ≥10 g/dL). Groups were analyzed for depth of spleen volume response (SVR), modified total symptom score (TSS) response, patient global impression of change (PGIC), and dose intensity. Results: Of 276 patients evaluable for spleen response, median age was 67 years, 51.5% had grade 3 fibrosis, 70% had primary MF, and 16% had prior JAK2 inhibitor exposure. Median dose intensity was >99.7% for the duration of the study across PLT and HB subgroups. Overall, 80% of patients had ≥10% SVR (SVR-10), 75.5% had TSS-10, and 78% reported that their symptoms were improved at week 24. Week 24 spleen reduction occurred consistently across PLT and HB strata, with 84-93% and 86-90% of patients respectively (Table). SVR-35 occurred in 23-25% of patients across PLT strata and in 21-28% of patients across HB strata. Symptom response was also consistent across strata, though TSS-50 occurred at highest rates (62.5%) in patients with HB <8 g/dL. There was no diminution in symptom burden reduction in patients with thrombocytopenia (Table). Across all subgroups, at least three-quarters of patients reported symptoms were “improved” at week 24. Conclusions: Pacritinib demonstrates consistent efficacy for spleen and symptom response in patients with MF regardless of blood counts. This consistent effect may be related to pacritinib’s unique kinome profile and its ability to be delivered at full dose in patients regardless of cytopenias. Clinical trial information: NCT01773187 , NCT02055781 . [Table: see text]
Outcomes of patients with a myeloproliferative neoplasm and atrial fibrillation.
Authors: Leiva Orly , How Chi-Joan , Brunner Andrew , Grevet Jeremy , Hobbs Gabriela
Published: June 2023

7070

Background: Patients with myeloproliferative neoplasms (MPN), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), are associated with increased risk of cardiovascular (CV) disease including arterial thrombosis (AT). Atrial fibrillation (AF) is also associated with increased risk of AT and often co-exists with MPN. However, thrombotic and bleeding outcomes in patients with MPN compared with those without have not been thoroughly investigated. Methods: Patients aged ≥ 18 years with a hospital admission for AF with and without a history of MPN in 2017 and 2018 were identified using the National Readmission Database. Primary outcomes were 30-day (D) and 90-D any-cause, AT-related (including stroke, myocardial infarction, arterial thromboembolism), and bleeding-related readmissions. Propensity score weighting (PSW) was performed in order to adjust for imbalances between MPN and non-MPN patients. PSW Cox proportional hazards was performed to estimate risk of 90-D readmission in patients with MPN compared with patients without. Results: A total of 468,094 patients with AF were identified with 1,617 patients having a history of MPN. CHA2DS2-VASC (mean 3.8 vs 3.7) and HAS-BLED scores (mean 2.4 vs 2.3), risk scores for AT and bleeding in AF, were similar between MPN and non-MPN patients. After PSW Cox proportional hazards, patients with MPN had an increased risk of 30-D all-cause (HR 1.72, 95% CI 1.70 – 1.74), AT (HR 1.45, 95% CI 1.38 – 1.53), and bleeding (HR 2.21, 95% CI 2.01 – 2.44) re-admissions. MPN patients had an increased risk of 90-day any cause (HR 1.38, 95% CI 1.37 – 1.40) and bleeding (HR 1.76, 95% CI 1.65 – 1.88) but not AT (HR 1.03, 95% CI 0.99 – 1.08) readmissions. Conclusions: Among patients admitted for AF, MPN is associated with increased risk of 30-D and 90-D any-cause and bleeding readmissions and 30-D AT readmissions despite similar CHA2DS2-VASC and HAS-BLED risk scores. Further studies are needed to identify risk factors for bleeding and AT in patients with MPN and AF and improve on current risk scores, which do not include MPN status. [Table: see text]
Outcomes of individuals with clonal hematopoiesis evaluated at a cancer center.
Authors: Chien Kelly Sharon , Ong Faustine , Kim Kunhwa , Li Ziyi , Kanagal-Shamanna Rashmi , Dinardo Courtney Denton , Takahashi Koichi , Montalban-Bravo Guillermo , Hammond Danielle , Sasaki Koji , Pierce Sherry , Kantarjian Hagop M. , Garcia-Manero Guillermo
Published: June 2023

7072

Background: Clonal hematopoiesis (CH) refers to the presence of somatic mutations in individuals without overt hematological disorders. CH, including CH of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), is associated with hematologic malignancies and other systemic comorbidities. There are currently no established guidelines regarding the optimal monitoring and management of patients with CH, and the impact of CH in patients with concomitant underlying malignancies remains unknown. Methods: Patients seen at a tertiary cancer center with at least 1 somatic mutation detected by next generation sequencing on bone marrow aspirate or peripheral blood between January 2015 and March 2021 were included. Patients with donor-derived CH or any morphologic evidence of a myeloid neoplasm were excluded. Results: We evaluated 78 patients – 76% had a history of malignancy and 73% had other comorbidities. The mutations most frequently observed were DNMT3A (40%), TET2 (31%), TP53 (26%), and ASXL1 (18%). The median overall survival for all patients was not reached (2-year survival rate of 79%). Most deaths were related to primary malignancies (35%), comorbidities (20%), or myeloid neoplasms (20%). Due to concomitant use of antineoplastic therapy and other causes of cytopenia in 19 patients, we further categorized patients into 4 groups: CHIP on treatment (CHIP-T), other CHIP (CHIP-O), CCUS on treatment or with a non-myeloid hematologic malignancy (CCUS-T), and other CCUS (CCUS-O). Transformation to a myeloid neoplasm occurred in 12 patients (15%). The 3-year cumulative incidence of transformation was higher in CCUS-O (24%) and CCUS-T (21%) compared to the CHIP group (6%, p = 0.48). On univariate analysis, increasing age, variant allele frequency (VAF) ≥ 0.2, hemoglobin < 10 g/dL, and any chromosomal abnormalities were associated with higher risk for transformation. By multivariate analysis, transformation was only significantly associated with VAF ≥ 0.2 (hazard ratio (HR) 18.25; 95% confidence interval (CI): 3.59, 92.73; p = 0.0005) and hemoglobin < 10 g/dL (HR 15.62; 95% CI: 3.29, 74.05; p = 0.0005). Conclusions: CH in predominantly cancer patients is associated with cardiovascular disease and transformation to myeloid neoplasms, especially in those with higher mutational burdens and anemia. However, patients die more frequently from their primary malignancy or comorbidities than from a myeloid neoplasm. Close monitoring of hematologic progression and extra-hematologic manifestations of CH is crucial. Further investigation into the identification of individuals at high risk of myeloid transformation and potential early therapeutic interventions for this population is warranted.
Lisocabtagene maraleucel (liso-cel) in R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of TRANSCEND CLL 004.
Authors: Siddiqi Tanya , Maloney David G. , Kenderian Saad , Brander Danielle M. , Dorritie Kathleen Anne , Soumerai Jacob , Riedell Peter A. , Shah Nirav Niranjan , Nath Rajneesh , Fakhri Bita , Stephens Deborah Marie , Ma Shuo , Feldman Tatyana A , Solomon Scott R. , Schuster Stephen J. , Perna Serena K. , Ou San-San , Papp Eniko , Chen Yizhe , Wierda William G.
Published: June 2023

7501

Background: In patients (pts) with R/R CLL/SLL that progressed on BTKi and failed venetoclax (ven)-based regimens, achieving CR with current treatment is uncommon. New therapies that achieve deep and durable responses are needed. We report the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study evaluating liso-cel in pts with R/R CLL/SLL. Methods: Pts must have received at least 2 prior lines of therapy, including a BTKi. Eligible pts received liso-cel at a target dose of either 50 (DL1) or 100 (DL2) × 106 CAR+ T cells. The primary endpoint was rate of CR and CR with incomplete marrow recovery (CRi) by IRC per 2018 iwCLL criteria in the prespecified subset of efficacy-evaluable pts with disease progression on BTKi and ven failure (primary efficacy analysis set [PEAS]) at DL2 (null hypothesis [H0]: ≤ 5%). Key secondary endpoints were ORR (H0: ≤ 40%) and rate of undetectable minimal residual disease (uMRD; 10−4) in blood (H0: ≤ 5%). Results: Of 137 leukapheresed pts, 117 received liso-cel (safety set), 96 (DL1 = 9; DL2 = 87) were efficacy evaluable, and 53 (DL1 = 4; DL2 = 49) were in the PEAS. In the safety set, median (range) age was 65 y (49–82), 83% had high-risk features, median (range) lines of prior therapy was 5 (2–12), and all pts had prior BTKi. Median (range) on-study follow-up was 21.1 mo (0.4–55.6) for the safety set. In the PEAS at DL2, the primary endpoint of CR/CRi rate was met at 18.4% (95% CI, 8.8–32.0; 1-sided P = 0.0006; Table). ORR was 42.9% and was not statistically significant (95% CI, 28.8–57.8; 1-sided P = 0.3931). The uMRD rate was 63.3% in blood and 59.2% in marrow. Median (95% CI) DOR was 35.3 mo (11.01–not reached [NR]) with a median follow-up of 19.7 mo. Median duration of CR/CRi was NR. In the safety set, rate of any-grade CRS was 84.6% (gr 3, 8.5%; no gr 4/5) and neurological events (NE) was 45.3% (gr 3, 17.9%; gr 4, 0.9%; no gr 5); 69.2% received tocilizumab and/or corticosteroids for CRS/NEs. Rate of gr ≥ 3 infections, hypogammaglobulinemia, and prolonged cytopenia was 17.1%, 15.4%, and 53.8%, respectively. One death related to liso-cel was due to hemophagocytic lymphohistiocytosis. Liso-cel exhibited rapid in vivo expansion and was detected by qPCR in blood up to 36 mo after infusion. Conclusions: Liso-cel demonstrated durable CR/CRi, high uMRD rates, and a manageable safety profile in pts with heavily pretreated, high-risk R/R CLL/SLL and high unmet need. Clinical trial information: NCT03331198 . [Table: see text]
Epcoritamab + R2 regimen and responses in high-risk follicular lymphoma, regardless of POD24 status.
Authors: Merryman Reid , Belada David , Sureda Anna , Leppä Sirpa , Vermaat Joost S.P. , Holte Harald , Hutchings Martin , Lugtenburg Pieternella , de Vos Sven , Abrisqueta Pau , Nijland Marcel , Christensen Jacob Haaber , Wahlin Björn E. , Linton Kim M. , Wang Liwei , Abbas Aqeel , Rana Ali , Quadri Syed , Falchi Lorenzo
Published: June 2023

7506

Background: Follicular lymphoma (FL) is a heterogeneous disease. Early progression after initial treatment (tx) with chemoimmunotherapy (CIT), POD24, occurs in around 20% of patients (pts) and strongly predicts poor outcomes. There is no standard tx approach for high-risk, relapsed or refractory (R/R) FL (high-risk subgroups in Table). Novel options are needed to improve efficacy in pts with high unmet need. Epcoritamab, a subcutaneous (SC) T-cell–engaging bispecific antibody, demonstrated impressive single-agent antitumor activity and a manageable safety profile in R/R FL (Hutchings et al, Lancet 2021) and shows promise combined with standards of care. Here we present pooled analyses from cohorts 2a and 2b of the ongoing phase 1/2 EPCORE NHL-2 trial (NCT04663347) of epcoritamab with rituximab + lenalidomide (R2). Methods: Pts with R/R CD20+ FL received epcoritamab SC + R2 for 12 cycles (Cs; 28 d each). Epcoritamab was dosed QW in C1–3, Q2W in C4–9, and Q4W in C≥10 (2a) or QW in C1–2 and Q4W in C≥3 (2b) for ≤2 y. Results: As of Oct 31, 2022, 109 R/R FL pts had received epcoritamab 48 mg + R2 in 2a and 2b. Median age was 65 y, 56% of pts had FLIPI 3–5, 61% had stage IV disease, and 59% had only 1 prior tx. Most had received alkylating agents (92%) or anthracyclines (62%); 2 had prior CAR T. At a median follow-up of 8.8 mo (range, 1.2–18.5), 82% were still on tx. The most common tx-emergent AEs were: CRS and neutropenia, 48% each; injection-site reactions, 38%; and fatigue, 33%. CRS events were mostly low grade (G; 46% G1–2, 2% G3) and mostly occurred following the first full dose on C1D15; all resolved and none led to discontinuation. ICANS occurred in 2 pts (G1, G2) and resolved. In 101 efficacy-evaluable pts, overall response rate (ORR) was 97%, with complete metabolic response (CMR) in 86%. Notably, pts achieved higher ORR/CMR rates with epcoritamab + R2 vs their immediate prior tx line (ORR, 97% vs 85%; CMR, 86% vs 60%). Estimated 6-mo progression-free survival was 93%. In second-line (2L) pts with POD24, ORR/CMR rates were 95%/90% (additional high-risk subgroup data in Table). Additional data with longer follow-up will be presented. Conclusions: Epcoritamab + R2 showed potent antitumor activity and a manageable safety profile in a large R/R FL population. Encouraging responses were seen in pts with high-risk disease, suggesting epcoritamab SC may abrogate negative effects of high-risk features. A separate POD24 cohort is planned, and epcoritamab + R2 is being studied in the phase 3 EPCORE FL-1 trial (NCT05409066). Clinical trial information: NCT04663347 . [Table: see text]
Response-adapted therapy (tx) with nivolumab plus brentuximab vedotin (nivo + BV) without autologous hematopoietic cell transplantation (auto-HCT) in children, adolescents, and young adults (CAYA) with low-risk relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL): CheckMate 744.
Authors: Harker-Murray Paul David , Cole Peter D. , Hoppe Bradford S. , Hodgson David C. , Beishuizen Auke , Garnier Nathalie , Buffardi Salvatore , Mascarin Maurizio , Lissat Andrej , Akyol Alev , Crowe Russell , Li Ju , Drachtman Richard A. , Kelly Kara M , Leblanc Thierry , Daw Stephen
Published: June 2023

7515

Background: Outcomes are poor for patients (pts) with cHL who develop R/R disease after first-line (1L) chemotherapy ± radiotherapy (RT). Salvage tx that attain high event-free survival (EFS) rates and minimize late toxicity by omitting high-dose chemotherapy (HDCT)/auto-HCT are needed. CheckMate 744 (NCT02927769) is the first multicenter phase 2 study evaluating a risk-stratified, response-adapted salvage tx with nivo + BV in CAYA with R/R cHL. In the standard-risk cohort, complete molecular response (CMR) rate before consolidation with HDCT/auto-HCT was 94% (Harker-Murray et al. Blood 2022). With highly active salvage tx, pts in low-risk cohort could achieve high EFS without HDCT/auto-HCT; we report data from this cohort. Methods: Pts were aged 5–30 y and had ≤ 3 cycles (C) of 1L anthracycline-based systemic tx. Risk stratification was described in Harker-Murray et al. Pts received 4C of nivo + BV induction. Pts with CMR received additional 2C nivo + BV before involved-site radiation therapy (ISRT) consolidation (dose, 30–30.6 Gy). Pts with suboptimal response received 2C BV + bendamustine intensification; pts with CMR proceeded to ISRT consolidation. Primary endpoints: CMR rate (Lugano 2014) any time before ISRT and 3-y EFS rate, both per blinded independent central review (BICR). For CMR and overall response rate (ORR), a 90% confidence interval (CI) was used per statistical plan. Results: Among 28 pts treated with nivo + BV, median (range) age was 17 (6–27) y; 64% of pts were aged < 18 y. Most (64%) pts had stage II disease at relapse; 82% had relapse ≥ 12 mo after 1L tx, 2 pts had prior RT. Median (range) follow-up was 31.9 (2.2–55.3) mo. CMR, ORR, 3-y EFS and PFS rates are shown in Table. Median duration of response was not reached; 87% of pts had sustained response at 36 mo’ follow-up. Efficacy outcomes were comparable in the pediatric population (CMR per BICR before ISRT, 88.9%; 3-y EFS rate, 78.3%). During induction, 22 (78.6%) pts had treatment-related adverse events (TRAEs; grade 3/4, 25.0% pts; hematologic, < 10% pts; immune-mediated, 21.4%). Serious AEs leading to discontinuation included rash, pyrexia, and acute kidney injury (1 pt each). Conclusions: The findings demonstrate that most CAYA with low-risk R/R cHL can be salvaged with chemoimmunotherapy with a favorable toxicity profile, and do not require HDCT/auto-HCT. Clinical trial information: NCT02927769 . [Table: see text]
Subgroup analyses of primary refractory (refr) vs early relapsed (rel) large B-cell lymphoma (LBCL) from the TRANSFORM study of lisocabtagene maraleucel (liso-cel) vs standard of care (SOC) as second-line (2L) therapy.
Authors: Nastoupil Loretta J. , Kamdar Manali K. , Chavez Julio C. , Ghesquieres Herve , Ghosh Monalisa , Holmes Houston , López Guillermo Armando , Martinez-Lopez Joaquin , Novak Urban , Ribrag Vincent , Roddie Claire , Waller Edmund K. , Feldman Tatyana A , Rosenthal Allison Claire , Sauter Craig , Von Bonin Malte , Karmali Reem , Montheard Sandrine , Previtali Alessandro , Abramson Jeremy S.
Published: June 2023

7526

Background: The TRANSFORM primary analysis (PA; NCT03575351) confirmed the superior efficacy of liso-cel vs SOC as 2L therapy in patients (pts) with primary refr or early rel LBCL (Abramson et al. Blood 2022). Response to first-line (1L) therapy (refr vs rel), which was a study randomization stratification factor, may influence future treatment response. Here, we present results for refr and rel LBCL subgroups from the TRANSFORM PA. Methods: TRANSFORM is a randomized phase 3 study of liso-cel vs SOC (salvage chemotherapy [CT] followed by high-dose CT [HDCT]/autologous SCT [ASCT]) in adults ≤ 75 y with LBCL primary refr to or rel ≤ 12 mo after 1L therapy and eligible for HDCT/ASCT. The primary endpoint was event-free survival (EFS); key secondary endpoints were CR rate, PFS, and OS. In this predefined subgroup analysis, refr was SD, PD, PR, or CR with rel < 3 mo after 1L therapy; rel was CR with rel ≥ 3 mo and ≤ 12 mo after 1L therapy. Results: 92 pts were randomized to each arm. Most pts in the liso-cel and SOC arms had refr disease (73% and 76%, respectively; rel disease, 27% and 24%). Baseline characteristics in the refr and rel subgroups, respectively, were generally balanced: median LDH (U/L; liso-cel, 228.5 and 225; SOC, 259 and 259); median SPD (cm2; liso-cel, 11 and 12; SOC, 15.5 and 18); high-grade B-cell lymphoma (liso-cel, 27% and 16%; SOC, 27% and 9%); diffuse LBCL not otherwise specified (liso-cel, 58% and 56%; SOC, 49% and 73%). Consistent with the overall study population, EFS, CR rate, and PFS favored liso-cel vs SOC in both subgroups (Table). Safety was also consistent. Grade ≥ 3 cytokine release syndrome (CRS) and neurological events (NE) were low in refr (1% and 4%) and rel (0 and 4%) subgroups, respectively, with no grade 4/5 CRS or NEs. Conclusions: In TRANSFORM, liso-cel showed benefits in EFS, PFS, and CR rate vs SOC irrespective of prior response to 1L therapy. As refr LBCL is historically difficult to treat, outcomes for liso-cel in this subgroup are encouraging. Clinical trial information: NCT03575351 . [Table: see text]
Patient perspectives on CLL treatment side effects: A sub-analysis of the VOICE survey.
Authors: Tam Constantine Si Lun , Pinilla-Ibarz Javier , Karakus Volkan , Pavlovsky Miguel , Šimkovič Martin , Stilgenbauer Stephan , Fenili Ana Cristina , Miroli Miguel Augusto , Castillo Carolina Garcia , Huntley Kathryn , Moura Catherine , Piotrowski Fernando , Mattar Mervat
Published: June 2023

7534

Background: Treatment for chronic lymphocytic leukemia (CLL), including chemoimmunotherapy and targeted drugs, is associated with various adverse events. We surveyed patients with CLL about their knowledge and attitudes regarding treatments and “side effects” (SEs), a more widely understood term for adverse events. Methods: Clinicians and patient advocacy group representatives developed and distributed a survey from March through December 2022 in 12 countries to patients with CLL who underwent ≥1 line of treatment. The anonymous survey was available via an electronic platform, digital questionnaires (.pdf), or paper forms. This sub-analysis includes items regarding SEs during treatment intervals, although the SEs queried were not comprehensive. Results: Treatment SEs had a moderate or high impact on 27%–43% of patients in every domain queried (Table). Most patients (300/370; 81%) discussed SEs with their physicians “always” or “sometimes”, but (117/277) were seeking more information about the benefits and SEs associated with their treatment, primarily via the internet. When asked how they would respond to common SEs, most patients would consult their physician first . Notably, >10% of them would continue treatment normally if they experienced arrhythmias or cardiac problems, and 21% would continue if they developed hypertension (Table). A similar proportion (11%) would continue treatment if they had an infection, while 23% of them would consider stopping treatment without medical advice if they developed skin cancer. Conclusions: These results show the impacts of SEs from CLL treatment affect substantial numbers of patients in multiple life areas. The responses suggest that despite patient-physician communication about SEs, there is a need to help patients find reliable information about their treatments online as well. Finally, patients’ willingness to stop or continue treatment in the event of various SEs, including cardiovascular or oncologic events, indicates a critical knowledge gap regarding the risk associated with these events. The real-world data presented herein highlights areas in which improved patient education initiatives could directly improve patient outcomes. [Table: see text]
Real-world (RW) dosing patterns and outcomes among chronic lymphocytic leukemia (CLL) patients (pts) with or without an ibrutinib (IBR) dose adjustment (DA) in first-line (1L).
Authors: Rogers Kerry Anne , Lu Xiaoxiao , Emond Bruno , Ding Zhijie , Lefebvre Patrick , Lafeuille Marie-Hélène , Mavani Heena , Qureshi Zaina P. , Ghosh Nilanjan
Published: June 2023

7537

Background: Pts treated for CLL with IBR, a once-daily Bruton’s tyrosine kinase inhibitor with dosing flexibility options, may adjust their daily dose to help prevent recurrence or worsening of adverse events, while preserving efficacy. This RW study describes outcomes for CLL pts treated with 1L IBR who did or did not have a DA. Methods: Electronic medical records from the Acentrus database (1/1/2016-4/30/2022) were used to identify CLL pts initiated on 1L IBR (index date). The first 6 months post-index were used to identify pts who remained on a starting dose of 420mg/day or with a DA (reducing to a dose lower than 420mg/day; reasons for DA not available). Treatment adherence (measured by proportion of days covered [PDC] and medication possession ratio [MPR]) and time to next treatment (TTNT) were described for patients with and without a DA. Descriptive analyses are reported for all pts and among a subgroup of pts with high cardiovascular (CV) risk, defined as having a pre-existing CV comorbidity or a high CV risk score (CV subgroup). Results: 1,171 CLL patients were initiated on 1L IBR at the recommended dose of 420mg/day (Table). Of those, 1,038 (88.6%) remained on 420 mg for ≥6 months (mean age=70.2 years, 33.6% female, median follow-up: 30.5 months); 229 (19.6%) had a DA at any time post-index (median time to DA: 5.5 months) and 126 had the DA during the first 6 months (mean age=72.2 years, 42.9% female, median follow-up: 35.1 months). Mean PDC and MPR were descriptively higher in pts with a DA (overall: PDC=0.81, MPR=0.84; CV subgroup: PDC=0.78, MPR=0.81) relative to pts with no DA (overall: PDC=0.70, MPR=0.73; CV subgroup: PDC=0.69, MPR=0.72). Median TTNT was not reached for pts with or without a DA; 12-month Kaplan-Meier (KM) rates were similar for pts with a DA (overall: 89.1%; CV subgroup: 92.7%) and with no DA (overall: 92.5%; CV subgroup: 92.0%). Conclusions: Among CLL pts initiating 1L with standard-of-care IBR, 19.6% had a DA. Those with a DA had descriptively higher treatment adherence with no detriment to TTNT, relative to those who maintained 420mg/day starting dose, regardless of baseline CV risk. These findings are consistent with other RW studies and suggest that IBR DA can be an effective treatment strategy that does not negatively affect efficacy while being well-tolerated outside of clinical trials. [Table: see text]
Ibrutinib dose modifications for management of cardiac adverse events in patients with B-cell malignancies: Pooled analysis of 10 clinical trials.
Authors: Stephens Deborah Marie , Brown Jennifer R. , Ma Shuo , Wang Michael , Moreno Carolina D. , Robak Tadeusz , Stevens Don A. , Li (Lee) Xin (Shane) , Saifan Chadi , Hsu Emily , Patel Sima , Burger Jan Andreas
Published: June 2023

7538

Background: Continuous therapy with once-daily ibrutinib (Ibr) is associated with long-term PFS in pts with B-cell malignancies. Dose reduction is a potential AE management approach that may optimize treatment outcomes. We evaluated outcomes with dose reductions in Ibr-treated pts with cardiac AEs. Methods: Data were pooled for Ibr-treated pts from 10 studies of CLL (n=781), mantle cell lymphoma (MCL; n=250), marginal zone lymphoma (MZL; n=63) or Waldenström macroglobulinemia (WM; n=169). Cardiac AEs, initial and recurrent, were identified by preferred terms within the cardiac disorders system organ class. Recurrence was defined as an AE of same or worse grade, and was measured up to 30 days after last dose of ibrutinib or start of next-line therapy, whichever occurred earlier. Results: Overall, 234/1263 pts (19%) had cardiac AEs of any grade. Twelve pts were excluded from the analysis: 9 who had a dose reduction prior to a cardiac AE (0.7%) and 3 who had a fatal cardiac AE with no prior cardiac AE (0.2%). Of the remaining 222 pts with grade 1-4 cardiac AEs, 22 (10%) had Ibr dose reduction to 420 mg (n=3), 280 mg (n=10), or 140 mg (n=9) after a cardiac AE. These pts (n=22) tended to be older (≥75 y: 45% vs 29%), less heavily pretreated (≥1 prior therapy: 45% vs 73%), and with a lower Ibr discontinuation rate (23% vs 48%) than those without dose reduction (n=200). Recurrence of the same cardiac AEs at the same or worse severity was less frequent in pts with dose reductions, both overall (14% vs 18%) and as serious AEs (5% vs 10%). No pt died due to cardiac AE recurrence. Among pts with cardiac AEs who started with the 420 mg Ibr dose (177/222; excludes 45 patients with MCL or MZL who per label start with 560 mg dose), no cardiac AE recurred at same or worse severity in the subset with dose reductions (Table). PFS was not negatively impacted by dose reduction, both overall (n=22; median PFS not reached [NR], 24-mo PFS: 91%), and in those who started with the 420 mg dose (n=18; median PFS NR; 24-mo PFS, 94%). Conclusions: Dose reduction for cardiac AEs may enable pts to continue to benefit from long-term Ibr and mitigate the risk of cardiac AE recurrence or worsening. Clinical trial information: NCT01105247 , NCT01236391 , NCT01578707 , NCT01722487 , NCT01611090 . [Table: see text]
Depth of metabolic response at interim PET and survival outcomes among patients with primary refractory and early relapsing diffuse large B-cell lymphoma (DLBCL).
Authors: Bock Allison Marie , Mwangi Raphael , Ataei Fatemah , Thorpe Matthew , Maurer Matthew J. , Pritchett Joshua , Shreve Jacob Tyler , Paludo Jonas , Khurana Arushi , Cerhan James Robert , Witzig Thomas E. , Habermann Thomas Matthew , Wang Yucai , Young Jason R. , Nowakowski Grzegorz S.
Published: June 2023

7543

Background: Total metabolic tumor volume (TMTV) and maximum standardized uptake value (SUVmax) may improve upon standard 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET-CT)-based assessment of advanced DLBCL during treatment. We report the association of TMTV and SUVmax changes at interim PET-CT (PET2) on survival outcomes in patients with primary refractory DLBCL (prDLBCL) and early relapsing DLBCL (erDLBCL). Methods: Adult patients with prDLBCL (less than a complete response (CR) or progression by the end of treatment (EOT)) or erDLBCL (CR at EOT with relapse within 12 months) between 2005 and 2019 at Mayo Clinic Rochester were included. The % change (Δ) from baseline to PET2 (after 2 cycles of 1L therapy) of TMTV and SUVmax were measured. A PET segmentation threshold of 1.5 liver mean SUV + two standard deviations with a minimum volume constraint of 0.5 mL was utilized (MIM Software, Inc., Cleveland OH, USA) with manual input as needed. Functional splines analysis determined SUVmax and TMTV threshold for analysis. Results: 131 patients had complete PET-CT data (N=79 prDLBCL, N=52 erDLBCL). Baseline median TMTV and SUVmax were 767.4 cm3 (range 0.9-6840.4) and 20.5 (2.0-52.6), respectively. At a median follow up of 77.6 months, 81 patients had died. 2-year OS rate was 53% (95% CI: 42-67) for patients with a PET2 ΔSUVmax decline ≥65% compared to 15% (95% CI: 7-29) for patients with a PET2 ΔSUVmax decline <65%(p<0.001). PrDLBCL had a 2-year OS rate of 48% (95% CI: 31-74) for a ΔSUVmax ≥65% compared to 7% (95% CI: 2-21) for a ΔSUVmax <65%(p<0.001), which captured 58% of prDLBCL patients (N=46). Two-year OS rate was 43% (95% CI: 34-54) for patients with a ΔTMTV ≥75% compared to 5% (95% CI: 1-35) for patients with ΔTMTV <75% (p<0.001). All patients with a ΔTMTV <75% had prDLBCL. PrDLBCL had a 2-year OS rate of 28% (95% CI: 18-44) for a ΔTMTV ≥75%. The outcomes for ΔSUVmax <65% and ΔTMTV <75% at PET2 remained significant in a cox regression model adjusted for IPI and bulky disease (>10cm)(Table). Conclusions: A ΔTMTV decline <75% or a ΔSUVmax decline <65% at PET2 identified an ultra-high-risk subgroup of DLBCL with particularly poor outcomes, that captured a high percentage of prDLBCL patients, and was significant after adjusting for IPI and bulky baseline disease. These patients may benefit from clinical trials evaluating alternative PET-adapted treatment strategies, but further evaluation among all patients with DLBCL is needed. [Table: see text]
Final three-year follow-up analysis of phase I/II study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma.
Authors: Asai Katsunori , Narita Yoshitaka , Nagane Motoo , Mishima Kazuhiko , Terui Yasuhito , Arakawa Yoshiki , Yonezawa Hajime , Fukuhara Noriko , Sugiyama Kazuhiko , Shinojima Naoki , Aoi Arata , Nishikawa Ryo
Published: June 2023

7548

Background: Primary central nervous system lymphoma (PCNSL) is known as an uncommon and extremely aggressive type of non-Hodgkin lymphoma of brain tumors. Tirabrutinib (TIR), a second-generation oral Bruton’s tyrosine kinase inhibitor, was approved for the treatment of relapsed or refractory PCNSL (rrPCNSL) based on the results of phase I/II study in Japan (Trial registration: JapicCTI-173646) in 2020. Methods: In this study, 44 Japanese patients with rrPCNSL received TIR QD at doses of 320 mg (n = 20), 480 mg (n = 7), or 480 mg while fasting (480 mg fasted: n = 17). The International PCNSL Collaborative Group criteria were used to assess the primary endpoint, which was the overall response rate (ORR). We previously reported the interim results with 14.9 (range:1.4–27.7) months of median follow-up in 2020 (Mishima et al., the 25th Society for Neuro-Oncology 2020). The final analysis results with a three-year follow-up are reported here (data cutoff: April 27th, 2022). Results: For the entire population, the ORR was 63.6% with 36.4% of complete response, the median duration of response was 9.2 months, the median progression-free survival was 2.9 months, and the median overall survival was not reached (median follow-up: 37.1 months). The most frequent adverse events (AEs) were skin and subcutaneous tissue disorders and blood and lymphatic system disorders at any grade, including rash (36.4%) and neutropenia (27.3%), leukopenia (25.0%), lymphopenia (18.2%), and thrombocytopenia (11.4%). Grade ≥3 AEs were neutropenia (9.1%), leukopenia (9.1%), lymphopenia (6.8%), and erythema multiforme (6.8%). One patient with 480 mg had grade 5 AEs (Pneumocystis jirovecii pneumonia and Interstitial lung disease), while neither new grade 5 AEs nor new safety profiles were observed since the last data cutoff. As of the current data cutoff, 15 and 6 of 44 patients had been receiving TIR for more than one and three years, respectively, and 5 of the 6 patients continued receiving TIR, including 4 patients who were receiving 480 mg fasted. Conclusions: In conclusion, TIR showed long-lasting effectiveness in a subset of patients with a tolerable safety profile of rrPCNSL. Clinical trial information: JapicCTI-173646. [Table: see text]