A Comparison of Prognostic Indices in Diffuse Large B-Cell Lymphoma within the UK NCRI R-CHOP 14 Versus 21 Phase III Trial

Abstract Background: The International Prognostic Index (IPI) was first described in 1993 and is the most widely used prognostication tool in diffuse large B-cell lymphoma (DLBCL). Five independent risk factors for OS: age (≤60 yrs versus >60 yrs), stage (I/II versus III/IV), number of extranodal (EN) sites (≤1 versus >1), performance status (PS) (0-1 versus ≥2) and serum lactate dehydrogenase (LDH) (normal versus elevated) were used to design a prognostic model which stratified patients into 4 prognostic groups according to the number of risk factors present: low (0-1), low-intermediate (2), high-intermediate (3), and high-risk (4-5); predicting 5-yr OS rates of 73%, 51%, 43% and 26% and 5-yr relapse-free survival (RFS) rates of 70%, 50%, 49%, 40% respectively. For patients aged ≤60 yrs 3 risk factors (stage, PS and LDH level) remained independently significant for OS, and an age-adjusted (aa) model (the aa-IPI) was proposed which predicted 5-yr OS for the low (0), low-intermediate (1), high-intermediate (2) or high-risk (3) groups of 83%, 69%, 46% and 32% respectively (Shipp et al, 1993). The British Columbia Cancer Agency re-evaluated the role of IPI in the rituximab era in their registry-based cohort of 365 patients in 2007. Although the IPI remained predictive, only 2 (rather than 4) prognostic groups were identified and the authors recommended use of the Revised-IPI (R-IPI) where redistribution of the absolute number of IPI risk factors better stratified patients into 3 prognostic groups: very good (0) good (1,2) and poor (3-5) (Savage et al, 2007). However, a subsequent analysis of pooled data from 3 prospective trials (Ziepert et al, 2010) confirmed that the IPI remained highly predictive of outcomes in the rituximab era. Here we report an evaluation of prognostic indices within the UK NCRI R-CHOP 14 vs 21 prospective trial cohort (Cunningham et al, 2013). Methods: The IPI and R-IPI were applied to the R-CHOP 14 versus 21 trial cohort (n=1,080) and for the subgroup of patients aged ≤60 yrs (n=515) and correlated with OS and progression-free survival (PFS). For patients aged ≤60 yrs the aa-IPI was applied in addition. It was not possible to evaluate the NCCN-IPI in our cohort as absolute LDH values were not collected at enrolment. The association between baseline clinical factors (age, gender, PS, stage, presence of >1 EN site of disease, presence of an elevated LDH, disease bulk and B symptoms) and patient outcomes were investigated in univariable and multivariable analysis (MVA). Performance of the prognostic indices was compared using the Concordance Probability Estimate (CPE) and Akaike's Information Criterion (AIC): CPE evaluates discriminatory power to assess the strength of statistical models (higher values indicate better discrimination); AIC estimates the quality of statistical models relative to each other in terms of fitting the data (lower values indicate a better model fit). Results: After a median follow-up of 6.5 years, both the IPI and R-IPI were significantly associated with OS (Figure 1) and PFS; the IPI performed better than the R-IPI for OS and PFS in terms of discrimination and model fit (Table 1). All IPI factors were significantly associated with OS, and remained in MVA with the exception of disease stage. For patients aged ≤60 yrs, the IPI, R-IPI and aa-IPI were all strongly associated with OS and PFS; the IPI performed best overall of the 3 prognostic indices in terms of discrimination and model fit (Table 2). All individual IPI risk factors, excepting stage, were again found to be significantly associated with OS in MVA for patients aged ≤60 yrs. Conclusion: For the entire DLBCL cohort both the IPI and R-IPI identified meaningful prognostic groups for OS and PFS. Although the IPI outperformed the R-IPI, neither index identified a patient subgroup with an OS of <50% at 5 years. When the analysis was limited to patients aged ≤60 yrs all 3 indices were prognostic, however the IPI performed best overall and was the only risk model to detect a patient subgroup with a 5-yr OS of 45.8%. Our findings suggest that neither the R-IPI nor aa-IPI offer an improvement over the standard IPI in predicting outcomes in DLBCL. Furthermore, our analysis highlights the lack of precision of the traditional prognostic indices in identifying very poor risk patients treated in the rituximab era. Disclosures Cunningham: Roche pharmaceuticals: Research Funding. Hawkes:Bristol Myers Squibb: Other: Speaker fee, Research Funding; Merck KGA: Research Funding; Astra Zeneca: Research Funding; Merck Sharpe Dohme: Research Funding; Celgene: Other: Advisory board, Research Funding; Takeda: Other: Speaker fee; Merck: Other: Advisory board; Roche: Other: Speaker fee; advisory board. Pocock:Kent & Canterbury Hospital: Employment. Ardeshna:Celgene: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference expenses, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Radford:Celgene: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; Novartis: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; BMS: Consultancy, Speakers Bureau; Pfizer: Research Funding. McMillan:Celgene: Honoraria, Other: travel support; BMS: Honoraria; Amgen: Honoraria; Takeda: Other: travel support; Roche: Consultancy, Honoraria, Other: travel support; Pfizer: Research Funding; MSD: Honoraria. Johnson:Janssen: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Boeringher Ingelheim: Consultancy; Kite: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Travel, accommodations, expenses; Novartis: Honoraria; Celgene: Honoraria; Eisai: Research Funding; Zenyaku Kogyo: Other: Travel, accommodations, expenses; Genmab: Consultancy.

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Ritumixab in Combination with Adapted-Dose of Ifosfamide and Etoposide As Salvage Treatment in Elderly Refractory/Relapsed Diffuse Large B-Cell Lymphoma Patients Non-Candidate for High Dose Therapy: A Retrospective Study of Lyon Hospital University

Blood ◽

10.1182/blood-2018-99-116734 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4215-4215

Author(s):

Guillaume Aussedat ◽

Delphine Maucort-Boulch ◽

Philippe Rey ◽

Violaine Safar ◽

Lionel Karlin ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Advisory Board ◽

High Dose ◽

First Line ◽

Advisory Committees ◽

Previously Treated ◽

Grade 3

Abstract Introduction: standard treatment for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is high-dose chemotherapy followed by autologous stem-cell transplantation (ASCT) but this strategy is not appropriate for elderly DLBCL patients (pts) related to a high risk of toxicities. Multiple chemotherapy regimens had been developed for heavily pretreated elderly DLBCL patients such as R-bendamustine, R-gemcitabine-oxaliplatin (R-GEMOX) and pixantrone; the median progression free survival (PFS) of these regimens were 2, 4 and 3.5 months, respectively in prospective phase II studies for patients previously treated with R (Sehn 2017, Mounier 2013, Pettengel 2016). Adapted dose of ifosfamide and etoposide was firstly developed as sequential consolidation regimen after high-dose CHOP (ACVBP regimen) in first line therapy of young DLBCL patients (Tilly 2003). This regimen with a safe toxicity profile was then used in combination with R in Lyon University Hospital in elderly R/R DLBCL ineligible to intensive strategy. Methods: we retrospectively reviewed the efficacy and the safety profile of this regimen performed in two Lyon University Hospitals (Centre Hospitalier Lyon Sud and Leon Berard Cancer Center). Between June 2004 and March 2017, 75 pts with R/R DLBCL (63 de novo DLBCL, 12 transformed DLBCL) received R (375 mg/m2) in combination etoposide (300 mg/m2) and ifosfamide (1500 mg/m2) on day 1 (N=72, 96%) and on days 1-2 (N=3, 4%) at 2 (N=46, 61%) or 3-week (N=29, 39%) intervals. All medical records were reviewed for clinical and biological characteristics, modality of treatment and supportive care, toxicities, responses and outcome. Results: the median age was 79 years (range, 64-92) at the beginning of R-ifosfamide/VP16 treatment with 46% of the patients over 80 years. 13% of pts had a CIRS-G grade 3 or 4 >2 categories and 35% had a cumulative CIRS-G score more than 6. The performance status according to EORTC scale was 2-4 in 37% of the pts and 93% had III-IV Ann Arbor stages. Age-adjusted IPI were 0-1 in 20 pts (27%) and 2-3 in 55 pts (73%). All patients were previously treated in first-line therapy by R in combination with chemotherapy (CHOP, N=56, 75%, low-dose CHOP, N=14, 19%, other, N=5, 6%). The patients received a median number of 1 previous line (range, 1-8) and no patient was previously treated by ASCT. The median time between initial diagnosis and R-ifosfamide/VP16 was 20 months (range 4-187). The median time between the last treatment and R-ifosfamide/VP16 was 5 months (range 0-181). A refractory disease to first-line treatment was showed in 14 pts (19%). 31% of the patients had a refractory disease to the last regimen performed before R-ifosfamide/VP16. Patients received a median of 6 cycles (1-12). At the end of treatment, the overall response rate (ORR), defined by the rate of complete response (CR) and partial response (PR) was 37%, with 18% of CR. Evaluations were assessed for 29% of the pts by TEP scanner. For toxicity, among the 387 cycles, 10 patients developed febrile neutropenia (2.6%); 15 (20%) a grade 3-4 neutropenia; 7 (9%) a grade 3-4 thrombocytopenia; 5 patients needed platelet units and 16 patients received packed red blood cell units. No grade 3-4 non-hematological toxicity was observed and no toxic death occurred. With a median follow up of 31.3 months (range, 5.0-202.8), the median progression-free survival (PFS) was 4.3 months with a 1-year PFS rate of 26.0% (95%CI, 17.7-38.3) (Figure 1A). The median overall survival (OS) was 8.2 months with a 1-year OS rate of 40.8% (95%CI, 30.9-54.0) (Figure 1B). The median duration of response was 4 months (range 1-97). The median PFS was adversely affected by response (refractory versus CR/PR) to the last treatment (3.0 months versus 5.5 months, P=0.001) (Figure 1C). Conclusions: in this retrospective study, R-Ifosfamide/VP16 regimen provided effective results in R/R DLBCL transplant-ineligible pts with 37% of ORR and a median of PFS of 4.3 months with a safe toxicity profile. This regimen could also be considered as a platform for combinations with novel targeted agents in these categories of patients. Disclosures Karlin: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sarkozy:ROCHE: Consultancy. Bachy:Gilead Sciences: Honoraria; Takeda: Research Funding; Sandoz: Consultancy; Amgen: Honoraria; Roche: Research Funding; Celgene: Consultancy; Janssen: Honoraria. Salles:Abbvie: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; Acerta: Honoraria; Novartis: Consultancy, Honoraria; Servier: Honoraria; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; BMS: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Janssen: Honoraria, Other: Advisory Board; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria. Ghesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy.

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High-Dose Chemotherapy (HDC) with Autologous Stem-Cell Transplant (ASCT) with Consolidative Radiation Therapy (RT) for Relapsed or Refractory (R/R) Primary Mediastinal B-Cell Lymphoma (PMBCL): 20-Year Experience at MD Anderson Cancer Center (MDACC)

Blood ◽

10.1182/blood-2020-134471 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Neeraj Saini ◽

Junsheng Ma ◽

Melissa Timmons ◽

Amin M. Alousi ◽

Paolo Anderlini ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

B Cell Lymphoma ◽

Advisory Board ◽

Older Age ◽

Long Term Results ◽

Cell Transplant ◽

Research Support ◽

Advisory Committees ◽

Grant Support

Background Most PMBCL pts are cured with frontline chemoimmunotherapy ± RT. Data are scant regarding the role of HDC/ASCT for R/R PMBCL, and the benefit of RT administered peri-HDC/ASCT. Our institutional approach has focused on developing potentially more active HDC regimens, and on consideration of post-ASCT consolidation RT, especially for pts who had not achieved a CR at the time of HDC. Methods We retrospectively analyzed all patients (pts) with R/R PMBCL treated with HDC/ASCT at MDACC between 01/01/2000-12/31/2019. All pts underwent similar standard pre-SCT evaluation and met eligibility criteria as per our institutional guidelines. Response assessment differed over time and included CT and gallium scan (N=9) and PET/CT (N=49). Cox proportional hazards regression models evaluated the associations of the specific HDC regimen and clinical covariates of interest with EFS and OS. Results 58 pts received HDC/ASCT with BEAM-rituximab (N=36) or rituximab/gemcitabine/busulfan/melphalan ± vorinostat (R-GemBuMel) (n=22) (Table 1). The R-GemBuMel group included more pts pretreated with >2 lines of therapy than the R-BEAM group (55% vs. 28%, p=0.025), had fewer pts in CR (41% vs. 69%, P=0.01) and more pts in PD/SD at ASCT (32% vs. 3%, P=0.01). Prior RT at a median 44 (36-48) Gy was administered to 29 pts (20 R-BEAM, 9 R-GemBuMel, P=0.27). Nineteen pts (89% not in CR at SCT) who had not previously received full doses of RT received post-SCT RT (6 after BEAM, 13 after R-GemBuMel, P<0.001) at median 40 Gy (36-48). There were 2 treatment-related deaths in the R-BEAM arm, none in the R-GemBuMel arm. At median follow-up of 69.1 months (interquartile range, 36.5-85.2), the EFS rates were 57.6% (overall), 67.6% (R-GemBuMel) and 52.7% (R-BEAM) (Figure 1a). Their respective OS rates were 69.3%, 81.1% and 63.9% (Figure 1b). On multivariable Cox regression analyses, R-GemBuMel (vs. R-BEAM) (HR=0.29, p=0.05), and 1 organ involved (vs. >1) (HR 0.28, p=0.009) were associated with improved EFS, whereas older age (HR= 1.08 per year above median, p=0.005), refractory disease (SD/PD) at SCT (vs. CR/PR) (HR 5.44, p=0.01) correlated with worse EFS. Likewise, R-GemBuMel (HR= 0.16, p=0.03) and 1 organ involved (HR=0.17, p=0.004) significantly resulted in improved OS, whereas older age (HR= 1.11, p=0.002), and refractory (SD/PD) disease at SCT (HR= 21.27, p=0.001) correlated with worse OS. Neither sex nor disease status (primary refractory vs. relapse) nor No. prior lines (2 vs. >2) nor pre-SCT RT nor post-SCT RT correlated significantly with EFS or OS. Conclusions HDC/ASCT for R/R PMBCL pts, with post-SCT RT for pts with active disease at SCT, results in favorable long-term results. R-GemBuMel ± vorinostat seems to improve EFS and OS compared to R-BEAM. Disclosures Alousi: Incyte: Honoraria, Research Funding; Therakos: Research Funding; Alexion: Honoraria. Hosing:NKARTA Inc.: Consultancy. Kebriaei:Amgen: Other: Research Support; Ziopharm: Other: Research Support; Kite: Other: Served on advisory board; Pfizer: Other: Served on advisory board; Jazz: Consultancy; Novartis: Other: Served on advisory board. Popat:Bayer: Research Funding; Novartis: Research Funding. Qazilbash:Angiocrine: Research Funding; Bioline: Research Funding; Janssen: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding. Shpall:Zelluna: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing Agreement. Champlin:Takeda: Patents & Royalties; Genzyme: Speakers Bureau; Cytonus: Consultancy; Omeros: Consultancy; Actinium: Consultancy; Johnson and Johnson: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees. Nieto:Affimed: Consultancy, Other: Grant Support; Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Secura Bio: Other: Grant Support.

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Safety and Antitumor Activity Study Evaluating Loncastuximab Tesirine and Rituximab Versus Immunochemotherapy in Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2020-136614 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Yuliya Linhares ◽

Mitul D Gandhi ◽

Michael Chung ◽

Jennifer Adeleye ◽

David Ungar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Advisory Board ◽

Publicly Traded ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Large B Cell

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who fail immunochemotherapy (IC) and are unsuitable for autologous stem cell transplantation (ASCT) and those who relapse shortly after ASCT have extremely poor prognosis and need additional treatment options. Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) composed of a humanized anti-CD19 antibody conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 2 study (NCT03589469), Lonca demonstrated single-agent antitumor activity with manageable toxicity in patients with relapsed/refractory (R/R) DLBCL. Rituximab is a CD20-targeting monoclonal antibody used in front-line IC for DLBCL and in salvage regimens, such as rituximab/gemcitabine/oxaliplatin (R-GemOx). The addition of rituximab to a CD19-targeting pyrrolobenzodiazepine ADC appears to prolong tumor control in preclinical studies, providing the rationale for evaluating Lonca combined with rituximab (Lonca-R) as a treatment for R/R DLBCL. Study Design and Methods: This is a Phase 3, randomized, open-label, 2-part, 2-arm, multicenter study of Lonca-R versus standard IC in patients with R/R DLBCL (NCT04384484). Part 1 is a nonrandomized safety run-in with Lonca-R. The toxicity of Lonca-R will be compared with previous single-agent Lonca safety data after 20 patients have completed Cycle 1 in Part 1. Provided no significant increase in toxicity is observed, Part 2 will be initiated. Part 2 is a randomized study of Lonca-R versus R-GemOx (Figure 1). Key inclusion and exclusion criteria are reported in Table 1. The primary objective of Part 2 is to evaluate the efficacy of Lonca-R versus R-GemOx, using progression-free survival (PFS) as the primary endpoint. PFS will be defined as the time between randomization and first documentation of recurrence, disease progression or death (central review) and the primary analysis will compare PFS between treatment arms using stratified log-rank testing. Secondary objectives include evaluation of safety, pharmacokinetics, and immunogenicity of the combination, in addition to the impact of treatment on symptoms, patient-reported outcomes and patients' overall health. In Part 1 and in the Lonca-R arm of Part 2, patients will receive intravenous (iv) Lonca at 150 µg/kg on day 1 of each 21-day cycle for 2 cycles, then at 75 µg/kg on day 1 for up to 6 additional cycles. Rituximab 375 mg/m2 iv will be administered subsequent to Lonca infusion on day 1 of each cycle. Patients treated with Lonca-R will also be given dexamethasone 4 mg (oral, twice a day), where not contraindicated, on the day before, the day of, and the day after Lonca-R infusion. In the R-GemOx arm, patients will receive rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatin 100 mg/m2 iv on day 1 of each 14-day cycle up to a total of 8 cycles. Patients will receive premedication and supportive care according to the respective prescribing information for rituximab, gemcitabine, and oxaliplatin. The trial is planned to open in Q3/Q4 2020, and target enrollment is 350 patients. Funding: This study is sponsored by ADC Therapeutics SA; https://clinicaltrials.gov/ct2/show/NCT04384484. Disclosures Linhares: Jazz Pharmaceuticals: Consultancy; ADC Therapeutics, Verastem Oncology, Bristol Myers-Squibb (Juno), AstraZeneca: Research Funding; Miami Cancer Institute, Baptist Health South Florida: Current Employment. Gandhi:TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Adeleye:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ungar:ADC Therapeutics: Current Employment, Current equity holder in publicly-traded company. Hamadani:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding. OffLabel Disclosure: Rituximab is licensed for treatment of NHL but is being used in combination with an unlicensed drug (loncastuximab tesirine) in this study

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Characterizing Specificities of Chronic Lymphoid Leukemia Harboring a BCL2 rearrangement

Blood ◽

10.1182/blood-2020-139210 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 29-30

Author(s):

Charles Herbaux ◽

Imelda Raczkiewicz ◽

Kamel Laribi ◽

Loic Ysebaert ◽

Agnes Daudignon ◽

...

Keyword(s):

Protein Expression ◽

Board Of Directors ◽

Research Funding ◽

Limit Of Detection ◽

B Cell Lymphoma ◽

Advisory Board ◽

Advisory Committees ◽

Ras Pathway ◽

Trisomy 12 ◽

A Cell

Introduction: Although survival dependence on Bcl2 is a well-known aspect of the pathophysiology of chronic lymphocytic leukemia (CLL), the mechanisms of Bcl-2 dysregulation are incompletely understood. Recurrent translocations involving BCL2 and immunoglobulin genes, including t(14;18)(q32;q21) and variants such as t(2;18) or t(18;22), are classically observed in follicular lymphoma or germinal center diffuse large B-cell lymphoma (GC DLBCL), but are uncommon (<5%) in CLL and usually associated with an indolent clinical course. Here, we characterize the mutational landscape and the functional Bcl-2 family dependencies of BH3 proteins in BCL-2-rearranged (BCL2-R) CLL. We used a functional approach known as BH3 profiling which measures the proximity of a cell to the threshold of apoptosis ("priming") and identifies which anti-apoptotic proteins a cell depends on for survival. Methods: Clinically annotated primary samples from BCL2-R CLL patients identified by karyotype were obtained from the French Innovative Leukemia Organization network and Dana-Farber Cancer Institute. Primary samples from CLL without BCL2 rearrangement were used as a control (ctrl CLL). Next generation sequencing (NGS) was performed using a custom-designed panel of 29 genes, including among others: BIRC3, NOTCH1, FBXW7, MLL2, RAS pathway, SF3B1 and TP53. The mean coverage obtained was 2000X (limit of detection (LOD): 1%). Digital droplet PCR (ddPCR) was used to quantify NOTCH1 c.7544_7545delCT (LOD: 0.025%). Protein expression (Bcl2, Mcl1, Bim) was assessed by Western blot. Baseline BH3 profiling was performed as per Ryan et al., Bio Chem 2016. To mimic the lymph node microenvironment, viability assays were performed in co-culture with the stromal cell line NK.tert. Viability was assessed by AnnexinV/Hoechst staining. Ex vivo drug treatments included: BCL2i (inhibitor): venetoclax; MCL-1i: AZD5991, S63845 and BCLXLi: A133. Statistical analyses were by unpaired and paired t-test with a two-tailed nominal p ≤ 0.05 considered as significant. Results: In our cohort of 110 patients, the median age was 70 years old, and 79% were male. BCL2-R were t(14;18) in 77.2%, t(18;22) in 16.3% and t(2;18) in 6.3% of patients. The translocation involving BCL2 gene was isolated in 23.6% of cases, and was associated with trisomy 12 in 45.4% of patients. The most frequently mutated genes in this cohort were in the NOTCH pathway (NOTCH1 mutation: 43.6 %, mostly subclonal (mean of variant allelic frequency: 6.1%) and FBXW7: 4.5%)) and RAS pathway (KRAS, NRAS, BRAF: 9.1%). BCL2 mutations were observed in 22.8% of the 57 examined cases. No mutation previously described in venetoclax resistant CLL, such as F104L or G101V variant, were observed. Furthermore, MLL2 mutations were observed in 14.5% cases and were significantly associated with complex karyotype (p=0.01) and trisomy 12 (p=0.04). Others mutated genes were: BIRC3 (5.4%), TP53 (3.6%), SF3B1 (1%) and MYD88 L265P(1%). No mutations in EZH2, CREBBP or EP300 were found. In 15 CLL representative samples from each group (BCL2-R and ctrl), Bcl2 protein expression was significantly higher in BCL2-R CLL (ratio Bcl2/actin 0.94 vs 0.74, p=0.009) as was expression of the pro-apoptotic protein Bim (ratio Bim/actin: 2.059 vs 1.524, p=0.007). BH3 profiling demonstrated that BCL2-R CLL and ctrl CLL samples (n=23 in each group) had comparable overall priming (cyto-C release 66.1% vs 63.3%, ns) and Bcl-2 dependence (cyto-C release 75.4% vs 76.3%, ns). Both also had low dependence on Bcl-xL (cyto-C release 8.2% vs 8.8%, ns). In contrast, Mcl-1 dependence was found to be significantly lower in BCL2-R CLL (cyto-C release 15.6% vs 37.4%, p<0.0001). Consistent with our BH3 profiling results, the activity of venetoclax and the Bcl-xLi (A133) did not differ significantly between the 2 groups (n=15). In contrast, both Mcl-1i were less active in the BCL2-R group: average viabilities after 24h treatment with AZD5991 were 76.4% vs 56.3% (p=0.006) and with S63845 77.3% vs 62.9% (p=0.02) in the BCL2-R vs ctrl group, respectively. Conclusion: The genomic landscape of BCL2-R CLL is characterized by a high frequency of trisomy 12, subclonal NOTCH and RAS pathway mutations, as well as BCL2 and MLL2 mutations. Protein expression, BH3 profiling and viability assays data are consistent with nearly exclusive dependence on Bcl-2. Our data suggest that Bcl-2 inhibition should be favored over Mcl-1 inhibition in BCL2-R CLL. Disclosures Herbaux: Roche: Consultancy, Honoraria, Research Funding. Laribi:abbvie: Honoraria, Research Funding; amgen: Research Funding; novartis: Honoraria, Research Funding; takeda: Research Funding. Ysebaert:Roche: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Morel:Janssen: Honoraria. Guieze:abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Brown:Sun: Research Funding; Acerta: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Gilead: Consultancy, Research Funding; BeiGene: Consultancy; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Kite: Consultancy; MEI Pharma: Consultancy; Nextcea: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Rigel Pharmaceuticals: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy.

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Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2019-126242 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4082-4082

Author(s):

Beth A. Christian ◽

Ying Huang ◽

Sabarish Ayyappan ◽

Robert A Baiocchi ◽

Jonathan E Brammer ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Board ◽

Advisory Committees ◽

Oral Agents ◽

Grade 3 ◽

Aggressive B Cell Lymphoma

Introduction: Venetoclax, a BCL2 inhibitor, has demonstrated efficacy both as a single agent and in combination with rituximabin several subtypes of B-cell non-Hodgkin lymphoma (NHL). The combination of obinutuzumab and lenalidomide has demonstrated safety and preliminary efficacy in follicular lymphoma (Fowler et al., JCO 2015; 35: 7531). We conducted a phase I study of obinutuzumab, venetoclax, and lenalidomide to determine the safety, maximum tolerated dose, and preliminary efficacy of the combination. Methods: Patients with relapsed/refractory diffuse large B-cell (DLBCL), transformed, high grade B-cell (HGBCL), marginal zone, and follicular (FL) lymphoma who have received ≥ 1 prior therapy were eligible. Prior autologous (ASCT) but not allogeneic stem cell transplant were permitted. Prior lenalidomide or BCL2 family inhibitors, CNS involvement, and active hepatitis or HIV infection were not permitted. ANC > 1000/mm3, platelets > 75,000/mm3, creatinine clearance ≥50 ml/min, ALT/AST ≤ 3 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required. Treatment consisted of obinutuzumab 1000 mg on days 1, 8 and 15 of cycle 1 and then on day 1 of cycles 2-6 with escalating doses of lenalidomide days 1-21 and venetoclax days 1-28 of a 28 day cycle (Table 1). A 3+3 dose escalation schema was followed. The DLT period was 1 cycle and patients had to receive 80% of the doses of the oral agents and all doses of obinutuzumab to be considered evaluable for DLT. DLTs included: treatment delays > 28 days; ANC < 500 / mm3 or platelets <25, 000 / mm3 persisting > 28 days; grade 4 febrile neutropenia or infection; grade 3 infection that fails to resolve within 7 days; and grade 3 or 4 non-hematologic toxicity. Patients without significant toxicity or progression could continue treatment up to 12 cycles. Response was assessed by CT or PET/CT every 3 months for 12 months and then every 6 months until disease progression. Results: 22 patients were treated. Median age was 61 years (range 31-78 years) with 16 males. Median prior therapies was 2 (range 1-10) and included 5 patients who had relapsed after chimeric antigen receptor T-cell therapy and 2 patients relapsed after ASCT. Median baseline lactate dehydrogenase was 259.5 U/L (range 147-5133, ULN 190 U/L). 16 patients had aggressive B-cell lymphoma including DLBCL, HGBCL, primary mediastinal and transformed FL, 5 patients had FL and 1 patient had marginal zone lymphoma. At dose level (DL) 1, one patient experienced a DLT, grade 3 neutropenic fever lasting > 7 days. DL 1 was expanded and no additional DLTs occurred. No further DLTs occurred at DL 2-4. DL 4 was expanded and was determined to be the MTD. Four patients, 1 in each dose level, were not evaluable for DLT and were replaced including 3 who did not receiving 80% of the oral agents due to required dose reductions and 1 patient for disease progression. Related grade 3-4 toxicities were primarily hematologic including neutropenia (n=20, 90.9%), thrombocytopenia (n=5, 22.7%), and anemia (n=3, 13.6%). Grade 3-4 infections (n=6, 27%) included sepsis, febrile neutropenia, pneumonia and a urinary tract infection. Other grade 3-4 AEs occurring once each included dysgeusia, dyspnea, nausea, vomiting, and hyperhidrosis. No clinically significant tumor lysis has occurred. Patients have received a median of 3 cycles (range 1-12) of treatment. Three patients remain on therapy and 5 patients are on follow up. Dose reductions of lenalidomide occurred for 17 patients (77%) and of venetoclax for 11 patients (50%). Nine patients have achieved a response (41%), including 8 complete (CR) and 1 partial responses (PR). Responses have occurred at each DL and include 4 patients with FL (2 CR, 2 PR), 4 patients with aggressive lymphoma (4 CR) and 1 patient with MZL (CR). 14 patients are off of the study, 9 with progression, 2 for alternative therapy, and 1 each for DLT, physician preference, and a diagnosis of MDS in a patient with 3 prior lines of chemotherapy. Conclusions: Combined treatment with obinutuzumab, venetoclax, and lenalidomide administered up to 12 cycles is feasible with activity in multiple subtypes of relapsed NHL. Enrollment in expansion cohorts of FL and aggressive B-cell lymphoma is ongoing. Disclosures Christian: Celgene: Research Funding; Janssen: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Research Funding; Bristol-Myers Squibb: Research Funding; Millennium Pharmaceuticals Inc: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Immunomedics: Research Funding; Acerta: Research Funding. Baiocchi:Prelude: Consultancy. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. William:Guidepoint Global: Consultancy; Celgene Corporation: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy; Techspert: Consultancy. Awan:Gilead: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Sunesis: Consultancy; Janssen: Consultancy; Genentech: Consultancy. Maddocks:BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Obinutuzumab - off label use in relapsed aggressive B-cell lymphoma and indolent B-cell lymphoma Venetoclax - off label use in relapsed B-cell lymphoma

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Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Idelalisib in Patients with B-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-113117 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5345-5345

Author(s):

Franck Morschhauser ◽

John Radford ◽

Loic Ysebaert ◽

Stephen E Spurgeon ◽

Ebenezer A Kio ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Median Number ◽

Advisory Board ◽

Duration Of Treatment ◽

Advisory Committees ◽

Phase 1B

Abstract Introduction: Tirabrutinib (TIRA; GS/ONO-4059) is a selective Bruton's tyrosine kinase (BTK) inhibitor. Idelalisib (IDELA), a first-in-class phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor, is approved for the treatment of CLL and follicular lymphoma (FL). Both have single agent activity in lymphoma and updated results from the combination of TIRA+IDELA from this ongoing phase 1b study (NCT02457598) are reported here. Methods: Patients with previously treated non-germinal-center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL) or two prior lines of therapy for FL, small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM) and no prior exposure to targeted inhibitors were eligible for enrollment. Patients were enrolled using a 3+3 dose escalation design with a fixed dose of IDELA at either 50 mg BID or 100mg QD and TIRA ranging from 20mg to 160mg QD. Cohorts were subsequently enrolled at multiple dose levels to evaluate disease-specific safety and efficacy. Results: As of March 5, 2018, 40 patients were enrolled on the combination. The median age was 65 (32-89) years and the disease subtypes were non-GCB DLBCL (n=17), FL (10), MZL (5), WM (5), SLL (2), and MCL (1). No maximum tolerated dose and no dose-response relationship was observed with daily dosing of both agents at the dose levels evaluated. For patients with non-GCB DLBCL (n=17), the median number of prior therapies is 3 (range 1-4). The median duration of treatment is 8 weeks (range 0.9, 44.1) with 2 patients still on treatment. 4/15 (27%) evaluable patients achieved a response; best overall response is shown in table 1. For the patients with indolent NHL (n=23), the median number of prior therapies is 3 (range 2-6). The median duration of treatment is 28 weeks (range 2.1, 120.0), with 5 patients still on treatment. 10/20 (50%) of the evaluable patients achieved a response with best overall response by indication shown in table 1. The most common treatment-emergent adverse events (AEs) are listed in table 2. Of the 40 patients who received treatment on study, AEs led to treatment interruption or discontinuation of both study drugs in 22 and 3 patients, respectively. There have been 7 deaths on study, 6 due to disease progression and 1 from an unknown cause. Conclusion: Once-daily dosing of GS-4059 up to 160 mg in combination with idelalisib 50 mg BID or 100 mg QD was generally safe and well tolerated. Early results show activity across all indications studied. Disclosures Morschhauser: Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Radford:GlaxoSmithKline: Equity Ownership; BMS: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; Celgene: Research Funding; ADC Therapeutics: Consultancy, Research Funding. Ysebaert:Gilead Sciences, Inc.: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Spurgeon:Bristol Myers Squibb: Research Funding; MEI Pharma: Consultancy; Oncternal: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding. Salles:Merck: Honoraria; BMS: Honoraria, Other: Advisory Board; Gilead: Honoraria, Other: Advisory Board; Servier: Honoraria, Other: Advisory Board; Takeda: Honoraria; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Servier: Honoraria; Janssen: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Abbvie: Honoraria; Acerta: Honoraria; Celgene: Honoraria, Other: Advisory Board, Research Funding; Amgen: Honoraria; Epizyme: Honoraria; Novartis: Consultancy, Honoraria. Huang:Gilead Sciences, Inc.: Employment. Mitra:Gilead Sciences, Inc.: Employment. Rule:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees. Dyer:Gilead Sciences, Inc.: Honoraria, Research Funding.

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Updated Preliminary Results of a Phase 1b Dose Escalation and Dose Expansion Study of Tirabrutinib in Combination with Entospletinib in Patients with B-Cell Lymphoma

Blood ◽

10.1182/blood-2018-99-113115 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5344-5344

Author(s):

Gilles Salles ◽

Martin J.S. Dyer ◽

Daniel James Hodson ◽

Krimo Bouabdallah ◽

Loic Ysebaert ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Median Number ◽

Advisory Board ◽

Duration Of Treatment ◽

Advisory Committees ◽

Phase 1B

Abstract Introduction: Tirabrutinib (TIRA; GS/ONO-4059) is a selective Bruton's tyrosine kinase (BTK) inhibitor. Entospletinib is a selective inhibitor of spleen tyrosine kinase (SYK). Both have single agent activity in lymphoma and updated results from the combination of TIRA+ENTO from this ongoing phase 1b study (NCT02457598) are reported here. Methods: Patients with previously treated non-germinal-center B-cell type (non-GCB) diffuse large B-cell lymphoma (DLBCL) or two prior lines of therapy for follicular lymphoma (FL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), or Waldenstrom's macroglobulinemia (WM) and no prior exposure to targeted inhibitors were eligible for enrollment. Patients were enrolled using a 3+3 dose escalation design with either ENTO 200mg or 400mg QD and doses of TIRA ranging from 20mg to 160mg QD. Cohorts were subsequently enrolled at multiple dose levels to evaluate disease-specific safety and efficacy. Results: As of March 5, 2018, 72 patients have enrolled on the combination. The median age was 67.5 years (range: 30-90) and the disease subtypes for patients enrolled were non-GCB DLBCL (n=32), FL (18), MZL (5), WM (7), SLL (2), MCL (8). No maximum tolerated dose and no dose-response relationship was observed with daily dosing of both agents at the dose levels evaluated. For patients with non-GCB DLBCL (n=32), the median number of prior therapies is 3 (range 1-7). The median duration of treatment is 8 weeks (range 2-98.1) with 6 patients still on treatment. 6/27 (22%) of the evaluable patients achieved a response; best overall response is shown in table 1. For patients with indolent NHL (n=40), the median number of prior therapies is 3 (range 1-6). The median duration of treatment is 36 weeks (range 0.1-116), with 29 patients still on treatment. 19/31 (61%) of the evaluable patients achieved a response with best overall response by indication shown in table 1. The most common treatment-emergent adverse events (AEs) are listed in table 2. Of the 71 patients who have received treatment on study, AEs led to treatment interruption or discontinuation of both study drugs in 10 and 1 patients, respectively. There have been 4 deaths on study, all due to disease progression. Conclusion: Once-daily dosing of TIRA up to 160 mg in combination with ENTO up to 400 mg QD was safe and well tolerated. Early results show activity in combination across all indications treated. Disclosures Salles: Novartis: Consultancy, Honoraria; Epizyme: Honoraria; Abbvie: Honoraria; Servier: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Pfizer: Honoraria; Merck: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Morphosys: Honoraria; Acerta: Honoraria; Janssen: Honoraria, Other: Advisory Board; Servier: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Dyer:Gilead Sciences, Inc.: Honoraria, Research Funding. Hodson:Gilead Sciences, Inc.: Research Funding. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cartron:Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Honoraria. Davies:Acerta Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; ADC-Therapeutics: Research Funding; Janssen: Honoraria; Karyopharma: Membership on an entity's Board of Directors or advisory committees. Danilov:Aptose Biosciences: Research Funding; Gilead Sciences: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy; Astra Zeneca: Consultancy. Fegan:Roche: Honoraria; Abbvie: Honoraria; Gilead Sciences, Inc.: Honoraria; Napp: Honoraria; Janssen: Honoraria. Huang:Gilead Sciences, Inc.: Employment. Mitra:Gilead Sciences, Inc.: Employment. Rule:Roche: Honoraria; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Morschhauser:Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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ASXL1 Mutation Is a Novel Risk Factor for Bleeding in Patients with Philadelphia-Negative Myeloproliferative Neoplasms (MPN)

Blood ◽

10.1182/blood-2021-146384 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3637-3637

Author(s):

Amro Elshoury ◽

Han Yu ◽

Wenyan Ji ◽

James E. Thompson ◽

Elizabeth A. Griffiths ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Myeloproliferative Neoplasm ◽

Advisory Board ◽

Factor V ◽

Continuous Variables ◽

Bleeding Events ◽

Advisory Committees ◽

Risk Of Bleeding

Abstract Background: Bleeding and thrombosis are prevalent across all myeloproliferative neoplasm (MPN) subtypes and have significant impact on morbidity and mortality. Although risk factors for thrombosis are well established, bleeding risk factors in these patients are poorly characterized. Identifying MPN patients at higher risk for bleeding could guide the duration of anticoagulation for patients with MPN associated thrombosis (balancing the risk between bleeding and thrombosis), select individuals at higher risk for bleeding during prophylactic anticoagulation, and predict for bleeding complications with surgical procedures. Methods: We performed a retrospective analysis of bleeding risk factors among consecutive adult MPN patients treated at Roswell Park Comprehensive Cancer Center. Bleeding events were classified as minor or major events as defined by the International Society of Thrombosis and Hemostasis (ISTH). The primary outcome of interest was time to initial bleeding after MPN diagnosis. Patient characteristics were summarized as range and medians (for continuous variables) and counts with percentages (for categorical variables) (Table 1). Cox regression was used to examine the associations between candidate risk factors with identified bleeding events in univariate and multivariable analyses. Variables with p<0.1 in univariate analyses were selected for multi-variate analysis. A time-dependent variable of thrombosis status was included in the model. A stepwise feature selection based on Akaike Information Criterion was used for model selection. Continuous variables were dichotomized at median for the regression analyses. Results: A total of 170-consecutive adult MPN patients were identified between 2005 and 2021. Median follow-up was 43.5 months (range 0.66-485.72). The rate of bleeding (major and minor) was 4.9/100 patient-years and rate of thrombosis was 5.4/100 patient-years (5.4/100 patient-years for arterial thrombosis and 2.9/100 patient-years for venous thrombosis). In univariable analysis, predictors of bleeding included age > 60 years (HR 2.8; 95% CI 1.47-5.34; p=0.001), diagnoses of primary myelofibrosis (PMF) (HR 2.98; 95% CI 1.29-6.9; p=0.01) and myelodysplastic syndrome/myeloproliferative neoplasm (MDS-MPN) overlap syndrome (HR 4.56, 95% CI1.91-10.88; p=0.0004), prior history of thrombosis (HR 3.3, 95% CI 1.27-8.8; p=0.01) and presence of ASXL1 (HR 4.13, 95% CI 2.13-8.04; p=0.0001), JAK2 V617F (HR 0.58; 95% CI 0.31-1.08; p=0.08) and TET2 mutations (HR 3.46; 95% CI 1.5-7.9; p=0.003). In multivariate analysis, the presence of JAK2 V617F (HR 4.8; 95% CI 1-21.5; p=0.03) and ASXL1 (HR 12.7, 95% CI 1.7-93; p=0.01) mutations were associated with increased risk of bleeding (Figure 2). Patients with polycythemia vera were at lower risk of bleeding (HR -3.5, 95% CI 0-0.8; p=0.03). Since ASXL1 mutation was associated with a higher risk of bleeding, we studied the association between ASXL1 mutation and other clinical variables. Patients with ASXL1 mutations were more likely to have a diagnosis of PMF and MDS-MPN overlap syndrome (p=0.0001), age > 60 years (p=0.0001), risk for thrombosis (p=0.04), lower hematocrit (p=0.009) and platelets (p=0.0003) but higher white blood cell count (WBC) (p= 0.04) (Figure 3). We then studied the correlation between ASXL1 mutation and factor VIII/Von Willebrand complex and factor V, the two most described abnormal coagulation factors in MPN. ASXL1 mutation was not associated with a statistically significant lower VWF Ag (p=0.07) or factor V (p=0.1) that could potentially explain the higher risk of bleeding seen with this mutation (figure 4). Conclusion: ASXL1 mutations are associated with a significantly higher risk of bleeding in adult MPN patients. The risk of bleeding with ASXL1 mutations was independent of prior thrombosis and was not associated with abnormalities in VWF profile or factor V. Confirmation of these findings in additional patients and studies of underlying platelet function to identify the possible mechanism of ASXL1 associated bleeding in these patients are ongoing. Figure 1 Figure 1. Disclosures Elshoury: Bristol Meyers Squibb: Other: advisory board. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Griffiths: Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Boston Biomedical: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Novartis: Honoraria; Astex Pharmaceuticals: Honoraria, Research Funding; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Genentech: Research Funding. Wang: Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Mana Therapeutics: Consultancy, Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

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Incidence and Risk Factors for Central Nervous System Relapse in Very Elderly Patients over 80 with Diffuse Large B-Cell Lymphoma: A Retrospective Analysis of Two Lysa Studies

Blood ◽

10.1182/blood.v128.22.927.927 ◽

2016 ◽

Vol 128 (22) ◽

pp. 927-927

Author(s):

Aurelie Cabannes-Hamy ◽

Frederic Peyrade ◽

Fabrice Jardin ◽

Jean-Francois Emile ◽

Sylvie Castaigne ◽

...

Keyword(s):

Risk Factors ◽

Elderly Patients ◽

Board Of Directors ◽

Research Funding ◽

Risk Group ◽

B Cell Lymphoma ◽

Very Elderly ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Cns Relapse

Abstract Background. The prevalence of diffuse large B-cell lymphoma (DLBCL) in patients aged over 80 years is reported to have tripled compared to patients in their sixties. Treating very elderly patients is particularly challenging given the likelihood of comorbidities and concerns over risks of toxicity. One of the most devastating and rapidly fatal complications in DLBCL is central nervous system (CNS) relapse. Most studies reporting incidence and risk factors of CNS relapse concern DLBCL patients under the age of 80 years, and little is known about CNS recurrence in the very elderly, aged over 80 years. CNS prophylaxis is rarely implemented in this population due to the burden of comorbidities, frequent antiplatelet or anticoagulant treatment along with renal failure and hypoalbuminemia, as well as potential prophylaxis toxicity of IV high dose methotrexate and/or the invasiveness of IT therapy. Aim. We retrospectively evaluated the incidence of CNS relapse, risk factors and specific survival in very elderly DLBCL patients aged 80 years Patients and Methods. Data were collected retrospectively from two multicentre, open-label, single arm phase II LYSA trials (LNH 03-7B (NCT01087424) between 2004 and 2007, LNH09-7B (NCT01195714) between 2009 and 2013) evaluating the addition of rituximab or ofatumumab to miniCHOP as front-line therapy. Results. A total of 270 elderly patients were included in the two trials, 150 treated with R-miniCHOP and 120 with O-miniCHOP. Median age was 83 years (range 79-95) and none received CNS prophylaxis. At inclusion, most patients (76%) presented with disseminated disease (Ann Arbor stage III or IV), and 37% had at least two extra-nodal sites. Overall 18% of patients had bone marrow involvement, while renal, adrenal, testis or cavum involvement was rare (4%, 2%, 3%, and 2%, respectively). After a median follow-up of 28.7 months (range 0.1-72.1), 8 (3%) cases of CNS relapse were reported. Median time between inclusion and CNS relapse was 19.2 months (range 3.2 - 32.6). Cumulative 1 and 2-year incidence of CNS relapse was 1.4% (95% CI 3.2-25.4) and 2.5% (95% CI 6.9-9.2), respectively. At inclusion, clinical characteristics of the CNS relapse patients were not significantly different from patients without relapse. At CNS relapse, all patients except one present a performance status ECOG > 2. neurological symptoms were either mild with loss of autonomy, asthenia, hearing impairment, urinary incontinence, or more prominent with delirium, aphasia, intracranial hypertension, or consciousness disorder. Treatment of CNS relapse was a supportive care based- treatment with corticosteroid only in 5 patients, radiation therapy in one patient, and chemotherapy for 2 patients including rituximab-temodal (5 cycles) in one patient and rituximab -aracytine-vepeside (2 cycles) for the other one. Patients survived for a median of 1.5 months after CNS relapse diagnosis (range, 0.4 to 4). The CNS international prognostic index (CNS-IPI) classified 33 (12%) patients in the low-risk group, 164 (62%) in the intermediate-risk group, and 71 (26%) in the high-risk group. The low-risk and intermediate-risk CNS-IPI groups showed 2-year rate of CNS disease of 3%, and the high-risk of 2.8% (p=0.9483). Conclusion. Incidence of CNS relapse in very elderly previously untreated patients is approximately 3% and is associated with a very poor survival. The absence of prophylaxis in this population did not appear to have a strong impact on CNS relapse incidence. Higher number of patients is warranted to identify risk factors for CNS relapse in this population Disclosures Coiffier: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salles:Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Thieblemont:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Results of a First in Human, Dose Ascending, Phase I Study Examining the Safety and Tolerability of KA2237, an Oral PI3K p110β/δ Inhibitor in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma

Blood ◽

10.1182/blood-2019-130401 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4099-4099 ◽

Cited By ~ 1

Author(s):

Loretta J. Nastoupil ◽

Sattva S Neelapu ◽

Eric Davis ◽

Felipe Samaniego ◽

Nathan H Fowler ◽

...

Keyword(s):

Phase I ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Advisory Board ◽

Advisory Committees ◽

Once Daily ◽

Anti Tumor Activity

Introduction: Despite therapeutic advances, there remains a considerable need for novel therapies for B-cell lymphomas. Although a high proportion of patients (pts) show response to initial therapy, many fail to achieve durable remissions and experience recurrent disease. Agents that target molecular pathways associated with the development and progression of lymphoma are likely to be highly effective and are desirable. The p110δ isoform of the PI3K enzyme is mainly expressed in lymphocytes and has been an attractive therapeutic target, with several PI3Kδ inhibitors demonstrating meaningful efficacy in B-cell lymphomas. Targeting the p110β isoform may further overcome tumor growth and escape mechanisms by mitigating the upregulation of the PI3K/AKT pathway, particularly in PTEN-deficient lymphomas. KA2237 is an oral, potent and selective inhibitor of the PI3K β and δ isoforms. The aim of this first in human, phase I, open-label, single arm study (NCT02679196) was to investigate the safety, tolerability, pharmacokinetic properties and pharmacodynamic effects of KA2237, in order to determine the maximum tolerated dose based on dose limiting toxicity and assess preliminary anti-tumor activity in pts with R/R B-cell lymphoma. Methods: Pts ≥ 18 years (yrs) of age, ECOG ≤ 2, with B-cell lymphoma R/R or intolerant of established therapies (including rituximab) were enrolled using a 3+3 dose escalation (50-400mg) design. KA2237 was given orally on a once daily continuous schedule until progression or unacceptable toxicity. Anti-tumor activity was evaluated by computed tomography and, when available, integrating 18F-FDG positron emission tomography response assessment, at 8, 16 and 24 weeks. Response was assessed according to Lugano 2014 criteria. Pts received PJP prophylaxis. Results: 21 pts with B-cell lymphoma were enrolled (8 DLBCL [diffuse large B-cell], 5 FL [follicular], 3 MCL [mantle cell], 3 CLL/SLL [chronic lymphocytic leukemia/small lymphocytic lymphoma], 1 MZL [marginal zone], 1 WM [Waldenstrom]). Pts received KA2237 at 4 dose levels: 50mg (n=6), 100mg (n=3), 200mg (n=7) and 400mg (n=5) daily; 21 pts were evaluable for safety assessment. Pharmacokinetic profiles were favorable with mean plasma half-life of 17-33 hours, compatible with once daily oral dosing. Median age was 69 yrs (range 48-84) with 76% males; median number of prior therapies was 3 (range 1-6). Median follow up duration was 8.5 months (range 6.9-24.6). Median duration of drug exposure was 82 days (range 10-714 days). 86% of pts experienced treatment-related adverse events (TRAE). 43% of pts experienced a grade ≥ 3 TRAE, with rash (n=3), transaminitis (n=2) and pneumonitis (n=2) occurring in more than 1 pt. 29% discontinued treatment due to a TRAE with pneumonitis (n=2) occurring in more than 1 pt. One grade 5 TEAE (multifocal pneumonia) was observed. 19/21 pts were evaluable for response, ORR was 37% (4 CR, 3 PR). Responses were observed across lymphoma subtypes including DLBCL, FL, CLL and MCL. Responses were often durable (see Figure) and in 2 pts with DLBCL who achieved CR permitted consolidation by autologous stem cell transplantation. Conclusions: KA2237 is an oral, once a day, selective dual inhibitor of PI3K β/δ with a manageable toxicity profile and promising single-agent clinical activity in heavily pretreated R/R B-cell lymphoma. The recommended phase II dose is 200mg daily. The findings of this study support the further evaluation of KA2237. Figure. Disclosures Nastoupil: Novartis: Honoraria; Spectrum: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding. Neelapu:Acerta: Research Funding; Merck: Consultancy, Research Funding; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Karus: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Precision Biosciences: Consultancy; BMS: Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Cell Medica: Consultancy. Fowler:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Westin:Janssen: Other: Advisory Board, Research Funding; Genentech: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Unum: Research Funding; Kite: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; MorphoSys: Other: Advisory Board. Wang:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta Pharma: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; MoreHealth: Consultancy, Equity Ownership; BioInvent: Consultancy, Research Funding; Aviara: Research Funding; BeiGene: Research Funding; Loxo Oncology: Research Funding; VelosBio: Research Funding; Pulse Biosciences: Consultancy; Juno Therapeutics: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Dava Oncology: Honoraria; Kite Pharma: Consultancy, Research Funding. Beer:Karus therapeutics Ltd.: Employment. Cecil:Karus Therapeutics: Employment. Dow:Karus Therapeutics: Employment. McHale:Karus Therapeutics: Employment. Silva:Karus Therapeutics: Employment. Ward:Karus Therapeutics: Employment. Yavari:Karus Therapeutics: Employment. Shuttleworth:Karus Therapeutics: Employment.

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