Telomere Length and CD49d Cooperate with IGHV Gene Status As Predictors of Long-Term Progression-Free Survival in CLL Patients Treated with FCR-Based Regimens

Background - Although there has been a revolution in the treatment of chronic lymphocytic leukemia (CLL), the challenge remains to identify the right drugs for the right patients. It is widely accepted that CIT, including the 'gold standard' fludarabine, cyclophosphamide and rituximab (FCR), is contraindicated for patients with TP53 disruption and, more recently, unmutated IGHV genes. Also patients with short, dysfunctional telomeres were shown to have inferior outcomes when treated with FCR-based regimens. To date, a role for CD49d in this setting has not been established. Aims - Here we evaluated the ability of telomere lenght (TL) and CD49d to cooperate with IGHV gene status to predict progression-free survival (PFS) in patients treated with FCR-based regimens in the frontline setting in three UK trials, ARCTIC, ADMIRE and CLL4. Methods - The study included a discovery cohort of 245 CLL treated with FCR/FCR-like regimens according to the two UK trials ARCTIC and ADMIRE. As there was no significant difference in PFS between the three arms of the study (P = 0.97), analysis was performed on the combined cohort. The median follow-up was 77.5 months with 157 progressions and 76 deaths. Twenty-nine patients were TP53 deleted and/or mutated, with shorter PFS compared to cases without TP53 disruption (final cohort, 216 TP53 wild-type CLL). The validation cohort was composed of 119 CLL samples derived from patients randomised to receive fludarabine, cyclophosphamide (FC) from the UK CLL4 trial. The median follow-up was 67.2 months with 99 progressions and 77 deaths. Fifteen CLL were TP53 mutated/deleted, with shorter PFS compared to cases without TP53 disruption (final cohort, 104 TP53 wild-type CLL). TL was measured using the high-throughput STELA assay and patients were bifurcated into two groups with either short telomeres inside the fusogenic range (TL-IFR) or long telomeres outside the fusogenic range (TL-OFR). CD49d was measured by flow cytometry and dichotomized as CD49dpos and CD49dneg based on the established 30% cut-off. For IGHV gene status, the 2% cutoff was used to split patients in mutated (IGHV-M) and ummutated (IGHV-UM). Results - In the 216 CLL with wild-type TP53 status from the ARCTIC/ADMIRE trials, CD49d expression was a predictor of PFS (P=0.02; HR=1.46 [1.03-2.06]). In keeping with previous reports, patients with IGHV-UM genes (P<.0001; HR=2.53 [1.79-3.58]) or TL-IFR (P=0.0002; HR=1.97 [1.30-2.98]) showed also significantly shorter PFS. This data was used as a starting point for a risk-stratification algorithm (Figure 1A). IGHV-UM cases could not be further dissected by TL or CD49d expression (P=0.76 log-rank test), their 8-year PFS being just 19.0%; (HR=5.58 [3.70-8.42]). In contrast, the IGHV-M group could be stratified by TL and CD49d expression (P<0.001 log-rank test). In particular, 13/84 (15.5%) of IGHV-M CLL with TL-IFR showed a median PFS of 3.0 years with a 8-year PFS of 15.4% (HR=6.45 [1.84-22.58]), similar to IGHV-UM cases (P = 0.19). Patients with IGHV-M genes and TL-OFR could be further stratified by CD49d expression into categories with different 8-year PFS: 43.1% in IGHV-M/TL-OFR/CD49dpos cases (HR=2.52 [1.08-5.89]), and 75.5% in the IGHV-M/TL-OFR/CD49dneg reference group (Table 1). Figure 1B shows the overlaid Kaplan-Meier curves for this hierarchical stratification. The proposed algorithm was then evaluated in the UK CLL4 trial. In keeping with the known inferiority of FC when compared with FCR, the 8-year PFS was just 5.2% in the IGHV-UM subset, irrespective of TL or CD49d expression. In concordance with the discovery cohort, the IGHV-M subset with TL-IFR had a similar median PFS to IGHV-UM cases (P=0.84). Furthermore, CD49d expression was able to stratify cases with TL-OFR; in particular, 18/104 (17.3%) were IGHV-M/TL-OFR/CD49dneg CLL which had a 8-year PFS of 77.8% (summary in Table 1 and Figure 1C). Conclusion - Our analysis shows that only IGHV-M/TL-OFR/ CD49dneg patients may benefit from CIT; this group represented just 56/321 cases (17.4%) of the combined cohort, suggesting that approximately 82% of patients should be considered for alternative therapies. Incorporation of this algorithm into clinical trial design and real-world practice would enable rational, risk-adapted, clinical management with the aim of treating all CLL patients with the optimal therapeutic regimen in the frontline setting. Disclosures Norris: TeloNostiX Ltd: Current equity holder in private company, Patents & Royalties. Hillmen:Gilead: Other: Financial or material support, Research Funding; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau. Rawstron:BD Biosciences (Intrasure): Patents & Royalties. Baird:TeloNostiX Ltd: Current equity holder in private company, Patents & Royalties. Fegan:TeloNostiX Ltd: Current equity holder in private company, Patents & Royalties. Pepper:TeloNostiX Ltd: Current equity holder in private company, Patents & Royalties.

Download Full-text

Management of Meningococcal Disease Risk in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) on Complement Inhibitors: 18 Years' Experience from the UK National PNH Service in Leeds

Blood ◽

10.1182/blood-2020-141780 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-6

Author(s):

Louise Arnold ◽

Ray Borrow ◽

Kathryn Riley ◽

Talha Munir ◽

Richard Kelly ◽

...

Keyword(s):

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Inhibitor Therapy ◽

Medical Attention ◽

Meningococcal Sepsis ◽

Complement Inhibitor ◽

Material Support ◽

Antibody Titers ◽

The Uk ◽

Support Research

Eculizumab, the monoclonal antibody targeting C5, is the only licensed treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH) in the UK. Inherent to the mechanism of action, C5 inhibitors increase patient susceptibility to encapsulated microorganisms, particularly Neisseria meningitidis. The PNH National service (UK), has 18 years of experience treating patients with PNH using complement inhibition. The risk of N. meningitidis is mitigated by vaccination, ciprofloxacin (500 mg bd) on days 1-13 since we moved to vaccination on day one of complement inhibitor therapy, followed by daily prophylaxis with penicillin (or erythromycin). Since a case of sepsis with penicillin-resistant meningococci was observed, patients also have a rescue course ciprofloxacin. Patient education, safety cards, prompt action in case of fever and a 24 hour on-call service for patients are equally important. Until 2010 patients were revaccinated with MenACWY every 3 years. Bexsero (MenB vaccine) vaccination (2 vaccines within first 6 months) with boosters every 5 years was added in 2015. In collaboration with the Public Health England Meningococcal Reference Unit in 2010 a program was developed to monitor antibody titers after vaccination and to revaccinate against MenACWY if titers declined to below protective levels. It is technically not possible to assay for meningoccal serogroup B antibody titers when on Eculizumab therapy. We present the outcome of this project. Methods: Antibody titers to serogroups ACWY were assayed following vaccination and then once per annum. Patients with unprotective antibody titers were revaccinated. We evaluate our practice and review the 9 meningococcal infections in 8 patients. We present disease characteristics, serogroup and outcome, vaccination history and antibody status. Results: Between May 2002 and July 2020, 324 patients commenced complement inhibitor treatment for PNH. 801 vaccinations with MenACWY were administered; median 2 vaccinations per patient (range 1 - 10). A total of 1,671 antibody titer assessments were conducted in 294 patients, median of 4 tests per patient (range 1 - 15). Every test assessed antibodies against all four serogroups. Titers were not assessed in 9% of patients (30), due to vaccination prior to change in practice or recent commencement on treatment. A protective antibody response to all serogroups after first vaccination was observed in 170 / 294 patients (57.8%) and a partial response (antibodies to 3 serotypes) in 51 /294 (17.3%). Revaccination of 51 partial responders resulted in an additional 21 patients with a full response. Revaccination of 73 non-responders (antibodies to 0-2 serotypes) resulted in 32 more partial or full responses. 287 of 324 patients received MenB vaccinations; median 2 vaccinations per patient (range 1 - 4). Eight of 324 (2%) patients with median age 22.5 years developed meningococcal sepsis (see table); patient 5 had 2 episodes. 3 of 5 cases with serogroup B infection were before serogroup B vaccination was introduced. The other 4 episodes in 3 patients were due to Y, C, W meningococci, in one the serogroup is unknown. All except patient 1 were compliant with antibiotic prophylaxis. Patient 7 died from meningococcemia, a delay in seeking medical attention may have contributed, however this was also a penicillin resistant strain. Discussion: We report the largest experience of managing meningococcal risk in patients on complement inhibitor therapy for PNH. Despite our proactive management we had 9 cases of meningococcal sepsis, with one fatal infection. Our most recently introduced practice of prompt treatment with ciprofloxacin if pyrexic on antibiotic prophylaxis will prevent cases like patient 7 with a penicillin resistant strain. Three patients had a meningococci sepsis with serogroups C, W and Y; whilst 1 patient had no check of titers due to recent commencement on treatment, the titres of the other 2 had suggested protective immunity. We demonstrated that a full antibody response can be obtained on a second vaccination in most patients if the first one failed. If no response is achieved upfront or revaccination then further MenACWY vaccination is not likely to be successful. Current practice significantly mitigates the risk of meningococcal disease, however it is essential patients remain vigilant for fever, seeking immediate medical attention stating their diagnosis of PNH on complement inhibitor therapy. Disclosures Arnold: Alexion Pharmaceuticals: Honoraria. Borrow:Pfizer: Research Funding; GlaxoSmithKline: Research Funding; Alexion pharmacueticals: Research Funding; Sanofi: Research Funding. Riley:Alexion: Honoraria. Munir:Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Kelly:Alexion: Honoraria. Pike:Apellis: Research Funding. Hillmen:Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Bleeding and Thrombosis Are Associated with Endothelial Dysfunction in CAR-T Cell Therapy and Are Increased in Patients Experiencing Neurologic Toxicity

Blood ◽

10.1182/blood-2020-142218 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 32-33

Author(s):

Andrew Johnsrud ◽

Juliana Craig ◽

John H. Baird ◽

Jay Y. Spiegel ◽

Lori S. Muffly ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Bleeding Events ◽

Private Company ◽

T Cell Therapy ◽

Car T Cell ◽

Car T ◽

Thrombotic Complications ◽

D Dimer ◽

Support Research

Background Treatment with chimeric antigen receptor (CAR) T cell therapies have shown dramatic, often durable responses for relapsed/refractory B-cell malignancies. However, it can be associated with significant side effects such as cytokine release syndrome (CRS), immune effector-cell associated neurotoxicity syndrome (ICANS) and life-threatening consumptive coagulopathies. The underlying pathobiology of such hemostatic defects and their distinct clinical sequelae remains obscure. This retrospective study aims at quantifying CAR T therapy associated bleeding and thrombotic complications and their association with CRS, ICANS, and laboratory derangements. Methods 130 adult patients with DLBCL or B-ALL treated between 2017-2020 with CD19 CAR-T therapy axicabtagene ciloleucel (N=90) or a bispecific CD 19/22 CAR construct utilizing 4-1BB costimulatory domains (N=40) were analyzed to determine dynamics of coagulation parameters and platelet counts as well as incidences of bleeding or thrombosis in the first three months after CAR T infusion. Events were included if graded ≥ 2 or if intervention was required. Platelet counts and coagulation parameters were collected prior to lymphodepletion (pre-LD), day 0, 3, 7, 14, 21, 28, 60 and 90. Results 12 (9.2%) and 8 (6.2%) patients developed bleeding and thrombotic complications in the first three months after CAR-T infusion, respectively. Events are characterized in Figure 1. All bleeding events occurred between days 0-30 (median 17.5, range 8-30), while thrombotic events occurred between days 2-91 (median day 29, range, 2-91). Two (1.5%) patients experienced both bleeding and thrombosis. Bleeding events coincided with the onset of thrombocytopenia and hypofibrinogenemia, and patients who bled had lower platelet (median 22.5 vs. 47 K/uL; p=0.03) and fibrinogen (median 151 vs. 351 ug/mL; p=0.007) nadirs in the first 30 days compared to those without bleeding. Temporally, the lowest median platelet nadir occurred at day 7 in patients with bleeding events vs. day 21 in patients without bleeding, while timing of fibrinogen nadirs were at day 21 in both. Patients with bleeding episodes were more likely to be older (median age: 70 vs. 60 yrs, p=0.03), have thrombocytopenia prior to lymphodepletion therapy (median 117.5 vs. 174.5 K/uL, p=0.01), and have elevated LDH (lymphoma subgroup; p=0.07). Other lab derangements in the first 30 days seen more frequently in patients with bleeding included prolonged thrombin time (TT) (21% vs. 6%; p=0.02), PT (16% vs. 5%; p=0.06), and elevated d-dimer (16% vs. 3%; p=0.01) indicative of a consumptive process. Thrombotic events were not significantly associated with elevated or peak d-dimer values (median 4.97 vs. 2.37 ug/mL, p=0.20). Interestingly, occurrence or severity of CRS was not associated with bleeding or thrombotic events, nor was it associated with marked derangements in coagulation abnormalities. However, higher grade ICANS (grade > 3) was associated with bleeding (42% vs. 15%; p=0.038), thrombosis (50% vs. 16%; p=0.03), and evidence of endothelial activation including PT prolongation (78% vs. 35%; p<0.001), hypofibrinogenemia (57% vs. 20%; p=0.001), and trend towards elevated d-dimer (70% vs. 46%; p=0.06). 13 (10%) patients received anticoagulation for prophylaxis or therapeutic indications that predated CAR T infusion. Four started anticoagulation secondarily for thrombotic events after CAR-T infusion, and one received tissue plasminogen activator (tPA) for an acute stroke. In this group, no patients developed bleeding complications from anticoagulation. Conclusion Both bleeding (9.2%), and thrombotic (6.2%) events are observed after CAR T cell therapy, with bleeding limited to the first month in our cohort. Notably, ICANS was uniquely associated with PT prolongation, hypofibrinogenemia, and increased fibrin degradation, in addition to both bleeding and thrombosis. These results suggest that a systemic coagulopathy coincides with high grade ICANS and whether these neurologic events truly represent sequelae of widespread vascular dysfunction warrants further investigation. Anticoagulation was safe in the patients whom it was indicated. Risk factors for bleeding and thrombotic complications should be studied prospectively to develop risk-assessment models and clinical guidelines for management of bleeding and thrombosis (including prophylaxis) during CAR T therapy. Disclosures Muffly: Adaptive: Research Funding; Servier: Research Funding; Amgen: Consultancy. Negrin:BioEclipse Therapeutics: Current equity holder in private company; Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; KUUR Therapeutics: Consultancy; Biosource: Current equity holder in private company; Amgen: Consultancy; UpToDate: Honoraria. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Meyer:Orca Bio: Research Funding. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Rezvani:Pharmacyclics: Research Funding. Mackall:Apricity Health: Consultancy, Current equity holder in private company; NeoImmune Tech: Consultancy; Nektar Therapeutics: Consultancy; Allogene: Current equity holder in publicly-traded company; BMS: Consultancy; Lyell Immunopharma: Consultancy, Current equity holder in private company. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding. Sidana:Janssen: Consultancy.

Download Full-text

Incomplete Complement Inhibition in Patients with PNH on Eculizumab - 5 Year Experience from the National PNH Service Leeds

Blood ◽

10.1182/blood-2020-140256 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Rachael Jones ◽

Petra Muus ◽

Talha Munir ◽

Alexandra Pike ◽

Louise Arnold ◽

...

Keyword(s):

Research Funding ◽

Suboptimal Control ◽

Dose Increase ◽

Intravascular Hemolysis ◽

Post Dose ◽

Material Support ◽

Complement Inhibition ◽

Transfusion Requirements ◽

Support Research ◽

Ldh Value

Background Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired disorder characterised by intravascular hemolysis and thrombosis. Patients with symptomatic PNH are commenced on the complement inhibitor eculizumab (600mg weekly for 5 weeks then 900mg 2 weekly). This monoclonal antibody targets C5 in the complement cascade, halting terminal complement activation thus inhibiting intravascular hemolysis. In some patients intravascular hemolysis is not adequately controlled on the standard regimen. Patient symptoms, transfusion requirements and raised Lactate dehydrogenase (LDH) levels are indicators for suboptimal control of PNH and review of eculizumab dosing. The 50% hemolytic complement (CH50) test is a functional assay assessing capability of serum complement components of the classical pathway to lyse sheep red blood cells pre-coated with rabbit anti-sheep red blood cell antibody. Patients with complement inhibited PNH should demonstrate absent lysis. As the test is expensive and difficult to organise, we tested if incomplete complete blockade as determined by CH50 activity would be better to confirm under-dosing than LDH value. Methods The Leeds (UK) PNH National Service reviewed patients who underwent CH50 assay between January 2015 and March 2020. All patients were on eculizumab with clinical concerns regarding suboptimal control of PNH. Patients receive eculizumab infusions intravenously every 14 days and routine follow up from the PNH Service. Serum samples were obtained 24 hours prior to infusions for CH50 assay; LDH values were routinely collected. Complete complement blockade was defined by <10% CH50 activity; intravascular hemolysis was indicated by LDH value >1.5x upper limit of normal (ULN). Confidence intervals were set at 95% and significance set at p<0.05. Results In the study period, 327 tests (median 2, range 1 - 8) were carried out in 146 patients (median age 54 years, range 16 - 89; 74 female). 81% (265) were successful; 19% (62) were unsuccessful due to processing errors. Of the successful tests, 74% (197 in 127 patients) indicated complete complement blockade and 26% (68 in 38 patients) indicated incomplete blockade. Of the patients with incomplete blockade, 68% (26) demonstrated complete blockade on repeat testing and 32% (12) had their eculizumab dose increased. Clinical symptoms of under-dosing in the 12 patients requiring a dose increase included increased transfusion requirements and/or breakthrough hemolysis (7), pregnancy (2; both returned to 900mg post pregnancy) and significant lethargy (3). Of the patients requiring a dose increase, 3 were on 1200mg before 2015; their dose was increased to 1500mg. Repeat testing was carried out in 10/12 patients after dose increase; 8 indicated complete blockade; 2 patients were incompletely blocked at 1200mg and received a further dose increase to 1500mg. Further testing indicated complete blockade in 1 patient; 1 required a 3rd dose increase to 1800mg due to incomplete blockade and ongoing transfusion requirement. Corresponding LDH values were analysed; median LDH for the complete blockade group was 1.16xULN (range 0.54 - 2.16) and 1.28xULN (range 0.76 - 2.38) for the incomplete blockade group. LDH values were not significantly higher in the incomplete blockade group compared to the complete blockade group, p=0.08. There was no significant difference in LDH values pre- and post-dose increase, p=0.38 (Figure 1); median pre-dose increase LDH 1.14xULN; median post-dose increase LDH 1.13xULN. Correlation coefficient shows that CH50 activity was positively correlated with LDH value, r(123)=0.18, p=0.04. Conclusion We report the effective utilisation of CH50 analysis where there is clinical concern of suboptimal control of PNH. All patients demonstrating hemolytic activity on CH50 assays indicated subsequent complement blockade following increase of eculizumab dose. Increasing eculizumab is costly requiring robust evidence of suboptimal complement inhibition; a positive correlation between CH50 activity and LDH values was shown however this is not sufficient to guide clinical decisions. LDH values of the incomplete blockade group were not significantly higher than those with complete blockade, suggesting the use of LDH values as an assessment of complement inhibition in patients with ongoing symptoms or transfusion requirements is not sufficient to guide eculizumab dose increases. Disclosures Munir: Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Pike:Apellis: Research Funding. Arnold:Alexion Pharmaceuticals: Honoraria. Hillmen:AstraZeneca: Consultancy, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21032 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21032-e21032

Author(s):

Xuanzong Li ◽

Linlin Wang

Keyword(s):

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Rank Test ◽

Wild Type ◽

Exact Test ◽

Entire Cohort ◽

Kaplan Meier ◽

Tumor Mutational Burden ◽

The Difference ◽

Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

Download Full-text

Long-Term Outcomes of Patients with Peripheral T-Cell Lymphoma after Autologous Hematopoietic Cell Transplantation

Blood ◽

10.1182/blood-2020-136493 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Olivier Veilleux ◽

Francisco Socola ◽

Sally Arai ◽

Robert Lowsky ◽

Judith A Shizuru ◽

...

Keyword(s):

T Cell ◽

Research Funding ◽

Cell Lymphoma ◽

Brentuximab Vedotin ◽

T Cell Lymphoma ◽

High Dose ◽

Study Cohort ◽

Private Company ◽

Autologous Transplant ◽

Support Research

Introduction: Patients with T-cell lymphoma have variable clinical manifestations and outcomes depending on the histology and their response to therapies. However, the overall outcomes are not as good as their B-cell lymphoma counterpart with induction chemotherapy alone. Therefore, autologous transplant is often used as consolidation in first remission or at relapse because of the poor outcomes with conventional therapy. We have reported previously on Stanford experience of these patients who underwent autologous transplant before 2007 (BBMT 2008, 14:741). Here, we reported a retrospective review of patients in the modern era (2008-2018) with emphasis on the impact of pre-transplant disease status on outcomes and post-transplant relapse management. Method: Between July 1, 2008 and July 31, 2018, 102 consecutive patients with T-cell lymphoma received high dose chemotherapy/autologous hematopoietic cell rescue at Stanford and constitute the study cohort (Figure 1). This study cohort was selected for adequate follow-up (>2 years) after transplant. Progression free survival (PFS) and overall survival (OS) was estimated from the date of transplant using the Kaplan-Meier method. PFS and OS were compared between groups with different pre-transplant disease status based on response to the last pre-transplant therapies (CR1 vs. PR1 vs. CR2). Result: This study cohort included patients with peripheral T-cell lymphoma, non-specified (n=21), angioimmunoblastic T-cell lymphoma (n=50), ALK-negative anaplastic large-cell lymphoma (n=14), ALK-positive anaplastic large-cell lymphoma (n=5), extranodal NK/T cell lymphoma (n=9), enteropathy-type T-cell lymphoma (n=1), adult T-cell leukemia/lymphoma (n=1) and hepatosplenic T-cell lymphoma (n=1). It had a male/female ratio of 61/41, and a median age of 58 years (range 23-71). At diagnosis the majority of the patients had stage III/IV disease (70%) and B symptoms (56%). The median time from diagnosis to transplant was 8.1 months (range 4-176). The majority of patients were in first complete remission (CR1, n=79) at the time of transplant, while others were in PR1 (n=11) or in CR2 (n=12) from last pre-transplant therapies. Ninety-one (89%) patients received high dose cyclophosphamide/carmustine/etoposide(CBV) and 11 patients received high dose carmustine/etoposide/cytarabine/melphalan (BEAM) prior to autograft infusion. Median follow-up post-transplant was 36.8 months (range 0.7-130) for the entire cohort. The estimated 3-year PFS and OS were 60% (95% CI 49-68%) and 75% (95% CI 65-82%), respectively (Figure 2A). Patients who were in CR1 had significantly better median PFS compared to patients in PR1 or CR2 (7.04 vs 1.19 years, p=0.039; 7.04 vs 0.48 years p=0.004, Figure 2B). The estimated 3-year PFS were 67% (95% CI 55-76%), 36% (95% CI 11-63%), and 29% (95% CI 8-56%) for the CR1, PR1 and CR2 groups respectively. Patients who were in CR1 also had significantly better median OS compared to patients in PR1 or CR2 (not reached vs 2.30 years, p=0.018; not reached vs 3.76 years p=0.045, Figure 2C).The estimated 3-year OS were 82% (95% CI 71-89%), 44% (95% CI 14-70%), and 53% (95% CI 21-78%) for the CR1, PR1 and CR2 groups respectively. In this cohort, there were no significant differences in either PFS or OS between different histology. Forty patients experienced disease relapse after transplant. The majority (n=28, 70%) of these patients received additional therapies including chemotherapy (n=13), brentuximab vedotin (n=12), HDAC inhibitor (n=7), and radiation (n=3) with a median systemic therapy of 2 (range 1-5). Thirteen patients eventually underwent allogeneic hematopoietic cell transplantation. The median OS after post-transplant relapse was 21.3 months (Figure 3). Both brentuximab vedotin and allogeneic transplant seemed to provide prolonged survival for these relapsed patients, with estimated 2-year post-relapse OS were 75% (95% CI 13-96%) and 63% (95% CI 28-84%) for the two groups respectively. Conclusion: Autologous transplant remains to be a good option as consolidation for patients with T-cell lymphoma, mostly in patients with first complete remission. While close to 40% of the patients experienced relapse after autologous transplant, additional therapies such as brentuximab vedotin or/and allogeneic transplant can provide long-term benefit for these patients. Disclosures Shizuru: Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Muffly:Servier: Research Funding; Amgen: Consultancy; Adaptive: Research Funding. Sidana:Janssen: Consultancy. Meyer:Orca Bio: Research Funding. Rezvani:Pharmacyclics: Research Funding. Miklos:Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Allogene Therapeutics Inc.: Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding. Negrin:Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; Biosource: Current equity holder in private company; Amgen: Consultancy; BioEclipse Therapeutics: Current equity holder in private company; UpToDate: Honoraria; KUUR Therapeutics: Consultancy.

Download Full-text

Lack of Prognostic Significance of the Conventional and Novel Prognostic Markers in Trisomy 12 Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v128.22.4354.4354 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4354-4354

Author(s):

Valter Gattei ◽

Riccardo Bomben ◽

Michele Dal Bo ◽

Antonella Zucchetto ◽

Francesca Rossi ◽

...

Keyword(s):

Flow Cytometry ◽

Research Funding ◽

Prognostic Markers ◽

Lymphocytic Leukemia ◽

Cytogenetic Abnormality ◽

Mutational Status ◽

Ighv Gene ◽

Trisomy 12 ◽

Gene Status

Abstract Background. Trisomy 12 (tris12) is a recurrent cytogenetic abnormality in chronic lymphocytic leukemia (CLL), occurring in approximately 15-20% of cases, often as the unique cytogenetic alteration, that is usually considered a clonal driver lesion occurring early in CLL evolution. In the Dohner hierarchical categorization, tris12 CLL are identified as having an intermediate prognostic risk, although recent reports suggest a more complex and heterogeneous clinical behavior. Compared to CLL lacking this cytogenetic abnormality, tris12 CLL show more atypical morphology and immunophenotype, more frequent expression of the negative prognostic markers CD49d and CD38, and presence of NOTCH1 mutations and an unmutated (UM) IGHV gene status. The increased fraction of tris12 CLL carrying adverse prognostic features is in contrast to the intermediate clinical behavior associated with most tris12 CLL cases. Aim. To perform a comprehensive evaluation of the clinical impact of the major genetic, immunogenetic and immunophenotypic prognostic markers in tris12 CLL. Methods. The study was based on a multicenter series of tris12 CLL defined according to Dohner (n=283, including 73 cases also bearing del13q), and a comparison group (control) of 553 cases with either del13q (n=308) or without any cytogenetic abnormality (no del17p, del11q, tris12, del13q, n=245). Median follow-up of patients in the tris12 and control groups were 4 years (range 0-22) and 7 years (range 0-28), with 54% and 57% treated patients, and 18% and 15% deaths, respectively. Patient characterization included modified Rai stage, CD49d (CD49dhigh, ≥30% positive cells by flow cytometry), CD38 (CD38high, ≥30% positive cells by flow cytometry) and ZAP-70 (ZAP-70high, ≥20% positive cells by flow cytometry) expression, and IGHV mutational status (mutated, M, or UM according to the 2% cutoff). TP53, BIRC3, NOTCH1 andSF3B1 mutations were screened either at diagnosis or before therapy by NGS with at least 1000X coverage and 1% of sensitivity. Groups were compared by chi-square test; overall survival (OS) was computed from diagnosis to death or censored at last observation, and analyzed by Cox regression analysis. Results. Comparing the tris12 and the control groups, median age was 64 years (range 30-92) vs 66 years (range 33-92), male gender 55% vs 56% (p=0.86), the modified Rai stage was early in 52% vs 54%, intermediate in 41% vs 42% and advanced in 7% vs 4% (p=0.20). As previously reported, tris12 CLL were characterized by a higher prevalence of cases expressing CD49d (85% vs 31%) and CD38 (62% vs 17%; all p<0.0001), and of UM IGHV cases (55% vs 25%, p<0.0001). Analysis of recurrent mutations highlighted a higher prevalence of NOTCH1 mutations (26% vs 8%, p<0.0001) and of BIRC3 mutations (21% vs 1%, p<0.0001) in tris12 vs control group CLL. Conversely, no differences were found in the fraction of cases with TP53 mutations (3% vs 4%, p=0.38) or SF3B1 mutations (7% vs 7%, p=0.89), and in cases expressing ZAP-70 (62% vs 52%, p=0.09). The impact of these features on OS was tested by univariate analysis: in tris12 CLL, only the UM IGHV gene status predicted shorter OS (HR=2.37, p=0.0063), while none of the other characteristics reaching statistical significance as OS predictors (CD49d HR=1.36, p=0.36; CD38 HR=0.42, p=0.052; ZAP-70 HR=3.12, p=0.07; TP53 HR=2.33, p=0.25; NOTCH1 HR=1.40, p=0.22; SF3B1 HR=2.05, p=0.17; BIRC3 HR=1.22, p=0.61). On the other hand, in the control cohort, a significantly higher HR was found for CD49d (HR 3.11, p<0.0001) and CD38 (HR 3.45, p<0.0001) expression, TP53 (HR 2.88, p=0.0026), NOTCH1 (HR 3.57, p<0.0001), and SF3B1 (HR 2.57, p=0.0038) mutations, as well as for the UM IGHV gene status (HR=2.81, p<0.0001), but not for ZAP-70 expression and BIRC3 mutations (HR=1.74 and HR=1.91, p=0.15 and p=0.37, respectively). Conclusions. Mutational status of IGHV genes was the sole prognostic factor able to stratify OS in tris12 CLL. Despite the high frequency of NOTCH1 and BIRC3 mutations, as well as of CD49d and CD38 overexpression, these markers failed to convey a prognostic risk in tris12 CLL. The lack of a significant clinical impact for TP53 and SF3B1 mutations might be partly explained by the low number of mutated cases combined with a relative short follow up in our tris12 cohort. These findings are in keeping with the hypothesis of a different patho-biological mechanism occurring in tris12 CLL, which however remains to be fully elucidated. Disclosures D'Arena: Janssen-Cilag: Honoraria. Rossi:Gilead: Honoraria, Research Funding; Abbvie: Honoraria; Janseen: Honoraria. Gaidano:Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Shanafelt:Genentech: Research Funding; Janssen: Research Funding; Celgene: Research Funding; GlaxoSmithkKine: Research Funding; Pharmacyclics: Research Funding; Cephalon: Research Funding; Hospira: Research Funding.

Download Full-text

Phase II trial of combined chemotherapy with irinotecan, S-1, and bevacizumab (IRIS/Bev) in patients with metastatic colorectal cancer (mCRC): Hokkaido Gastrointestinal Cancer Study Group (HGCSG) trial—Comparison of the efficacy of KRAS status.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.536 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 536-536

Author(s):

Michio Nakamura ◽

Satoshi Yuki ◽

Masayoshi Dazai ◽

Yoshimitsu Kobayashi ◽

Takashi Kato ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

Statistical Tests ◽

Progression Free Survival ◽

Rank Test ◽

Wild Type ◽

Target Number ◽

Mutant Type ◽

Free Survival ◽

Kras Status

536 Background: Mutations of the KRAS gene were identified as a predictive marker in mCRC for anti-EGFR antibody. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab (BV) treatment in mCRC is independent of alterations in the KRAS status. We analized efficacy of BV combined irinotecan and S-1 (IRIS/Bev) in mCRC relative to KRAS status. Methods: In the retrospective analysis (n=53) of patients who participated in the Phase II trial of IRIS/Bev, additional statistical analyses were done with data from KRAS mutational analyses. In this trial, eligible patients had to have mCRC with a confirmed diagnosis of adenocarcinoma, an age of >20 years, and no history of prior chemotherapy. S-1 40-60 mg twice daily p.o. was given on days 1-14 and irinotecan 100 mg/m2 and bevacizumab 5 mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine Progression-free survival (PFS) and OS. Log-rank test was used to compare with mutant or wild-type KRASin terms of PFS and OS. All statistical tests were performed using SPSS. Results: The target number of 53 patients was enrolled as of March 2009. KRAS status was assessed in 43 patients (wild = 27, mutant = 16). Response rate was 63.0% with wild-type and 68.8% with mutant-type KRAS, that was not significant (p=0.752). The median Progression-free survival was 17.1 months with wild-type and 22.7 months with mutant-type KRAS, that was not significant (p=0.531). And median OS was 49.0 months with wild-type and 38.0 months with mutant-type KRAS, that was not significant(p=0.906) as well. Conclusions: IRIS/Bev provides clinical benefit in patients with mCRC expressing either mutant or wild-type KRAS. Randomized control trial comparing this regimen with oxaliplatin containing regimen(XELOX or mFOLFOX6 plus bevacizumab: TRICOLORE study) is already started. Comparison of the efficacy of KRAS status is also planned in this study. Clinical trial information: NCT00569790.

Download Full-text

High MYC Protein Expression in MDS Is Associated with Early Transformation to AML

Blood ◽

10.1182/blood-2020-137116 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 39-40

Author(s):

Seongseok Yun ◽

David Gajzer ◽

Najla Al Ali ◽

Nicole D. Vincelette ◽

Pukhraz Basra ◽

...

Keyword(s):

Protein Expression ◽

Research Funding ◽

Cox Model ◽

Progression Free Survival ◽

Automated System ◽

Rank Test ◽

Differential Count ◽

Cell Transplant ◽

Hypomethylating Agents ◽

Protein Levels

Acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC) is shown to be associated with dismal clinical outcomes and there remains a pressing need for new therapeutic strategies to improve survival outcomes. It is also important to identify targetable markers that could predict an earlier AML transformation from preexisting MDS. Our recent studies demonstrated that high expression level of MYC oncoprotein is associated inferior survival outcome in AML-MRC patients and that MYC plays an oncogenic role by epigenetic regulation of hydroxylation of 5-methylcytosine. However, the role of MYC in MDS to AML progression remain to be answered. Here, we investigated MYC protein expression levels in bone marrow (BM) specimens of patients with preexisting MDS and their subsequent AML-MRC specimens to determine whether increased MYC expression is associated with early AML progression. We retrospectively identified 32 patients with histologically confirmed AML-MRC evolving from MDS and evaluated MYC protein levels in BM biopsy specimens at the time of initial MDS diagnosis and at the time of disease transformation to AML-MRC, respectively. Clinical data including age at diagnosis, gender, CBC with differential count, cytogenetics, somatic mutations common in myeloid disease, blasts count, and IPSS were extracted at the time of MDS and AML-MRC diagnosis. MYC expression was assessed by immunohistochemistry on 4-5µm tissue sections. Deparaffinized slides were stained with anti-MYC antibody (clone Y69, Roche Diagnostics) using a Ventana Benchmark automated system. MYC expression was scored independently by two hematopathologists and categorized as low vs. high as previously described. The cut-off for high MYC expression is ≥5% positive cells. The MDS-to-AML progression free survival (PFS) and overall survival (OS) were calculated from the date of MDS diagnosis and outcomes were estimated with the Kaplan-Meier method and compared using the log-rank test. All statistical analyses were performed using SPSS v24.0. Among 32 patients, 69% (n=22) and 31% (n=10) patients had low and high MYC expression at MDS diagnosis (Table 1). The median age was 67.9 (33.5-78.7) and 61.1 (38.9-73.4) and the % of MYC positive blasts were 1% (range, 0-4.5) and 17.5% (range, 5-27.5) in low and high MYC groups, respectively, at the time of MDS diagnosis. There was no statistical difference in BM blast counts between low vs. high MYC groups (median 5% vs. 7.5%, p=0.4951). IPSS risk assessment in a total of 26 patients (19 in low MYC and 7 in high MYC) showed that 9% (n=2), 27% (n=6), 32% (n=7), and 18% (n=4) in low MYC group and 0% (n=0), 20% (n=2), 20% (n=2), and 30% (n=3) in high MYC groups had low, intermediate-I, intermediate-II, and high risk at the time of MDS diagnosis (Table 1). A total of 84% (86% [n=19] in low MYC and 80% [n=8] in high MYC) patients received treatments for MDS; ESA in 16% (n=5), hypomethylating agents in 81% (n=26), and Revlimid in 16% (n=5) (Table 1). Allogeneic stem cell transplant (allo-SCT) was performed in 12.5% (n=4) patients (n=3, low MYC; n=1, high MYC). Following AML progression, a total of 91% (n=29) patients received treatment for AML including induction chemotherapy (n=18), hypomethylating agents (n=7), and other therapies including trial (n=4) (Table 1). In the univariate analyses, patients with low MYC expression had significantly longer MDS-to-AML PFS (median 15.8 vs. 7.25 months, HR=0.1745, 95%CI=0.0591-0.5157, p=0.0016) (Figure 1), however, there was no OS difference between two groups (4.32 vs. 2.35 years, HR=0.5131, 95%CI=0.1064-2.475, p=0.6909). In a multivariate Cox model (adjusting for IPSS, age, front-line therapy, gender, allo-SCT, and MYC level), high MYC expression (HR=3.939, 95%CI=1.107-14.012, p=0.034) and IPSS risk (HR=1.903, 95%CI=1.139-3.181, p=0.014) were significant factor for MDS-to-AML PFS. In conclusion, high MYC expression at the MDS stage was associated with shorter time to AML progression, indicating that MYC plays an oncogenic role in MDS to AML transformation. Although our findings need further validation by prospective studies with greater sample size, our results support a combination treatment of hypomethylating agents with novel agents targeting MYC or/and its downstream pathways and warrant further study to identify underlying mechanisms of MYC-driven MDS to AML progression. Disclosures Talati: Pfizer: Honoraria; Astellas: Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; AbbVie: Honoraria. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Padron:Novartis: Honoraria; Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding. Komrokji:JAZZ: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy.

Download Full-text

DNA Damage-Response Pathway in Lymphoma Determines Interactions with Macrophages By Altered PD-L1 Expression and Exosome Formation

Blood ◽

10.1182/blood-2018-99-120264 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 275-275

Author(s):

Daniela Vorholt ◽

Elena Izquierdo-Alvarez ◽

Benedict Sackey ◽

Jan Schmitz ◽

Nadine Nickel ◽

...

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Research Funding ◽

Therapeutic Response ◽

Wild Type ◽

Lymphoma Cells ◽

Damage Response ◽

Dna Damage Response Pathway ◽

Support Research

Abstract The tumor microenvironment is characterized by multiple interactions of transformed malignant cells with non-transformed stroma or immune cells. Particularly macrophages play a pivotal role in this network determining disease progression and therapeutic response. In previous work we could show that macrophages are an essential mediator of therapeutic response in the synergistic response to the administration of the chemoimmunotherapy. The combination treatment strongly increases tumor clearance by repolarization of tumor-associated macrophages from a suppressive to an activated phenotypic state. Here, se analyzed the functional implications of the DNA damage response pathway for the generation of the ASAP and synergy in chemoimmunotherapy. We attempted to disrupt DNA damage response pathway in lymphoma cells generated from the hMB humanized Double-Hit-Lymphoma model by knock-down of key elements like ATM, DNA-PK or p53. We could prevent the formation of the stimulatory cytokine release effect on macrophage phagocytic capacity. Here, p53 status displays a key regulatory role on macrophage mediated malignant cell depletion. TP53 activation via Nutlin-3A treatment of lymphoma cell enhances ADCP in in p53 wild-type cells, while not displaying enhancement in p53-deficient lymphoma cells. Addressing the treatment in vivo using the hMB model for modeling of Double-Hit Lymphoma bearing mice we could demonstrate diminished ASAP and ADCP for p53-deficient lymphoma treated with cyclophosphamide in vivo. Using primary human CLL patient cells comparing both wild-type and p53-deficient status, the p53-deficient CLL cells failed to induce the stimulatory, cytokine-mediated effect on macrophage phagocytosis in response to combination treatment as seen with the p53 proficient CLL cells. Using a CLL mouse model by treating Eµ-TCL1/p53wt/wt as well as Eµ-TCL1p53-/- mice we could show that low-dose cyclophosphamide treated Eµ-TCL1p53-/- mice failed to induce an antibody mediated stimulatory effect on macrophage phagocytosis capacity as seen with Eµ-TCL1/p53wt/wt mice. A similar effect was seen for primary multiple myeloma cells in response to daratumumab displaying significantly less ADCP of p53-deficient multiple myeloma cells. As for the mechanism of p53-defined interaction within the tumor microenvironment we subjected p53-wild-type and p53-deficient lymphoma cells for proteomic analysis. Here we could identify a significantly deregulated protein expression profile for exosome release in p53 deficient lymphoma cells. Verifying this finding by assessing size and frequency exosomes released by respective cell populations we reveal profound changes induced by p53 loss. Furthermore we could identify up-regulation of PD-L1 in p53-deficient cells. Blocking this checkpoint in the ADCP assay could significantly restore phagocytic capacity of macrophages and overall therapeutic response. In this work, we indicate that p53 functional status determines phagocytic function and therapeutic response to monoclonal antibodies. We can verify this finding in independent models in vitro and in vivo as in primary CLL and myeloma patient cells. We furthermore identify altered exosome profiles and checkpoint inhibitor expression in lymphoma cells as underlying mechanism of macrophage modulation. Finally our ongoing research offers possibility to reveal and tailor new combinatorial treatment approaches for chemo-refractory patients. Disclosures Wendtner: Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding. Hallek:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Pallasch:Gilead: Research Funding.

Download Full-text

Changes in Multiple Myeloma Treatment Patterns during the Early COVID-19 Pandemic Period

Blood ◽

10.1182/blood-2021-148998 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4092-4092

Author(s):

Natalia Neparidze ◽

Rong Wang ◽

Amer M. Zeidan ◽

Nikolai Podoltsev ◽

Rory M. Shallis ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Features ◽

Research Funding ◽

Treatment Initiation ◽

Clinical Presentation ◽

Treatment Patterns ◽

Rank Test ◽

Time To Treatment ◽

Time To Treatment Initiation ◽

Support Research

Abstract Background: Early during the COVID-19 pandemic patient and provider anxiety concerning in-person visits and travel restrictions may have delayed cancer diagnosis and altered treatment. We evaluated changes in clinical presentation and treatment patterns in multiple myeloma (MM) during the early COVID-19 period compared to historical pre-COVID periods. Methods: Using the nationwide Flatiron Health EHR-derived de-identified database, we compared clinical presentation and treatment patterns in the immediate post-COVID period (2020) to a comparable pre-COVID period (2018 and 2019). We focused on two separate clinical settings: 1) patients newly diagnosed with MM during February-June in the years of interest (NEWPT) with evidence of management within 90 days and follow-up for 7 months; and 2) patients diagnosed with MM during 2014-2019 receiving active treatment as of February (2018, 2019, 2020, ACTIVE) and follow-up for 11 months. Delayed clinical presentation was assessed using baseline (90 days before diagnosis/index date) measures of ISS stage, ECOG performance status, anemia, and kidney function. We examined treatment patterns (choice of regimen) of both cohorts in the two time periods. We compared clinical features of initial presentation in pre-COVID and COVID period using Pearson's χ 2 test. For NEWPT, we also utilized Kaplan-Meier curves and log-rank test to compare time to treatment initiation between the two periods. Multivariable Cox proportional hazards regression model with death as a competing risk was used to determine impact of COVID on treatment initiation by adjusting sex, age at diagnosis, race, insurance, stage, baseline ECOG, and hospital setting. All analyses were conducted in SAS (Version 9.4, SAS Institute, Cary, North Carolina) with 2 sided tests and a type I error of 5%. Results: Our study included 1319 NEWPT (964 pre-COVID and 355 COVID) and 2206 ACTIVE (1014 pre-COVID and 1192 COVID) patients. In the NEWPT cohort, we observed no differences between the pre-COVID and COVID periods in terms of baseline characteristics, including clinical features like stage, ECOG performance status, anemia or kidney function (Table A). Patients in the pre-COVID period were more likely to initiate any treatment (91.1% vs 86.2%, p<.01). Median time to treatment initiation was 30 days pre-Covid and 32 days during the Covid period (log-rank test p=0.04, Figure A). After adjusting for patient demographic, clinical features (extent of anemia, hypercalcemia, kidney dysfunction), and hospital variables (US region, practice type academic vs community), the difference between the two periods was not significant (COVID vs pre-COVID hazard ratio=0.88, 95% confidence interval 0.78-1.10, p=0.07). In NEWPT cohort, compared with their pre-COVID counterparts, patients in COVID period were more likely to receive monoclonal antibody (mAb) (14.4% vs 4.8%, p<.01, Figure B) and used IMID-based regimen as their first line of therapy (80.4% vs 74.3%, p<.01). In ACTIVE cohort, more patients in the pre-COVID period were anemic (Hemoglobin <10 g/L, 14.9% vs 9.7%, p<.01) at baseline than those in the COVID period. As in NEWPT cohort, ACTIVE patients in the COVID period used mAb-based regimen more commonly (28.9% vs 16.9%, p<.01) (Figure C). In addition, fewer ACTIVE treatment patients in the COVID period received cyclophosphamide regimens (7.9% vs 15.1% p<.01). Conclusions: During early COVID-19 pandemic we did not observe evidence of delayed diagnosis or more advanced stage, anemia or kidney disease for NEWPT with MM. MM treatment patterns were notable for higher utilization of mAb, IMID-based therapies and decreased use of cyclophosphamide regimens, without significant change in time to treatment initiation. Reassuringly, changes in treatment-patterns during COVID pandemic were modest, some likely reflecting changes in MM treatment landscape (advances in mAb regimens) rather than direct impact of COVID. Further studies are needed to understand how these changes evolve and affect clinical outcomes over time beyond 2020. Figure 1 Figure 1. Disclosures Neparidze: GlaxoSmithKline: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Zeidan: Jasper: Consultancy; AstraZeneca: Consultancy; Aprea: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Astellas: Consultancy; Agios: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Jazz: Consultancy; Pfizer: Other: Travel support, Research Funding; Genentech: Consultancy; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; ADC Therapeutics: Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Astex: Research Funding; BeyondSpring: Consultancy; Incyte: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Epizyme: Consultancy; BioCryst: Other: Clinical Trial Committees; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy; Ionis: Consultancy; Amgen: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Podoltsev: Pfizer: Honoraria; PharmaEssentia: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Novartis: Honoraria; CTI BioPharma: Honoraria; Bristol-Myers Squib: Honoraria; Celgene: Honoraria. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding. Davidoff: Amgen: Consultancy; AbbVie: Other: Family member consultancy. Huntington: AstraZeneca: Consultancy, Honoraria; TG Therapeutics: Research Funding; Thyme Inc: Consultancy; Flatiron Health Inc.: Consultancy; Genentech: Consultancy; SeaGen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy, Honoraria; Servier: Consultancy; Bayer: Honoraria; DTRM Biopharm: Research Funding; AbbVie: Consultancy; Celgene: Consultancy, Research Funding.

Download Full-text