Résumé
In phase 1 of CC-92480- MM- 001 (NCT03374085), the recommended phase 2 dose (RP2D) of mezigdomide plus dexamethasone (MEZI-d) was selected at 1 mg once daily for 21/28 days. Here we report preliminary results from the MEZI-d dose-expansion cohort in patients with heavily pretreated RRMM. Key eligibility criteria were: RRMM;>=3 prior lines of therapy;disease progression <=60 days of last myeloma therapy;refractoriness to lenalidomide/pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody. Oral mezigdomide 1 mg was given on days 1-21 of each 28-day cycle, plus weekly dexamethasone (40 mg;20 mg if >75 years of age). Primary objective was to evaluate efficacy (overall response rate [ORR]);secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. As of 16/Sep/2022, 101 patients had received MEZI-d at the RP2D. Median age was 67 (range 42-85) years, median time since initial diagnosis was 7.4 (1.1-37.0) years;39.6% of patients had plasmacytomas and 37/101 patients had high-risk cytogenetics (56/101 not evaluable). Median number of prior regimens was 6 (3-15);prior therapies included stem cell transplantation (77.2%) and anti-BCMA therapy (29.7%). All patients were refractory to last myeloma regimen and triple-class refractory. Median follow-up was 7.5 (0.5-21.9) months, with a median of 4 (1-20) cycles;10.0% of patients continued treatment;progressive disease was the main reason for discontinuation (60.4%). ORR was 40.6% for all patients. Whilst data are not mature yet, median PFS was 4.4 (95% CI 3.0-5.5) months and median duration of response was 7.6 (95% CI 5.4-9.5) months. ORR was 30.0% in patients with plasmacytomas (N = 40) and 50.0% in patients with prior anti-BCMA therapy (N = 30). Ninety-one (91.1%) patients experienced a grade 3/4 treatment-emergent adverse event (TEAE). Most frequent hematologic grade 3/4 TEAEs were neutropenia (75.2%), anaemia (35.6%), and thrombocytopenia (27.7%);34.7% of patients had grade 3/4 infections, including grade 3/4 pneumonia (15.8%) and COVID-19 (7.0%). Occurrence of other grade 3/4 non-hematologic TEAEs was generally low. Due to TEAEs, 76.2% and 29.7% of patients had mezigdomide dose interruptions and reductions, respectively;90.1% of patients discontinued mezigdomide. Mezigdomide induced substrate degradation and increases in activated and proliferating T cells in patients, including those directly refractory to pomalidomide-based therapies. MEZI-d had a manageable safety profile with encouraging efficacy in patients with triple-class refractory RRMM, including patients with prior BCMA-targeted therapies. These results strongly support the continued development of mezigdomide in MM, and especially in combination.
Résumé
BACKGROUND: Multiple myeloma (MM) and Waldenström macroglobulinemia (WM) are associated with significant immunoparesis. Based on the ongoing COVID-19 pandemic, there is an urgent need to understand whether patients are able to mount a sufficient response to COVID-19 vaccines. METHODS: MM and WM patients are vaccinated with mRNA-1273 (Moderna), BNT162b2 mRNA (Pfizer/BioNTech), or JNJ-78436735 (Johnson & Johnson) in a prospective clinical trial. Primary endpoint is SARS-CoV-2 spike protein (S) antibody (Ab) detection 28 days after final vaccination. Secondary endpoints include functional serologic assessments and T-cell responses at 28 days, 6 months, 9 months, and 12 months following vaccination. S Abs were detected by Elecsys assay (Roche Diagnostics), with 3 0.80 U/mL defined as positive and titers > 250 U/mL considered stronger correlates of neutralization. SARS-CoV-2 wildtype and variant S-specific Ab isotypes and FcγR binding profiles were quantified by custom Luminex assay. Antibody-dependent neutrophil and cellular phagocytosis (ADNP and ADCP) were assessed using flow cytometry. RESULTS: To date 141 patients have been enrolled, 137 (91 MM and 46 WM) of whom had an S Ab assessment. Median Ab titer was 178.0 (IQR, 16.10-1166.0) for MM and 3.92 (IQR, 0-278.9) for WM. S Ab response rate was 91% (83/91) in MM and 56% (27/46) in WM. However, responses achieving S Ab >250 U/mL were 47.3% (43/91) in MM and 26.1% (12/46) in WM. In patients 375 years, responses >250 u/mL were 13.3% (2/15;p<0.05). Vaccine-specific S Ab responses >250 u/mL following mRNA-1273, BNT162b2, and JNJ-78436735 were 67.6% (23/34;p<0.05), 38.3% (18/47;p=NS), and 20% (2/10;p=NS) in MM and 50.0% (8/16;p<0.05), 14.8% (4/27;p<0.05), and 0% (0/3;p=NS) in WM. Among MM patients with progressive disease, S Ab response >250 u/mL occurred in 30% (6/20) as opposed to 55.6% (30/54) for VGPR+ (p<0.05). MM patients having autologous stem cell transplant within 12 months demonstrated 100% (5/5;p<0.05) S Ab responses. For MM patients actively receiving an anti-CD38 monoclonal Ab or an immunomodulatory drug, S Ab response occurred in 38.9% (14/36;p=NS) and 50.9% (28/55;p<0.05). Among WM patients, S Ab responses >250 U/mL occurred in 63.6% (7/11;p<0.05) previously untreated;0% (0/9;p<0.05) who received rituximab within 12 months;10% (2/20);p<0.05) on an active Bruton Tyrosine Kinase (BTK) inhibitor;and 20% (3/15;p=NS) who received other therapies. Functional Ab studies were performed on 14 MM patients, 14 WM, patients, and 14 healthy donors (HD) (Figure 1). All patients were assessed 28 days following their final vaccination and myeloma patients had an additional assessment 28 days following initial vaccination. MM and WM patients demonstrated less IGG1 and IGG3 S Ab production than HD. MM patients showed increased IgA and IgM S Ab production as well as increased FcgR2A binding following a second vaccine in contrast to HD. Both ADNP and ADCP were reduced in MM and WM patients. MM patients demonstrated improved ADCP in SARS-CoV-2 variants B.1.351, B.1.117, and P.1 versus wildtype (p<0.05). CONCLUSIONS: We report the first known evidence of impaired functional humoral responses following COVID-19 vaccines in patients with MM and WM. Overall, WM patients showed more severe impairment of COVID-19 S Ab responses. Most previously untreated WM patients achieved S Ab responses, however the most significant reduction in S Ab responses were seen in WM patients who received rituximab within 12 months or active BTK inhibitors. For MM patients, being in disease remission associated with improved S Ab response. Among MM and WM patients, age 375 years associated with significantly lower rates and vaccination with MRNA-1273 (Moderna) elicited significantly higher S Ab response rates than other vaccines. A defect in ADNP and more profound defect in ADCP suggests overall compromised opsinophagocytic activity among MM and WM patients. Data comparing first and second vaccine responses in MM patients, suggest less efficient class switching to IGG as well as incomple e maturation of their FcgR2A binding profiles but normal maturation of FcgR3A. Interestingly, ADCP was improved in several emerging SARS-CoV-2 variants. T-cell studies are pending and will be updated. Further understanding of the immunological response to COVID19 vaccination is needed to clarify patients risks, and necessity for booster or alternative protective measures against COVID-19. (Figure Presented).
Résumé
Introduction: Ixazomib is an oral proteasome inhibitor (PI) that is currently approved to be administered once weekly in combination with lenalidomide (LEN) and dexamethasone in RRMM (Moreau et al N Eng J Med 2016;374:1621-1634). As most patients are LEN refractory at the time of first relapse, pomalidomide-based regimens are commonly utilized due to their proven efficacy in this population. We hypothesized that twice weekly dosing of ixazomib may be more efficacious as this has been previously studied as monotherapy (Richardson et al, Blood 2014 Aug 14;124(7):1038-46) and in combination with LEN demonstrating promising activity and safety (Richardson et al, Br J Haematol. 2018 Jul;182(2):231-244). We present results of our phase I/II trial of twice weekly ixazomib in combination with pomalidomide and dexamethasone in RRMM, including the recommended phase II dose and first report of efficacy of this combination. Methods: This is a phase I/II multicenter, single-arm, open label study evaluating the combination of twice weekly ixazomib with pomalidomide and dexamethasone in RRMM. The primary objective for phase I portion is to determine safety and the maximum tolerated dose (MTD) of this combination using a standard 3+3 dose escalation design and primary objective of the phase II portion is overall response rate (ORR) with secondary outcomes including progression-free survival (PFS) and clinical benefit rate (CBR) Ixazomib is studied at doses of 3mg or 4mg on days 1, 4, 8, 11, pomalidomide at a dose of 2mg, 3mg and 4mg on days 1-14 and dexamethasone is administered at a dose of 12mg on days 1, 2, 4, 5, 8, 9, 11, 12 (8mg for patients > 75 years old) on a 21 day cycle (Table 1). Patients were included if they received 2 prior lines of therapy, but 1 prior line was allowed if first line treatment included a PI and an immunomodulatory agent and disease relapse occurred within 60 days of last therapy. Patients who were ixazomib exposed or pomalidomide refractory were excluded. Results: At the time of data cutoff, 22 patients have been enrolled across all cohorts. There were two dose-limiting toxicities (DLT) noted during the dose escalation phase (upper respiratory infection and neutropenia, respectively) establishing the RP2D of 4mg ixazomib and 4mg pomalidomide. Median age at the time of enrollment was 68 years old with ISS stage at diagnosis of I (14%), II (32%), and III (23%). High-risk FISH abnormalities were seen in 43% of patients as follows: del 17p (9%), gain 1q (36%), t(4;14) (5%), t(14;16) (9%). Median prior lines of therapy was 2 (range 1-4) with 100% of patients having prior treatment with lenalidomide and 95% with prior bortezomib. Fifty-nine percent of patients had a prior autologous stem cell transplant. Ten patients have been enrolled at the RP2D at the time of data cut off. The most common treatment-related toxicities were mainly low grade (Grade 1-2) and included neutropenia (45%), lower extremity edema (41%), insomnia (36%), dyspnea (32%) and weight gain (32%). Grade 3 or greater toxicities were noted in 36% of patients and included neutropenia (18%), thrombocytopenia (5%), anemia (5%), atrial fibrillation (5%), dehydration (5%), diarrhea (5%), fall (5%), lung infection (5%), and pneumonitis (5%). Dose reductions occurred in 13 patients and predominantly involved dexamethasone due to weight gain, insomnia, atrial fibrillation and fatigue. There have been no discontinuations due to toxicity and no treatment related mortality at the time of data cutoff. The ORR in all cohorts was 45%, with 9% achieving sCR, 9% VGPR and 86% achieving stable disease or better. At the RP2D, the ORR was 50% with 30% of patients achieving VGPR or better. At the median follow up of 10 months, median PFS was 13 months (95% CI: 11-NR) and median overall survival was not reached. Conclusions: Twice weekly ixazomib in combination with pomalidomide and dexamethasone is a generally well-tolerated regimen with promising activity. The recommended phase II dose has been established at 4mg of ixazomib and 4mg of pomalidomide demonstrat ng efficacy in a high-risk cohort of RRMM patients. The all-oral nature of this regimen has allowed for robust accrual during the COVID 19 pandemic. [Formula presented] Disclosures: Nadeem: BMS: Membership on an entity's Board of Directors or advisory committees;Karyopharm: Membership on an entity's Board of Directors or advisory committees;GSK: Membership on an entity's Board of Directors or advisory committees;Takeda: Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Mo: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria;GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees;Epizyme: Consultancy;Eli Lilly: Consultancy;BMS: Membership on an entity's Board of Directors or advisory committees;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;AbbVIE: Consultancy. Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy;MJH: Honoraria;Karyopharm: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria. Sanchorawala: Celgene: Research Funding;Pfizer: Honoraria;Sorrento: Research Funding;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Research Funding;Prothena: 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;Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding;Regeneron: Membership on an entity's Board of Directors or advisory committees;Proclara: Membership on an entity's Board of Directors or advisory committees;Oncopeptide: Research Funding;Karyopharm: Research Funding. Sperling: Adaptive: Consultancy. Munshi: Janssen: Consultancy;Takeda: Consultancy;Bristol-Myers Squibb: Consultancy;Celgene: Consultancy;Amgen: Consultancy;Karyopharm: Consultancy;Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties;Legend: Consultancy;Abbvie: Consultancy;Adaptive Biotechnology: Consultancy;Novartis: Consultancy;Pfizer: Consultancy. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees;Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees;AstraZeneca: Membership on an entity's Board of Directors or advisory committees;Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company;Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Richardson: AbbVie: Consultancy;Karyopharm: Consultancy, Research Funding;Janssen: Consultancy;Protocol Intelligence: Consultancy;Takeda: Consultancy, Research Funding;GlaxoSmithKline: Consultancy;Regeneron: Consultancy;Secura Bio: Consultancy;Sanofi: Consultancy;AstraZeneca: Consultancy;Celgene/BMS: Consultancy, Research Funding;Oncopeptides: Consultancy, Research Funding;Jazz Pharmaceuticals: Consultancy, Research Funding.
Résumé
Introduction: Despite recent advances, MM remains incurable and new therapeutic options are needed, particularly for pts with RRMM. IBER is a novel, potent oral cereblon E3 ligase modulator (CELMoD ®) compound with enhanced tumoricidal and immune-stimulatory effects compared with immunomodulatory (IMiD ®) agents. Preclinically, IBER demonstrated marked synergy with DEX and with other standard myeloma treatments. CC-220-MM-001 (NCT02773030) is an ongoing phase 1/2 study evaluating IBER with different treatment combinations in independent cohorts of pts with RRMM;in phase 1, the recommended phase 2 dose of IBER, when given in combination with DEX, was determined at 1.6 mg (Lonial S, et al. Blood 2019;134[suppl 1]:3119). Here we report results from the dose expansion of IBER + DEX in pts with heavily pretreated, triple-class exposed (including ≥ 1 IMiD agent, ≥ 1 proteasome inhibitor [PI], and ≥ 1 anti-CD38 monoclonal antibody [mAb]) RRMM. Methods: Eligible pts had RRMM;had received ≥ 3 prior lines of therapy, including lenalidomide (LEN), pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb;had experienced disease progression within 60 days of last myeloma therapy;and were refractory to an IMiD agent, a PI, a glucocorticoid, and an anti-CD38 mAb. Pts with central nervous system involvement were not eligible. Pts who had received prior anti-BCMA therapy were excluded, but included in a supportive cohort for safety and preliminary efficacy assessment. IBER (1.6 mg) was given orally on days (D) 1-21, in combination with DEX (40 mg;20 mg if > 75 years of age) on D1, 8, 15, and 22 of each 28-day cycle. Thrombo-embolism prophylaxis was mandatory for all pts. Primary objective was to determine efficacy expressed as overall response rate (ORR). Secondary endpoints included additional efficacy and safety assessments. Exploratory endpoints included evaluation of health-related quality of life (HRQoL). Results: As of June 2, 2021, 107 pts had received IBER + DEX. Median age was 64 (44-83) years;median time since initial diagnosis was 6.9 (1.6-24.5) years. Extramedullary plasmacytomas were present in 25.2% of pts;29.9% of pts had high-risk cytogenetics. Median number of prior regimens was 6 (3-23). All pts were triple-class exposed;prior therapies included autologous stem cell transplantation (78.5%), PIs (100%), IMiD agents (LEN [100%] and POM [100%]), and anti-CD38 mAbs (100%);99.1% of pts were refractory to last myeloma regimen and 97.2% of pts were triple-class refractory. Median follow-up was 7.69 (0.5-17.5) months, with a median number of 4 (1-17) cycles received and 13 (12.1%) pts continuing treatment. Main reason for discontinuation was progressive disease (69.2%). ORR was 26.2%, with 1 (0.9%) stringent complete response, 8 (7.5%) very good partial responses, and 19 (17.8%) partial responses (Table);the clinical benefit rate (≥ minimal response) was 36.4% and disease control rate (≥ stable disease) was 79.4%. Median duration of response was 7.0 (4.5-11.3) months (Table), median progression-free survival was 3.0 (2.8-3.7) months, and median overall survival was 11.2 (9.0-not reached) months. Similar response rates were observed among a cohort of pts also exposed to BCMA therapies (N = 24, Table). Grade (Gr) 3-4 treatment-emergent adverse events (TEAEs) were reported in 88 (82.2%) pts. Most frequent (≥ 20% pts) hematologic Gr 3-4 TEAEs were neutropenia (44.9%;and 4.7% febrile neutropenia), anemia (28.0%), thrombocytopenia (21.5%), and leukopenia (20.6%). Gr 3-4 infections were reported in 27.1% of pts;Gr 3-4 pneumonia and COVID-19 occurred in 10.3% and 4.7% of pts, respectively. Occurrence of other Gr 3-4 non-hematologic TEAEs was generally low, including gastrointestinal disorders (5.6%), fatigue (2.8%), rash (1.9%). Fifty-six (52.3%) pts and 20 (18.7%) had IBER dose interruptions and reductions due to TEAEs, respectively. Five (4.7%) pts discontinued due to TEAEs. No pt discontinued IBER due to neutropenia. Overall, HRQoL was maintained in these pts. Conclusions: IBER + DEX demonst ated promising efficacy in pts with heavily pretreated, triple-class exposed and refractory RRMM, as well as in pts who had previously received anti-BCMA therapy;this combination was generally well tolerated and TEAEs were manageable with dose reductions and interruptions. These results support the further development of IBER in MM, including phase 3 trials in combination regimens. [Formula presented] Disclosures: Lonial: Abbvie: Consultancy, Honoraria;AMGEN: Consultancy, Honoraria;Takeda: Consultancy, Honoraria, Research Funding;GlaxoSmithKline: Consultancy, Honoraria, Research Funding;TG Therapeutics: Membership on an entity's Board of Directors or advisory committees;Merck: Honoraria;BMS/Celgene: Consultancy, Honoraria, Research Funding;Janssen: Consultancy, Honoraria, Research Funding. Popat: GlaxoSmithKline: Consultancy, Honoraria, Research Funding;Abbvie, Takeda, Janssen, and Celgene: Consultancy;Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES;AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria;Janssen and BMS: Other: travel expenses. Hulin: Sanofi: Honoraria;Celgene/BMS: Honoraria;Janssen: Honoraria;Takeda: Honoraria;abbvie: Honoraria. Jagannath: Legend Biotech: Consultancy;Bristol Myers Squibb: Consultancy;Karyopharm Therapeutics: Consultancy;Janssen Pharmaceuticals: Consultancy;Sanofi: Consultancy;Takeda: Consultancy. Oriol: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson: Karyopharm: Consultancy, Research Funding;Regeneron: Consultancy;AbbVie: Consultancy;Celgene/BMS: Consultancy, Research Funding;Oncopeptides: Consultancy, Research Funding;GlaxoSmithKline: Consultancy;Protocol Intelligence: Consultancy;Janssen: Consultancy;Secura Bio: Consultancy;Takeda: Consultancy, Research Funding;Sanofi: Consultancy;AstraZeneca: Consultancy;Jazz Pharmaceuticals: Consultancy, Research Funding. Weisel: Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Abbvie: Consultancy;Novartis: Honoraria;Pfizer: Honoraria. Minnema: Cilag: Consultancy;Janssen: Consultancy;Alnylam: Consultancy;Celgene: Other: Travel expenses;Kite/Gilead: Consultancy;BMS: Consultancy. Badros: J&J: Research Funding;Janssen: Research Funding;BMS: Research Funding;GlaxoSmithKline: Research Funding. Knop: BMS/Celgene: Consultancy, Honoraria, Research Funding;Amgen: Research Funding;Janssen: Consultancy;Oncopeptides: Consultancy;Pfizer: Consultancy;Sanofi: Consultanc . Stadtmauer: Janssen: Consultancy, Honoraria;Takeda: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Amgen: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Chen: Bristol Myers Squibb: Current Employment. Nguyen: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Amin: Bristol Myers Squibb: Current Employment. Kueenburg: Celgene a BMS company: Current Employment. Peluso: Celgene, a Bristol-Myers Squibb Company: Current Employment. van de Donk: BMS/Celgene: Consultancy, Honoraria;Janssen: Consultancy, Research Funding;Amgen: Consultancy, Research Funding;Cellectis: Research Funding;Takeda: Consultancy;Roche: Consultancy;Novartis /bayer/servier: Consultancy.
Résumé
Background: The clinical spectrum of COVID-19 ranges from pauci-symptomatic forms to severe disease characterized by respiratory failure requiring mechanical ventilation and intensive care unit (ICU) management, as well as multisystem involvement characterized by sepsis, organ dysfunction and death. Treatment of COVID-19 is not standardized, and respiratory failure from ARDS is the leading cause of mortality;in-hospital mortality at 28-days in our tertiary care center in Lombardia, northern Italy was 23% during the first wave in 2020(Ciceri et al. 2020). Endothelial damage and thrombo-inflammation have been identified as common to both COVID-19 pathophysiology and veno-occlusive disease (VOD/SOS). Defibrotide (DF) has endothelial-protective properties, with pro-fibrinolytic, anti-thrombotic, anti-ischemic, anti-inflammatory, and anti-adhesive activity, but no significant systemic anticoagulant effects and is approved for the treatment of severe VOD/SOS. Aim: A prospective, multicenter, phase II, single-arm, open label trial (DEFI-VID19, NCT04335201) was conducted in patients (pts) with COVID-19 ARDS to evaluate the efficacy of DF in addition to best available therapy per institutional guidelines. The primary endpoint was respiratory-failure rate (RFR) defined as progression of respiratory failure, i.e. severe gas transfer deficit (PaO2/FiO2<200 mmHg), need of ICU or death at day+14 from treatment start. Secondary endpoints included overall survival (OS) at 28 days, duration of hospitalization and safety. A sample size of 50 pts was calculated to detect an absolute reduction of 20% in RFR at day+14, assuming a failure rate in non-treated pts of 70% (alpha=5%, power=90%, two-sided test). Pts received DF intravenously at 6.25 mg/kg/dose by 2-hour infusion repeated every 6 hours. Expected treatment duration was 14 days, with earlier discontinuation if clinical improvement occurred. LMWH at prophylactic dose was allowed. Approval was provided by the National IRB for COVID-19 trials at Institute Spallanzani (Rome) and by the Italian Agency for Drug (AIFA). All patients provided written informed consent. Results: Overall, 52 pts were enrolled from September 2020 to April 2021;48 were evaluated for efficacy and safety;4 pts were excluded due to screen failure (n=2) or withdrawal of informed consent at day 2 after defibrotide was initiated (n=2). Median age was 60.5 years (range 53-71);35 pts (73%) were male and 65% had comorbidities, with high blood pressure, obesity and COPD most common. Two pts had pre-existing diagnoses of non-Hodgkin lymphoma. Median time from onset of COVID-19 symptoms and from Sars-COV2 PCR by nasal swab to enrollment were 8 (range 7-10) and 3 days (range 1-6), respectively. All pts were hospitalized and scale 5 of 8-category ordinal scale by WHO criteria, requiring noninvasive ventilation with CPAP or high-flow oxygen, with a median P/F ratio of 211 (range 134-275) mmHg. At treatment start, the median and (range) lymphocyte counts, LDH, CRP, ferritin, D-dimer and IL-6 were 0.7 (0.5-0.9) x 10e9/L;404 (291-491) U/L;49 (22-97) mg/L;823 (363-1088) ng/ml;0.44 (0.28-1.29) µg/mL and 20 (11-32), respectively. Median treatment duration was 8.5 days (range 6-11). Overall, 13/48 pts (27%) discontinued the treatment due to clinical worsening and/or need of further therapies: 9 pts experienced progressive respiratory failure and 6 of those were transferred to ICU for IOT (one pt required ECMO), and 4 required full anticoagulation due to pulmonary embolism (n=1), ischemic stroke (n=1), and femoral deep venous thrombosis (n=2). All pts who completed the treatment 35/48 (73%) were discharged with no need of oxygen support. Overall, 14 SAEs have been reported in a median time of 6 days (range 2-10): all unrelated to DF. No pts experienced hemorrhagic events. The incidence of RFR at day 14 was 25 (+/- 6)%, and at day 28, 27 (+/- 6) %. Probability of OS at day 28 was 89 (+/-4) %, at day 60 83 (+/- 5)%. Overall, 8 pts died from COVID-19 -related complications. No pts required re-admission after hospital discha ge (median 14 days) or died after discharge. Conclusion: Treatment with DF in pts with grade 5 WHO COVID 19 ARDS does not induce bleeding, and is associated with rapid restoration of respiratory function (73% of pts). Notably, no oxygen support was needed at discharge and a 1-month OS rate of 89% was observed, which is higher than historical controls (77%) treated in the same setting. Disclosures: Richardson: Takeda: Consultancy, Research Funding;AbbVie: Consultancy;Karyopharm: Consultancy, Research Funding;AstraZeneca: Consultancy;Oncopeptides: Consultancy, Research Funding;Jazz Pharmaceuticals: Consultancy, Research Funding;Protocol Intelligence: Consultancy;Secura Bio: Consultancy;Regeneron: Consultancy;Celgene/BMS: Consultancy, Research Funding;GlaxoSmithKline: Consultancy;Janssen: Consultancy;Sanofi: Consultancy. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Carlo-Stella: Incyte: Honoraria;Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Sanofi: Consultancy, Research Funding;AstraZeneca: Honoraria;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;Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen Oncology: Honoraria;Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees.
Résumé
Background: SARS-CoV-2 related acute respiratory distress syndrome (ARDS) is associated with endothelial dysfunction and profound dysregulation of the thrombotic/fibrinolytic pathway, with thrombotic complications common in affected patients (pts). Fibrin deposition may be a key feature of the pathobiology, with markedly elevated levels of PAI-1 reported. Defibrotide (DF), a polyanionic naturally-derived polydeoxyribonucelotide with endothelial stabilizing activity, has fibrinolytic, antithrombotic and anti-inflammatory properties, with known activity in reducing PAI-1 levels and inhibiting heparanase. We now report a prospective, open label, safety and tolerability trial of defibrotide for the management of patients with advanced SARS-CoV-2 related ARDS. Patients and Methods: Eligible patients (pts) were ≥18 years in age, with clinical and radiographic signs of ARDS, no signs of active bleeding, a serum D-Dimer > 2X ULN, and a positive PCR-based assay for SARS-CoV-2. Concomitant use of systemic anticoagulants or fibrinolytics was initially precluded, with the study amended to allow prophylactic doses of systemic heparin in its latter stages. Defibrotide (6.25 mg/kg/dose IV q. 6 hours) was administered for a planned 7-day course, with day 1 defined as the first day of study therapy. Therapy was able to be discontinued prior to day 7 in pts who met the pulmonary response parameter at that earlier timepoint. Patients with a partial response to therapy (> 20% reduction in FiO2) by day 7 were allowed to receive an additional 7 days of therapy (14 days total). Response was defined as complete cessation of supplemental O2 support, or ≥ 2 point reduction in WHO ordinal score for 48 consecutive hours by day 7. Patients were recruited from a single center between October 2020 and March 2021. Results: Twelve pts (median 63 years, range 35-73 years) were treated, with 10 of 12 pts on mechanical ventilation (median FiO2 55%, PEEP 18 mmHg), and six on vasopressor support at the time of study entry. Baseline PaO2/FiO2 ratios ranged from 82 - 200 mmHg. The median D-Dimer was 3.25 mcg/ml (range 1.33-12.3 mcg/ml), and fibrinogen 637 mg/dl (range 250-1208 mg/dl) at study entry. Dexamethasone and remdesivir had been administered prior to DF in all pts, with no other SARS-CoV-2 targeted treatment given during DF therapy. Eleven pts received ≤7 days of therapy, with one pt receiving 14 days. The first 9 pts received DF without other concomitant anticoagulants, with the last 3 pts concurrently receiving prophylactic heparin plus DF. No hemorrhagic or bleeding complications occurred during DF therapy, including the 3 pts receiving concurrent heparin prophylaxis. Likewise, no thrombotic complications developed during study therapy, including the 9 patients in which DF was their sole anti-coagulant. All 12 patients were evaluable for response. Four pts met the day 7 pulmonary response parameter, with 2 pts having a complete cessation of O2 support within this period. Three pts died from progressive pulmonary disease, at 11, 17 and 34 days from study entry. The 3 pts (who died) had the lowest baseline PaO2/FiO2 ratios (82-115 mmHg) of all study subjects. Nine pts (75%) remain alive, 64 to 174 days from study entry, all 9 discharged from their primary hospitalization. Day 30 all-cause mortality was 17% (95%CI: 0-35%). Serial coagulation and fibrinolytic assays were available in 7 patients. Total PAI-1 levels decreased from a median 167 ng/ml (range 105-264 ng/ml) to a median 104 ng/ml (range 55-166 ng/ml) by day 4 of therapy, with all 7 subjects showing a decline in PAI-1 levels at that time point. Total tPA levels increased from a median 3.02 ng/ml (range 0.72 - 36.1 ng/ml) at baseline to 4.5 ng/ml (range 1.1-8.2 ng/ml) by day 4 in study subjects. Allowing for the small sample size, baseline PAI-1, tPA or D-Dimer levels did not impact response. One of two patients with a baseline D-Dimer > 10 mcg/ml responded, while both patients with a baseline D-Dimer <2.0 mcg/ml failed to meet the response parameter. Conclusion: The use of DF for t e management of SARS-CoV-2-related ARDS proved safe and tolerable in a prospective, open label trial. No hemorrhagic or thrombotic complications were reported during therapy. Outcomes were promising, including an overall survival of 75% in a patient population with a historically high mortality rate. (The study was supported by a research grant from Jazz Pharmaceuticals) Disclosures: Yanik: Jazz Pharmaceutical: Research Funding. Pipe: Sangamo Therapeutics: Other: Scientific Advisory Board;ASC Therapeutics: Other: Scientific Advisory Board;Apcintex: Consultancy;Bayer: Consultancy;Biomarin: Consultancy;Catalyst Biosciences: Consultancy;CSL Behring: Consultancy;Freeline: Consultancy;Grifols: Consultancy;HEMA Biologics: Consultancy;Novo Nordisk: Consultancy;Octapharma: Consultancy;Pfizer: Consultancy;Roche: Consultancy;Sanofi: Consultancy;Takeda: Consultancy;Spark Therapeutics: Consultancy;uniQure: Consultancy. Sisson: Translatebio: Other: Data Safety Committee member. Richardson: Celgene/BMS: Consultancy, Research Funding;Karyopharm: Consultancy, Research Funding;Oncopeptides: Consultancy, Research Funding;Janssen: Consultancy;Secura Bio: Consultancy;AstraZeneca: Consultancy;Takeda: Consultancy, Research Funding;Regeneron: Consultancy;AbbVie: Consultancy;Protocol Intelligence: Consultancy;GlaxoSmithKline: Consultancy;Sanofi: Consultancy;Jazz Pharmaceuticals: Consultancy, Research Funding. Lawrence: MDI Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Defibrotide: Off label use for ARDS