ABSTRACT
The International Initiative on Thrombosis and Cancer is an independent academic working group of experts aimed at establishing global consensus for the treatment and prophylaxis of cancer-associated thrombosis. The 2013, 2016, and 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines have been made available through a free, web-based mobile phone application. The 2022 clinical practice guidelines, which are based on a literature review up to Jan 1, 2022, include guidance for patients with cancer and with COVID-19. Key recommendations (grade 1A or 1B) include: (1) low-molecular-weight heparins (LMWHs) for the initial (first 10 days) treatment and maintenance treatment of cancer-associated thrombosis;(2) direct oral anticoagulants for the initial treatment and maintenance treatment of cancer-associated thrombosis in patients who are not at high risk of gastrointestinal or genitourinary bleeding, in the absence of strong drug-drug interactions or of gastrointestinal absorption impairment;(3) LMWHs or direct oral anticoagulants for a minimum of 6 months to treat cancer-associated thrombosis;(4) extended prophylaxis (4 weeks) with LMWHs to prevent postoperative venous thromboembolism after major abdominopelvic surgery in patients not at high risk of bleeding;and (5) primary prophylaxis of venous thromboembolism with LMWHs or direct oral anticoagulants (rivaroxaban or apixaban) in ambulatory patients with locally advanced or metastatic pancreatic cancer who are treated with anticancer therapy and have a low risk of bleeding.
ABSTRACT
Introduction: Acid sphingomyelinase deficiency (ASMD), also historically known as Niemann-Pick disease A (OMIM #257200) and B (OMIM#607616), is a rare and debilitating lysosomal storage disease caused by pathogenic variants in SMPD1 gene. Deficient activity of the lysosomal enzyme acid sphingomyelinase (ASM) leads to sphingomyelin accumulation in various organs. Visceral manifestations of ASMD include interstitial lung disease and pulmonary dysfunction, splenomegaly, hepatomegaly, dyslipidemia, thrombocytopenia, and anemia and are present across ASMD phenotypes (ASMD type A, B and A/B). In more severe cases of ASMD (ASMD type A), there are also central nervous system manifestations. No disease-specific treatment is currently approved for patients with ASMD. Olipudase alfa, an intravenous-recombinant-human ASM, is in late-stage development (Sanofi Genzyme) for the non-central-nervous-system manifestations of ASMD in children and adults. Two open-label trials, a phase 1b trial in 5 adults (NCT01722526) and a phase 1/2 trial in 20 children with chronic ASMD (ASCEND-Peds, NCT02292654) demonstrated improvement of pulmonary function, reduction of liver and spleen volume, reversal of dyslipidemia, decreased disease biomarkers, and in children, improved growth. A phase 2/3 placebo-controlled trial, the ASCEND study (NCT02004691) in 36 adults with ASMD who had splenomegaly and pulmonary dysfunction, has completed its primary analysis. Olipudase-alfa-treated patients compared to placebo-treated patients (1:1 randomization) had statistically significant increases in percent-predicted diffusing capacity of carbon monoxide (DLCO) and statistically significant decreases in spleen and liver volume after 1 year of placebo or olipudase alfa. Thirty-five of 36 patients continued in an open-label trial extension including 17 of the 18 patients who initially received placebo in the first year and all 18 patients who received olipudase alfa. Here we report Year 2 results of the ASCEND trial for the former placebo group after 1 year of olipudase alfa treatment and for the initial olipudase alfa group after 2 years of olipudase alfa treatment. Methods: All patients underwent gradual dose-escalation to 3.0 mg/kg every 2 weeks for approximately 14 weeks when starting olipudase alfa. Efficacy outcomes include percent-predicted DLCO, spleen volume, liver volume, lung high-resolution computerized tomography (HRCT) scores for ground glass appearance, histopathologic clearance of sphingomyelin in the liver, platelet count, plasma lyso-sphingomyelin, liver function, and lipid profile. Change from baseline results are presented as least-square mean (analysis of covariance [ANCOVA]) percent change ± standard error of the mean (SEM), except for ground glass appearance, which is the least-square mean ANCOVA absolute change from baseline, and percent liver tissue area occupied by sphingomyelin and plasma lyso-sphingomyelin, which are presented as mean changes ± standard deviation (SD). Absolute values at Baseline, Year 1, and Year 2 are presented as mean ± SD (Table). Results: Overall, 33 of 35 patients completed Year 2 of ASCEND;one former placebo patient withdrew due to COVID-19 travel restrictions, and one continuing olipudase alfa patient withdrew consent. COVID-19 travel restrictions also resulted in at least one missed assessment in six patients. In Year 2, improvements for patients in the former placebo group paralleled the olipudase alfa group in the primary analysis while clinical improvement continued for patients who received 2 years of olipudase alfa (Table). For patients in the former placebo group, percent-predicted DLCO increased by 28.0 ±6.2% (n=10);spleen volume decreased by 36.0 ±3.0% (n=11);liver volume decreased by 30.7 ±2.5% (n=11), and platelet count increased by 21.7 ±6.4% (n=15). In patients with 2 years of olipudase alfa treatment, percent-predicted DLCO increased by 22.2 ±3.4% (n=17) at Year 1 and 28.5±6.2% at Year 2 (n=10);spleen volume decreased by 39.5 ±2.4% (n=17) at Year 1 and 47.0 ±2.7% (n=14) at Year 2 liver volume decreased by 27.8 ±2.5% (n=17) at Year 1 and 33.4 ±2.2% (n=14) at Year 2, and platelet count increased by 16.6 ±4.0% at Year 1 (n=18) and 24.9 ±6.9% (n=13) at Year 2. HRCT ground glass appearance score decreased 0.30 ±0.5 (n=14) at Year 2 for patients in the former placebo group and decreased by 0.45 ±0.13 (n=18) at Year 1 and 0.48 ±0.07 (n=16) at Year 2 for patients continuing to receive olipudase alfa. Liver sphingomyelin clearance at Year 2 was 93.3 ±5.0% (n=10) for patients in the former placebo group and 92.7 ±5.8% at Year 1 (n=13) and 98.4 ±2.0% at Year 2 (n=10) for patients continuing to receive olipudase alfa. Plasma lyso-sphingomyelin decreased by 79.4 ±11.3% (n=14) for patients in the former placebo group and by 78.0 ±11.1% (n=18) at Year 1 and 64.4 ±28.5% (n=15) at Year 2 for patients continuing to receive olipudase alfa;several patients had transient increases due to missed infusions. Alanine aminotransferase decreased by 45.2 ±34.4% (n=15) for patients in the former placebo group, and by 36.5 ±8.4% (n=18) in Year 1 and 32.0 ±10.2% (n=12) in Year 2 for patients continuing to receive olipudase alfa. For patients in the former placebo group, high-density lipoprotein cholesterol (HDL-C) increased by 59.7 ±9.7% (n=14) and low-density lipoprotein cholesterol (LDL-C) decreased by 27.5 ±6.8% (n=13) in Year 2. For patients continuing to receive olipudase alfa, HDL-C increased by 40.0 ±6.8% (n=18) in Year 1 and 64.4 ±10.5% (n=12) in Year 2 and LDL-C decreased by 25.8 ±4.8% (n=18) in Year 1 and 23.0 ±7.1% (n=12) in Year 2. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles in patient with previously documented cardiomyopathy). No patient discontinued due to an adverse event. Conclusion: During Year 2 of ASCEND, patients crossing over from placebo to olipudase alfa had the same magnitude and time course of clinical improvement seen in patients receiving olipudase alfa for 1 year, while continuing olipudase-alfa patients had sustained or further improvements. Olipudase alfa reduced sphingomyelin storage in the liver and lyso-sphingomyelin in plasma. Clinically, olipudase alfa improved pulmonary function, reduced splenomegaly and hepatomegaly, and improved liver function and dyslipidemia for up to 2 years. These results are consistent with the published 30- and 42-month data for adults reported in the long-term extension of the open-label Phase 1b study. Treatment with olipudase alfa reduces manifestations of chronic ASMD in adults and has sustained efficacy. [Formula presented]
ABSTRACT
Acid sphingomyelinase deficiency (ASMD) is a rare debilitating lysosomal disease characterized by pulmonary dysfunction, hepatosplenomegaly, and dyslipidemia. Olipudase alfa, intravenous-recombinant-human ASM, is in late-stage development (Sanofi Genzyme) for non-central-nervous-system manifestations of ASMD. We report 2-year outcomes for 33/36 ASMD adults with splenomegaly (mean baseline spleen volume: 11.3 multiples of normal [MN]) and respiratory impairment (mean baseline percent-predicted-diffusing capacity for carbon monoxide [DLCO]: 49.3%) who participated in the 1-year double-blind placebo-controlled primary-analysis period [PAP] of the ASCEND trial of olipudase alfa (NCT02004691) and completed a second year in the open-label extension. Patients underwent gradual dose-escalation to 3.0 mg/kg/2-weeks. During the PAP, olipudase-alfa-treated compared to placebo-treated patients (1:1 randomization) had statistically significant increases in DLCO and decreases in spleen and liver volume. One placebo patient withdrew during year-1. In year-2, improvements in former placebo patients paralleled the olipudase-alfa group in the PAP (all values: ANCOVA LS-mean percent change from trial baseline ± SEM): DLCO increased 28.0 ± 6.2% (n = 10);spleen volume decreased 36.0 ± 3.0% (n = 11);liver volume decreased 30.7 ± 2.5% (n = 11). Olipudase-alfa patients who received 2 years of treatment continued improving: DLCO increased 28.5 ± 6.2%, n = 10 (year-1 increase: 22.2 ± 3.4%, n = 17);spleen volume decreased 47.0 ± 2.7%, n = 14 (year-1 decrease: 39.5 ± 2.4%, n = 17), liver volume decreased 33.4 ± 2.2%, n = 14 (year-1 decrease: 27.8 ± 2.5, n = 17). Improvements in dyslipidemia, liver function, liver sphingomyelin clearance, and plasma lyso-sphingomyelin in former placebo patients paralleled those seen in olipudase-alfa patients in the PAP;continuing olipudase-alfa patients maintained these benefits in year-2. Overall, 99% of treatment-emergent adverse events were mild/moderate, with one treatment-related serious adverse event. During year-2, six patients missed ≥1 assessments and one patient discontinued due to COVID-19 travel restrictions;one additional patient discontinued (withdrawal of consent). In summary, during year-2 of ASCEND, crossover-placebo patients improved to a similar extent as olipudase-alfa patients in year-1 and patients continuing on olipudase alfa showed sustained or further improvements.