Elevated Creatine Phosphokinase Research Articles

Haff Disease in Salvador, Brazil, 2016-2021: Attack rate and detection of toxin in fish samples collected during outbreaks and disease surveillance

From late 2016 to early 2021, cases of Haff disease, a rare cause of rhabdomyolysis, possibly due to poisoning by palytoxin-like compounds in seafood, were detected in Salvador, Brazil. Surveillance was established to detect additional cases aiming at describing the clinical characteristics of the cases, identifying associated factors, estimating disease attack rate, and investigating the presence of biotoxins and trace metals in selected fish specimens obtained from cases. Between December/2016-January/2021, surveillance investigated Haff disease suspected cases, and obtained clinical and fish samples to test. Of 65 cases investigated during the 2016-2017 outbreak, 43 (66%) had high creatine phosphokinase (CPK) levels. Among those with laboratory-confirmed rhabdomyolysis, 38 (88%) were hospitalized, 11 (26%) required intensive care, and three (7%) dialysis. Ingestion of marine fish 24h before disease onset was reported by 74% of the cases with elevated CPK and by 41% of those without CPK measurement (P=0·02). Attack rate for individuals who ate fish related to the outbreak was 55%. Following this outbreak, surveillance identified 12 suspected cases between 2017-2019, and a second outbreak in 2020-2021, with 16 laboratory-confirmed rhabdomyolysis patients (five required intensive care; one died). No traces of ciguatoxins and metals were detected in fish specimens obtained in 2016, found to be Seriola rivoliana. Some fish samples from 2020 were screened for palytoxin (PlTX)-like compounds and contained detectable levels of molecule fragments characteristics of isobaric PlTX, ovatoxin-a (OVTX-a), OVTX-b and OVTX-d. These findings support the hypothesis that compounds related to PlTX accumulated in marine fish may be the toxic agent causing the disease. Haff disease is a life-threatening condition, requiring clinical suspicion for patients with sudden-onset myalgia following fish ingestion. Suspected cases should be reported to health authorities for investigation.

Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAFV600 mutant melanoma: safety and tolerability results from the phase I IMMU-TARGET trial

BackgroundCombination of immune checkpoint inhibitors and mitogen-activated protein kinase (MAPK) pathway inhibitors (MAPKi) has been proposed to enhance the durability of anti-tumour responses induced by MAPKi. Here, we present phase I safety results from an open-label, phase I/II study of pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) triplet therapy in advanced, B-Raf proto-oncogene serine/threonine kinase (BRAF)V600–mutated melanoma (IMMU-TARGET, NCT02902042). MethodsThe dose finding phase I part used a 3 + 3 design, starting with the approved doses of PEM (200 mg every three weeks), ENC (450 mg once daily [QD]) and BIN (45 mg twice daily [BID]) as dose level (DL) 0. Reduction of the ENC and BIN doses (300 mg QD and 30 mg BID at DL-1 and 200 mg QD and 30 mg BID at DL-2) was preplanned in case of ≥2 dose-limiting toxicities (DLTs). Primary objectives were to estimate the recommended phase II dose of the triplet combination, DLT and safety. As per the sponsor's decision, the study was terminated after the phase I part, as the clinical efficacy of the combination is currently being investigated in a pivotal, placebo-controlled (PEM mono), double-blinded phase III trial (STARBOARD,NCT04657991). ResultsFifteen patients were enrolled. DLTs of DL0 were creatine phosphokinase (CPK) elevation plus cytokine release syndrome (n = 1) and gamma glutamyl transferase (GGT) increase (n = 1). No DLT was observed in further 3 + 3 patients at DL-1. One (isolated GGT elevations) DLT of DL0 was questionable, as the patient had further episodes of isolated GGT elevations after treatment discontinuation. Hence, further 6 patients were enrolled at DL0: here, no DLT occurred. In total, 13 of 15 patients (87%) experienced a treatment-related adverse event (TRAE) and 8 patients (53%), a grade ≥III TRAE; there were no TRAE-related deaths. Increases in aspartate aminotransferases, GGT (6/15 patients) and CPK elevations (4/15) were the most common grade III–IV TRAE. In median, patients received triplet therapy for 24 weeks (interquartile range [IQR], 12–45). Of the 14 patients evaluable for efficacy, the overall response rate was 64% (95% confidence interval [CI], 35–87). At a median follow-up of 25 months (IQR, 9–28), progression-free survival at 12 months was 41% (95% CI, 13–68). ConclusionsTriplet therapy with PEM, ENC and BIN as used in the study was feasible and safe and led to clinically meaningful disease control.

A safety and clinical efficacy analysis of PCSK9 monoclonal antibodies in patients with markedly elevated creatine phosphokinase levels

Abstract Introduction PCSK9 inhibitors have been used in statin intolerant patients to reduce low-density lipoprotein cholesterol (LDL-C) safely and effectively. However, evidence is lacking regarding the safety and clinical utility of PCSK9 inhibition in patients with markedly elevated creatine phosphokinase (CPK) levels. Methods We searched a large HMO database for patients with CPK levels above 1000 U/L, who were initiating PCSK9 inhibition therapy (Jan 2016–Dec 2019). The patients' treatment plans, adherence, CPK and LDL-C levels were analyzed. Results Of the1600 patients initiating PCSK9 inhibitors, 26 met study criteria, and all were previously treated by statins (in 18 patients ≥3 different statin types were prescribed). Myalgia was evident in most patients (n=24), and 5 were clinically diagnosed with rhabdomyolysis. Abnormal liver function tests were noted in 8 of the 26 patients. Most were very-high cardiovascular risk patients, with concurrent atherosclerotic cardiovascular disease (n=17) and baseline LDL-C levels >190 mg/dL (n=19). Peak CPK levels ranged from 1050–53540 U/L [median (IQR), 3687 (1876–8344)]. Concomitant secondary factors for CPK elevation included renal failure (n=5), inflammatory rheumatoid disorders (n=3), severe hypothyroidism (n=3), intensive exercise (n=2), nephrotic range proteinuria (n=1) and genetic muscular disease (n=1). The monoclonal antibodies, Alirocumab and Evolocumab, were initiated in 12 and 14 patients respectively. In 24 patients (92%) CPK reduction of >50% was noted and in 12 patients (46%) CPK levels returned to normal range (Figure). Under PCSK9 inhibition, 17 patients (65%) achieved LDL-C levels <70 mg/dL and in 12 patients (46%) LDL-C was <55 mg/dL. Only 2 patients discontinued PCSK9 inhibitors. Conclusions High-risk patients with markedly elevated CPK levels, can safely reduce LDL-C levels with PCSK9 inhibitors, and although statin intolerance is a major cause of elevated CPK, other predisposing and precipitating factors are common. Funding Acknowledgement Type of funding sources: None.

Peroxisome Proliferator-Activated Receptor Delta Agonist (PPAR- δ) and Selective Androgen Receptor Modulator (SARM) Abuse: Clinical, Analytical and Biological Data in a Case Involving a Poisonous Combination of GW1516 (Cardarine) and MK2866 (Ostarine)

A 43-year-old male, sport coach, presented him-self at the Emergency unit of a local hospital for epigastric pain, myalgia pain and severe headache. He claimed having used for some days a combination of GW1516 (cardarine), a peroxisome proliferator-activated receptor delta agonist (PPAR- δ) and MK2866 (ostarine), a selective androgen receptor modulator (SARM) to gain skeletal muscles. Cytolysis with marked increase of alanine aminotransferase or ALT (up to 922 UI/L) and aspartate aminotransferase or AST (up to 2558 UI/L) and massive rhabdomyolysis with elevated creatine phosphokinase or CPK (up to 86435 UI/L) were the main unusual biochemistry parameters. Using a specific liquid chromatography coupled to tandem mass spectrometry method, cardarine and ostarine tested positive in blood at 403 and 1 ng/mL, respectively. In urine, due to extensive metabolism, the parent GW1516 was not identified, while ostarine was at 88 ng/mL. Finally, both drugs were identified in hair (2 cm in length, brown in colour), at 146 and 1105 pg/mg for cardarine and ostarine, respectively. This clearly demonstrates repetitive abuse over the last 2 months. Asthenia was persistent for 2 weeks and 6 weeks after the admission, the subject fully recovered.

Statin associated adverse reactions in Latin America: a scoping review

ObjectivesWe aim to describe the frequency and type of adverse drug reactions (ADRs) in patients on statins in published studies from Latin American (LATAM) countries.DesignScoping review.MethodsA literature search was conducted...

Аutosomal recessive limb-girdle muscular dystrophy type 2A: two cases in Ukraine with different age of onset

The paper reports on two cases of young women from Ukraine with autosomal recessive limb-girdle muscular dystrophy type 2A with different age of symptoms onset and an absence of any family history presented with gradual onset of proximal muscle weakness in four limbs and thinning of shoulders, arms and thighs. Both patients had elevated creatine phosphokinase level and c.550delA mutations in CAPN3 gene. Sequence analysis and deletion/duplication testing of the 159 genes from skeletal muscles disease testing panel of 5-year-old girl identified deletion of exon 8 (heterozygous) and c.550delA (p.Thr184Argfs*36) mutation (heterozygous), were in CAPN3 gene. Magnetic Resonance Imaging of soft tissue of the proximal lower extremities was performed which showed signs of symmetrical atrophic changes in the major adductor muscle, the long and short adductor muscles, the semitendinosus muscle of the thigh, as a manifestations of autosomal recessive limb-girdle muscular dystrophy type 2A. Homozygous, pathogenic variant of the defect in the CAPN3 gene c.550del (p.Thr184Argfs * 36) was identified in a 25-year-old woman. Type 2A is the most common form of limb-girdle muscular dystrophy, accounting for about 30% of cases. The autosomal recessive limb-girdle muscular dystrophy type 2A is on caused by mutations in the CAPN3 gene, and it is characterized by selective atrophy and weakness of proximal limb and girdle muscles. The age of onset of muscle weakness is extremely variable; the most common being between 8 and 15 years, although it can range between 2 and 50 years. The diagnosis can be suspected by findings on a muscle biopsy or when a doctor experienced in muscular dystrophy examines you. A serum creatine kinase blood test may also show raised levels which indicate a problem in the muscles. The diagnosis has to be confirmed by means of identifying a mutation in the CAPN3 gene which is done on a deoxyribonucleic acid sample from a blood test. To date there are no specific treatments for limb-girdle muscular dystrophy, however careful management of the symptoms of the condition can improve a person’s quality of life. Joint contractures (tightening) can occur in limb-girdle muscular dystrophy and therefore regular physiotherapy is recommended.

Factors affecting creatine phosphokinase elevation during daptomycin therapy using a combination of machine learning and conventional methods

Musculoskeletal toxicity is a typical side effect of daptomycin (DAP). However, the risk factors have not been well established. Here, we aimed to identify independent factors affecting DAP-induced musculoskeletal toxicity using a combination of machine learning and conventional statistical methods. A population-based, retrospective, observational cohort study was conducted using the Japanese electronic medical record database. Patients who received DAP between October 2011 and December 2020 were enrolled. Two definitions of musculoskeletal toxicity were employed: (1) elevation of creatine phosphokinase (CPK) value more than twice from baseline and >200 IU/L, and (2) >1000 IU/L. First, multiple logistic regression analyses (a conventional statistical method) were performed to identify independent factors affecting CPK elevation. Then, decision tree analyses, a machine learning method, were performed to detect combinations of factors that change CPK elevation risk. Of the 2970 patients who received DAP, 706 were included. Elevation of CPK values >200 IU/L and >1000 IU/L occurred in 83 (11.8%) and 17 (2.41%) patients, respectively. In multiple logistic regression analysis, baseline CPK value and concomitant use of hydrophobic statins were commonly extracted as independent factors affecting each CPK elevation, but concomitant use of hydrophilic statins was not. In decision tree analysis, patients who received hydrophobic statins and had high baseline CPK values were classified into the high-risk group. Our novel approach revealed new risk factors for CPK elevation. Our findings suggest that high-risk patients require frequent CPK monitoring.

Absence of significant clinical benefit for a systematic routine creatine phosphokinase measurement in asymptomatic patients treated with anti-programmed death protein (ligand) 1 immune checkpoint inhibitor to screen cardiac or neuromuscular immune-related toxicities

AimDespite unprecedented results of anti-programmed death protein (ligand) 1 (PD-(L)1) immune checkpoint inhibitor in the oncology's armamentarium, immune-related adverse events (irAEs) represent a therapeutic hurdle. Currently, there is no consensual recommendation on a routinely monitored biomarker to early detect irAE. Biological markers such as serum creatine phosphokinase (CPK) are commonly used to measure muscular tissue injury. The potential of routine serum CPK monitoring to predict cardiac or neuromuscular irAE in patients treated with immunotherapy remains unknown. MethodsIn this retrospective study between January 2016 and December 2018 at Gustave Roussy Cancer Campus, 1151 cancer patients treated with anti-PD–(L)1 immunotherapy were systematically monitored with serum CPK measurements before each immunotherapy cycle. We considered significant CPK increases according to Common Terminology Criteria for Adverse Events v5.0 (CTCAEV5) of grade ≥2 severity. Comparisons were performed in patients with immune-related CPK (ir-CPK) elevations symptomatic versus asymptomatic. ResultsOverall, 53 of 1151 (4.6%) patients showed a CPK increase. Elevations of CPK were deemed to be immunotherapy-related in 31 of 1151 (2.7%) patients. Among them, 12 of 31 (38.7%) patients experienced symptomatic cardiac or neuromuscular irAE, whereas the other 19 of 31 (61.3%) patients remained asymptomatic. In patients with symptomatic irAE, the mean ir-CPK level was higher compared with asymptomatic patients (1271 versus 771 UI/L, P value = 0.02). In the asymptomatic group, all patients experienced a spontaneous resolution of the ir-CPK increase, and none required medical intervention. ConclusionMost patients with immune-related CPK increase remained asymptomatic. The CPK serum increase did not alter the clinical management of asymptomatic patients. The results of this study did not support a significant clinical interest for a systematic routine CPK monitoring in patients amenable to anti-PD-(L)1 immunotherapy.

A novel mutation in ACADVL causing very long-chain acyl-coenzyme-A dehydrogenase deficiency in a South Asian pediatric patient: a case report and review of the literature

BackgroundVery long-chain acyl-coenzyme-A dehydrogenase deficiency is a rare, severe life-threatening metabolic disorder of mitochondrial fatty acid oxidation, caused by mutations in ACADVL gene. Here we present a genetically confirmed case of a South Asian baby girl with severe, early-onset form of very long-chain acyl-coenzyme-A dehydrogenase deficiency due to a novel mutation in ACADVL gene.Case presentationIndex case was the second baby girl of second-degree consanguineous South Asian parents. She had an uncomplicated antenatal period and was born by spontaneous vaginal delivery at term with a birth weight of 2910 g. She had been noted to have fair skin complexion, hypotonia, and 3 cm firm hepatomegaly. Since birth, the baby developed grunting, poor feeding, and recurrent episodes of symptomatic hypoglycemia and convulsions with multiple semiology. Her septic screening and urine ketone bodies were negative. The baby had high anion gap metabolic acidosis and elevated transaminases and serum creatine phosphokinase levels. Echocardiogram at 4 months revealed bilateral ventricular hypertrophy. Acylcarnitine profile revealed elevated concentrations of tetradecanoylcarnitine (C14), tetradecanoylcarnitine C14:1, and C14:1/C16. Unfortunately, the baby died due to intercurrent respiratory illness at 4 months of age. Sequence analysis of ACADVL gene in perimortem blood sample revealed homozygous frame shift novel variant NM_001270447.1, c.711_712del p.(Phe237Leufs*38), which confirmed the diagnosis of very long-chain acyl-coenzyme-A dehydrogenase deficiency.ConclusionsThis case demonstrates the importance of early diagnosis and management of very long-chain acyl-coenzyme-A dehydrogenase deficiency in improving the outcome of the patients. Implementation of newborn screening using tandem mass spectrometry in Sri Lanka will be beneficial to reduce the morbidity and mortality of treatable disorders of inborn errors.

Identifying Content Themes in Primary Care Physician and Rheumatologist Communications Within Electronic Consultations: A Qualitative Study.

ObjectiveElectronic consultation (eConsult) communications between primary care physicians (PCPs) and rheumatologists may reveal common knowledge gaps and educational opportunities. The aim of our study was to identify content themes in PCP questions and rheumatology recommendations through analysis of eConsult and the need for rheumatology appointments and facilitated urgent visits post‐eConsult.MethodsA descriptive cross‐sectional study involving qualitative and quantitative analysis of rheumatology eConsults in a single center was performed from May 1, 2019, to January 9, 2020. Conventional content analysis was used to derive content themes in PCP questions and rheumatology recommendations. We evaluated the proportion of eConsults, which included a need for rheumatology appointments and expedited visits through frequency counts.ResultsAmong 120 rheumatology eConsults, six PCP questions and five rheumatology recommendation content themes were identified. The most common PCP question themes were the following: 1) joint pain, 2) suspected rheumatic disease differential, and 3) abnormal laboratory tests. The most common rheumatology recommendation or teaching themes were the following: 1) education on differential diagnoses of rheumatic diseases, 2) education on the specific rheumatic disease, and 3) laboratory test interpretation. The majority of eConsults (82%) recommended a subsequent rheumatology appointment, and 27% facilitated an expedited appointment.ConclusionIn this analysis of eConsults, we identified common knowledge gaps in PCPs and rheumatology educational topics, including differentiating inflammatory from noninflammatory arthritis, using caution in interpreting abnormal laboratory tests without clinical manifestations, managing chronic gout, evaluating elevated creatine phosphokinase levels, and differentiating C‐reactive protein (CRP) from high‐sensitivity CRP. Timely feedback through eConsult recommendations may allow for focused educational opportunities.

Brachio-cervical inflammatory myopathy associated with systemic sclerosis. Case series and review of literature.

This study was aimed at describing a case series of brachio-cervical inflammatory myopathy (BCIM) associated with systemic sclerosis (SSc), due to its rarity and limited coverage in published data. Another aim was to provide a literature review. We reported four cases of BCIM-SSc from our tertiary center. In addition, we researched the literature and found six articles featuring 17 patients who fit this phenotype. We pooled all cases and reported their features. Most patients were female and had limited SSc, and the median time of BCIM presentation was three years after SSc diagnosis. Asymmetric muscle involvement, scapular winging, dropped head, axial weakness, camptocormia, dysphagia, and dermatomyositis stigmas were common features. All patients had esophageal involvement. Most had positive antinuclear antibody results, a scleroderma pattern in their capillaroscopy images, elevated serum creatine phosphokinase, myopathic electrophysiology, and muscle involvement in magnetic resonance imaging. Muscle histopathological findings varied widely, but in general all showed the presence of lymphoid infiltrates, muscle atrophy, increased MHC-I expression, MAC deposits, vasculopathy, and muscle fiber necrosis. The response to immunosuppressive therapy was highly irregular. BCIM-SSc is a rare disorder that shares many similar phenotypes among the described cases, but has a highly heterogeneous response to treatment. At present, more data on the physiopathology, clinical features, and treatment is still needed.

The efficacy and safety of immunotherapy in thymic epithelial tumors: more effective, more risky: a systematic review.

BackgroundThymic epithelial tumors (TETs) are rare malignant neoplasms originating from thymic epithelial cells. The current treatment for localized TETs is surgical removal. However, 20–30% of thymomas and 70–80% of thymic carcinomas are unresectable, recurrent, or metastatic at the time of detection. The standard therapy for these patients is chemotherapy, but the effect is limited. With a deeper understanding of tumor immunity, immunotherapy for various cancers has rapidly developed. Antibodies against cytotoxic T-lymphocyte antigen-4, programmed death-1, and programmed death-ligand 1 have been approved for the treatment of many solid tumors. Compared with traditional treatments, these immune checkpoint inhibitors (ICIs) have better efficacy and lower toxicity. Recently, ICIs have been used more enthusiastically in the treatment of TETs. However, due to the unique biological characteristics of the thymus, immunotherapy usually causes severe immune-related adverse events (irAEs). Most previous studies on immunotherapy in TETs had small sample sizes and reported diverse conclusions.MethodsWe collected relevant studies in PubMed during the last five years and analyzed the available data to discuss the efficacy and safety of ICIs in TETs.ResultsAccording to 14 previous studies in the past five years, all TETs showed expression of programmed death-ligand 1, while thymic carcinomas showed 100% expression. The best median progression-free survival (mPFS) among the five studies was 6.5 months, and the best median overall survival (mOS) was 24.9 months. In addition, the most common irAEs were myasthenic symptoms, liver enzyme elevation, and elevated creatine phosphokinase levels.ConclusionsICIs can be used in TET treatment, especially for thymic carcinomas, in the absence of standard second-line treatment. However, more attention should be paid to irAEs.

Interim Results from a Phase 1 Study of ADCT-301 (Camidanlumab Tesirine) Show Promising Activity of a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate in Relapsed/Refractory Hodgkin/Non-Hodgkin Lymphoma

Interim Results from a Phase 1 Study of ADCT-301 (Camidanlumab Tesirine) Show Promising Activity of a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate in Relapsed/Refractory Hodgkin/Non-Hodgkin Lymphoma

Phase 1 Study of TAK-659, an Investigational Reversible Dual SYK/FLT-3 Inhibitor, in Patients (Pts) with Lymphoma: Updated Results from Dose-Escalation and Expansion Cohorts

Phase 1 Study of TAK-659, an Investigational Reversible Dual SYK/FLT-3 Inhibitor, in Patients (Pts) with Lymphoma: Updated Results from Dose-Escalation and Expansion Cohorts

Comparative Risk Assessment of Imatinib, Nilotinib and Dasatinib in Randomized Controlled Trials: A Meta-Analysis

Background:Imatinib, nilotinib and dasatinib are standard frontline therapy for chronic myeloid leukemia (CML). Although generally safe, they are associated with adverse events (AEs), each with a distinct toxicity profile. We conducted a meta-analysis of reported AEs to assess their toxicity profile at a larger scale.Methods:We searched reports from Pubmed/Medline, CENTRAL Cochrane registry, clinicaltrials.gov, and available final trial reports from pharmaceutical companies. We selected randomized phase 2 and 3 trials where imatinib, nilotinib and/or dasatinib were used and all-grade and grade 3-4 AEs were reported. We calculated the relative risk (RR), 95% confidence interval (95CI), and I2 statistic testing of heterogeneity.Results:A total of 24 randomized clinical trials were included (11 phase 2, 13 phase 3) including 7491 pts treated for CML (15 studies), gastrointestinal stromal tumor (2), prostate cancer (3), breast cancer (2), pancreatic cancer (1), glioblastoma (1) and portal hypertension (1). (Table 1).Imatinib had a high risk of fluid retention: RR of all-grade peripheral edema 2.04 (95CI 1.68-2.49); periorbital edema 18.46 (10.38-32.83); face edema 4.31 (2.72-6.84); eyelid edema 10.43 (6.58-16.53); superficial edema 5.24 (4.22-6.5), fluid retention 2.19 (1.77-2.71). Correlation with grade 3-4 of these events was not statistically significant.Musculoskeletal AEs were also most common with imatinib: musculoskeletal pain, muscle spasm and elevated blood creatine phosphokinase had RR of 3.59 (2.86-4.51), 3.97 (3.15-4.99) and 3.26 (1.85-5.72). Muscle inflammation and muscle cramps were reported in 1 trial as 5.1 (2.65-9.82) and 5.2 (3.77-7.16). All-grade eye disorders in imatinib-treated patients had RR 2.07 (1.76-2.45).Hepatobiliary disorders dominated in the nilotinib group with RR 3.85 (2.82-5.27), specifically: elevated AST, elevated ALT, elevated GGT and hyperbilirubinemia : 1.8 (1.49-2.16), 2.83 (2.4-3.35), 2.83 (2.4-3.35), 11.98 (2.58-55.5) and 5.46 (4.33-6.88).Dasatinib-induced pleural effusion and associated symptoms were reported with RR of all-grade pleural effusion 6.21 (95CI: 4.51-8.56; p<0.00001); cough 1.39 (1.16-1.68; p=0.0005) and dyspnea 1.57(1.32-1.87; p<0.00001).Hematological toxicities, all-grade leucopenia, neutropenia and lymphopenia were more pronounced with imatinib RR 1.65 (1.41-1.93), 1.42 (1.31-1.53) and 1.21 (1.03-1.41), respectively. Corresponding values for grade 3-4 were 1.81 (1.15-2.86), 1.39 (1.17-1.65) and 3.02 (1.24-7.38). There was higher RR of high-grade infections with imatinib 2.07 (1.44-2.97). Dasatinib was associated with higher risk of all-grade anemia and thrombocytopenia : 1.25 (1.16-1.35) and 1.23 (1.1-1.37).For dermatological toxicities, nilotinib was associated with higher RR of all-grade rash, pruritis and alopecia : 2.46 (2.03-2.99), 2.4 (1.74-3.31) and 2.55 (1.65-3.96). Dasatinib was associated with dermatitis acneiform in 2 trials, RR 21.26 (3.67-123.07).Gastrointestinal toxicities varied by drug. All-grade nausea and vomiting were more common with imatinib: 1.19 (1.11-1.29) and 1.22 (1.06-1.4); nilotinib correlated with all-grade constipation 2.46 (1.8-3.37); and all-grade diarrhea with dasatinib 1.23 (1.13-1.33).Metabolic/electrolyte disturbances with imatinibincluded all-grade hypophosphatemia,hypocalcemia and hypokalemia : 1.8 (1.55-2.1), 1.31 (1.01-1.7) and 1.99 (1.51-2.63), and grade 3-4 hypophosphatemia 3.15 (2.28-4.36). Nilotinib had higher RR of hyperglycemia and elevated lipase 1.81 (1.48-2.22) and 1.46 (1.18-1.79).Conclusion:Our meta-analysis further demonstrates the different toxicity profile of different TKIs across several trials and different diseases. This information may be useful when selecting therapy for patients in need of a TKI. [Display omitted] DisclosuresKantarjian:Novartis: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding; Amgen: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:Sun Pharma: Research Funding; Teva: Research Funding; Pfizer: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

Daptomycin in combination with rosuvastatin induced blood creatine phosphokinase elevation

We present the case of a 73-year-old male patient who was hospitalised with infective endocarditis, and report an elevation in his blood creatine phosphokinase (CPK) after receiving daptomycin and rosuvastatin...

OP24 Efficacy and safety of upadacitinib induction therapy in patients with Moderately to Severely Active Ulcerative Colitis: Results from the phase 3 U-ACHIEVE study

BackgroundAn unmet therapeutic need remains in patients with ulcerative colitis (UC). U-ACHIEVE is one of two phase 3 induction trials evaluating the safety and efficacy of the selective Janus kinase–1 inhibitor upadacitinib (UPA) 45 mg once daily (QD) in adults with UC.MethodsU-ACHIEVE is a multicentre, double-blind, placebo (PBO)–controlled trial (NCT02819635) that randomized patients with moderately to severely active UC 2:1 to UPA 45 mg QD or PBO for 8 weeks. Patients were stratified by response to biologic therapy (inadequate vs non–inadequate responder), baseline corticosteroid use (yes or no), and baseline adapted Mayo score (≤7 or >7). The primary endpoint was proportion of patients achieving clinical remission (per adapted Mayo Score) at week 8.Ranked secondary endpoints included endoscopic improvement, endoscopic remission, and clinical response per adapted Mayo Score at week 8; clinical response per partial adapted Mayo Score at week 2; and histologic-endoscopic mucosal improvement at week 8. Non-responder imputation incorporating multiple imputations for missing data due to COVID-19 are reported. Safety was assessed through week 8.Results474 patients were randomized (UPA, n=319; PBO, n=155). Baseline characteristics were well balanced between groups (Table 1). A significantly higher proportion of patients receiving UPA (26.1%) vs PBO (4.8%) achieved clinical remission at week 8 (adjusted treatment difference [95% CI], 21.6% [15.8, 27.4]; P<0.001; Figure 1). For all ranked secondary endpoints, UPA was superior to PBO (P<0.001; Figure 1). A significant difference in clinical response favouring UPA vs PBO was seen as early as week 2 (60.1% vs 27.3%) and was sustained over 8 weeks (79.0% vs 41.6%; Figure 2). There were more serious adverse events (AEs), severe AEs, and AEs leading to study drug discontinuation with PBO (Table 2). The most common AEs were acne, creatine phosphokinase elevation, and nasopharyngitis with UPA and worsening of UC and anaemia with PBO. Incidence of serious infection was similar between UPA and PBO. Neutropenia and lymphopenia were reported more frequently with UPA vs PBO (Table 2).No adjudicated gastrointestinal perforation, major cardiovascular AEs, or thrombotic events and no active tuberculosis, malignancy, or deaths were reported. ConclusionIn patients with moderately to severely active UC, UPA 45 mg QD induction therapy was superior to PBO in inducing clinical remission/response, and endoscopic remission/response over 8 weeks; responses were significant and rapid. UPA 45 mg QD was well tolerated; safety was comparable with the known safety profile of UPA, and no new safety signals were identified.

Biochemical and hematological biomarkers of reproductive failure in bottlenose dolphins Tursiops truncatus.

The physiological demands of pregnancy inevitably result in alterations in both biochemical and hematological parameters as fetal development occurs. The shifts observed in successful pregnancy in bottlenose dolphins Tursiops truncatus to support both fetal physiological needs and maternal basal requirements have been established according to each trimester. Detecting aberrations in blood-based biomarkers could help facilitate diagnosis of gestational abnormalities, improve our understanding of factors influencing reproductive outcomes and aid in prediction of reproductive failure. This study retrospectively analyzed 263 blood samples from 15 bottlenose dolphins in 21 failed pregnancies over 28 yr (1989-2017). Most samples remained within normal pregnancy reference ranges; however, significant shifts were observed between trimesters. Hematological alterations, compared to successful pregnancy reference ranges from previously published data, were consistent across failed pregnancies and included an increased prevalence of elevated 2nd and 3rd trimester neutrophils, elevated 2nd trimester monocytes and decreased 3rd trimester eosinophils. In addition, low hematocrit and low red blood cells were more prevalent in the 2nd trimester. Biochemical shifts included an increased prevalence of elevated creatine phosphokinase in the 3rd trimester outside of the normal reference ranges. Across failed pregnancies, calcium and iron were decreased in the 3rd trimester. Significantly decreased progesterone in the 3rd trimester was a negative prognostic indicator of pregnancy outcome with decreasing 3rd trimester progesterone associated with failed pregnancy. This study demonstrates the use of blood-based biomarkers as possible predictors of pregnancy outcome in bottlenose dolphins.

Triplet therapy with pembrolizumab (PEM), encorafenib (ENC) and binimetinib (BIN) in advanced, BRAF V600 mutant melanoma: Final results from the dose-finding phase I part of the IMMU-Target trial.

9532 Background: Survival of BRAF-mutated melanoma profoundly improved since the introduction of immune checkpoint inhibitors (ICI) and MAPK pathway inhibitors (MAPKi). Response kinetics of ICI and MAPKi are complementary, mechanistic evidence indicates that MAPKi may affect the tumor immune microenvironment. Combined use of both drug classes may further enhance clinical benefit. IMMU-Target was set-up as a prospective, open-label, phase I/II trial, with a safety phase I part followed by a randomized phase II part, to study the tolerability and clinical activity of PEM, ENC and BIN triplet therapy. Methods: Treatment naïve adult patients (pts) with stage IIIB-IV (AJCC 2017), BRAF V600 mutant melanoma with measurable disease but no active brain metastasis were eligible. The dose finding part used a 3+3 design, starting with a dose level (DL) 0 applying the clinically recommended doses of PEM (200 mg Q3W), ENC (450 mg QD) and BIN (45 mg BID). In case of ≥2 dose-limiting toxicities (DLT), a reduction of the ENC and BIN doses (300 mg QD and 30 mg BID at DL-1, 200 mg QD and 30 mg BID at DL -2) was foreseen. Primary endpoints of the phase I part were safety and tolerability. Results: From April 2018 until May 2020, 14 pts with BRAF V600 mutations were enrolled. 2 of 3 pts at DL 0 developed DLT (creatine phosphokinase (CPK) elevations grade 3 plus cytokine release syndrome grade 4; gamma glutamyl transferase (GGT) elevations grade 3), and had to stop therapy early. Therefore, 3+3 further pts at DL -1 were included with no DLT observed in these 6 pts. One (isolated GGT elevations grade 3) of the 2 DLT observed in the 3 pts of DL 0 enrolled initially was questionable as DLT, as the patient had further episodes of isolated GGT elevations without therapy. As a result, further 5 pts were enrolled at DL 0: here no DLT-matching treatment-related adverse event (TRAE) occurred. In total, 12 out of 14 pts (86%) experienced a TRAE and 7 (50%) experienced a grade ≥3 TRAE; there were no fatal AE or TRAE-related deaths. Increases in alanine and in aspartate aminotransferases, GGT and CPK elevations (6 of 14 pts) were the most common grade 3-4 TRAE. In median, pts at DL 0 (n=8) received triplet therapy for 18 weeks (IQR 7.5-29), at DL-1 (n=6) for 46 weeks (IQR 27-102). The overall response rate was 64% (95% CI=35-87). At a median follow-up of 10.0 months at DL 0 and 27.0 months at DL-1, progression-free survival at 12 months was 37.5% (95% CI 9- 67) and 60% (95% CI 13-88), respectively. Conclusions: Triplet therapy was feasible and safe at both dose levels leading to clinically meaningful disease control. The phase II part was not initiated, since the clinical efficacy of PEM plus ENC and BIN is currently investigated in STARBOARD ( NCT04657991 ), a prospective, randomized, placebo-controlled (PEM mono), double-blinded phase III trial. Clinical trial information: NCT02902042.

Acute polymyositis presenting as chronic graft-versus-host disease: A systemic review.

e19025 Background: Chronic graft-versus-host disease (cGvHD) remains a significant complication of allogenic hematopoietic stem cell transplantation (allo-HSCT), with an estimated incidence of over 50%. Commonly targeted organs are skin, eyes, mouth, gastrointestinal tract, and liver. Muscular involvement and presentation as acute polymyositis (APM) remains a rare manifestation of cGvHD. We present a systemic review of APM associated with cGvHD to summarize current evidence regarding epidemiology, clinical presentation, diagnosis, treatment, and prognosis. Methods: A systemic review was conducting following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We screened 97 articles from 3 databases (PubMed, Embase, and Cochrane) using the MeSH terms and keywords for “Allogenic stem cell transplantation,” “Chronic graft-versus-host disease,” “Polymyositis” and “Myositis” from the date of inception to Jan 2021. After excluding duplicate, review and non-relevant articles, we included 36 studies (3 retrospective, others case series/reports) reporting APM associated with cGvHD after allo-HSCT. Results: We identified 72 patients, presented with APM associated with cGvHD after allo-HSCT. It involves cases of all ages, with male predominance. The onset of APM ranges as early as 100 days to 5 years, with a median range of 1.6 years post-allo-HSCT. Over half (59%) of patients had prior acute GvHD. Majority (85%) of cases presented with myalgia and progressive bilateral proximal muscle weakness with elevated Creatine phosphokinase (CPK) and/or Aldolase. Isolated presentation of APM without other manifestations of GvHD was rare, and concurrent skin involvement was present in 42% cases. Steroids remain the mainstay of treatment, achieving complete treatment response in up to 78% of cases. In some refractory cases, Rituximab has also been effective. Conclusions: APM can present as a sole manifestation of cGvHD with an estimated incidence of up to 3.4%. Diagnosis can be challenging as it can mimic idiopathic polymyositis. Radiologically targeted muscle biopsy showing characteristic myonecrosis remains the gold standard for diagnosis. Most (90%) cases respond to steroids and immunosuppression agents. Nevertheless, refractory cases remain challenging to treat and can cause significant morbidity and mortality. Characteristics of APM in 3 cohorts of allo-HSCT patients.[Table: see text]