Cardiovascular diseases are commonly associated with disturbances in parasympathetic heart rhythm control; therefore, the development of new methods for assessing vagal cardiotropic effects is an important biomedical task. The purpose of this research was to study the synchronization of respiration-related oscillations of mean arterial pressure (MAP) and heart rate (HR) depending on the duration of the expiration phase, during which cardiac vagal effects increase. The study involving nine young men included a passive head-up test performed at a fixed respiratory rate of 0.2 Hz (12 cycles/min) and different ratios of inspiration and expiration phase durations (30/70 and 70/30

Vamotinib (PF-114) is a 3rd -generation, ATP-competitive oral tyrosine kinase inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1T315I. We present final results of a phase-1 vamotinib dose-escalation study to identify maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) followed by expansion cohorts. 51 subjects with chronic myeloid leukaemia (CML) failing ≥ 1 2nd generation TKI or with BCR::ABL1T315I were enrolled. Subjects received vamotinib, 50–750 mg/d, continuously. Median exposure was 6 months (range, < 1–52 months). Median CML duration pre-study was 10 years (range, < 1–23 years). 27 subjects received ≥ 3 prior TKIs and 16 had BCR::ABL1T315I. The MTD was 600 mg with the Grade-3 psoriasis-like skin toxicity as the DLT. There were no vascular occlusive events nor deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 14 of 44 subjects, complete cytogenetic response (CCyR) in 10 of 50 and major molecular response (MMR) in 7 of 51 subjects who did not have a CHR, MCyR, CCyR or MMR at enrollment. The best safety/efficacy dose was 300 mg with MCyR achieved in 6 of 7 subjects, CCyR in 5 of 9 and MMR in 4 of 9 subjects who did not have a MCyR, CCyR or MMR at enrollment. 5 of 16 subjects with BCR::ABL1T315I responded including 3 achieving a CHR, 3, a MCyR, and 1,a CCyR. 2 of 5 subjects failing ponatinib achieved a CHR. Vamotinib dose for further phase-3 study is 300 mg/d.

Background Vamotinib (PF-114), an oral tyrosine kinase-inhibitor (TKI) is active against wild-type and BCR::ABL1 variants. Whether it is safer and more effective compared with high-dose imatinib in people with chronic phase chronic myeloid leukaemia (CML) failing conventional dose imatinib is unknown. Method Multi-centre open-label phase-3 trial with endpoints of safety and 1-year major molecular response (MMR). Other endpoints are rates of BCR::ABL1IS < 1% (MR2), MR4 and MR4.5. Subjects with imatinib-resistant BCR::ABL1 variantswere excluded. Results 180 subject (vamotinib, 300 mg; N = 89; imatinib; 800 mg; N = 91) were enrolled. 117 were men. Median age was 44 years (Range 18-75 years). Median CML duration pre-study was 4 years (Range, < 1-24 years). 65 subjects (73%) in the vamotinib cohort and 65 (71%) in the imatinib cohort had pre-study BCR::ABL1 ≥ 10%. Rate of achieving 1-year MMR with vamotinib was 47% compared with imatinib, 12% ( p < 0.001). Rates of other endpoints were also higher with vamotinib. There were no significant differences frequency of adverse events (AEs). Skin toxicity was the most common AE for vamotinib. Conclusion Vamotinib, 300 mg, is as safe as imatinib, 800 mg, but more effective in achieving 1-year MMR. The study is ongoing.

ABSTRACT:Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ∼70% of patients discontinue ruxolitinib after ∼5 years, a third of whom report suboptimal splenic response. ADORE was a phase 1b/2 study with an innovative open platform design that assessed the safety, efficacy, and pharmacokinetics of novel compounds in combination with ruxolitinib in patients with MF who had a suboptimal response to ruxolitinib alone. A total of 44 patients were enrolled in part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Most patients were allocated to receive ruxolitinib plus siremadlin (N = 23). The most frequent adverse events with siremadlin were gastrointestinal (nausea and diarrhea) and hematological (thrombocytopenia, anemia, and neutropenia). Siremadlin 30 mg orally once daily on days 1 to 5 of a 28-day cycle was selected as the recommended phase 2 dose. The most robust spleen volume reduction (SVR) at 24 weeks was observed with ruxolitinib plus siremadlin 30 mg. Reductions in percent JAK2V617F allele burden at week 24 were observed, notably in several patients with SVR. An increase in growth differentiation factor 15 protein levels in patients receiving siremadlin demonstrated the on-target modulation of downstream p53 targets. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821.

Aerobic exercise training is aimed to prevent and correct various cardiovascular disorders. To study its effects, various rodent models are currently in use, among which the rat model of voluntary wheel running is of particular interest, as its pattern of motor activity is close to natural rat locomotion, while being non-stressful. This work was aimed at a comprehensive investigation of wheel running effects on the neural control of heart rate (HR) in rats. The animals, aged 6 weeks, were divided into two groups: training (TR, free access to wheels, n = 11) and sedentary control (CON, n = 12). After a 6-week training, ECG was recorded in freely moving rats using skin electrodes in three modes: at rest, after autonomic blockade of cardiotropic influences, and during 4-min air-jet stress. Autonomic neural influences were analyzed by administering the β1-adrenoceptor blocker atenolol (2 mg/kg) and the peripheral M-cholinoceptor antagonist methylatropine (1 mg/kg), as well as by analyzing HR variability via spectral and wavelet analyses. At rest, the TR group showed a decrease in the baseline HR level vs. CON group. Аtenolol decreased HR equally in two groups, but methylatropine elicited a more significant increase in HR in the TR vs. CON group. After atenolol and methylatropine co-administration, HR levels in two groups were similar. TR rats showed an increased contribution of high-frequency (0.75–3 Hz) oscillations to the total RR interval power spectrum. During emotional (air-jet) stress, the TR group demonstrated a more pronounced increase in HR vs. CON group. In addition, stressed TR rats exhibited a decrease in the amplitude of HR high-frequency oscillations, which was absent in the CON group. Thus, voluntary wheel running in rats is accompanied by an increase in parasympathetic influences on the heart, as manifested in an increase both in respiratory sinus arrhythmia and in vagal effects on the resting HR level (increased tachycardia). Moderate resting bradycardia promotes a more pronounced increase in HR under emotional stress conditions due to suppression of parasympathetic cardiac influences.

The ratio of low-frequency (LF, 0.1 Hz) waves of RR interval duration (RRI) and systolic blood pressure (SAP) reflects the cardiac baroreflex sensitivity (BRS). Gravitational unloading (GU) may alter BRS during head-up tilt test (HUT) and lower body negative pressure (LBNP) test. Both effects cause blood redistribution to the lower body, but HUT is accompanied by greater unloading of sinocarotid baroreceptors than LBNP and activation of the vestibulosympathetic reflex. However, GU effects on BRS in these tests have not been directly compared previously. In this study we tested the hypothesis that the effect of dry immersion (DI, on-ground model of GU) on BRS in the same subjects will be more pronounced during HUT than during LBNP, while causing a comparable decrease in stroke volume (SV). Nine healthy men participated in two test sessions (before and after 7-day DI) consisting of five 3-min HUT (65°C) and five 3-min LBNP (–35 mmHg) with data averaging in each test. Wavelet analysis was used to determine the amplitude of the RRI and SAP waves in the 0.05–0.13 Hz range. The amplitude of LF waves of SAP increased in both tests, after DI—more significantly in HUT. The amplitude of LF RRI waves decreased in two tests; the percentage decrease did not differ between tests and did not change under the influence of DI. The α-coefficient (the ratio of RRI and SAP LF wave amplitudes) decreased equally in two tests before DI. After DI, more pronounced α-coefficient reduction was observed in HUT test but not in LBNP test. Thus, the effect of DI on BRS is evident in HUT, but not in LBNP, which may be explained by the more pronounced influence of HUT on the mechanisms of neural control of heart rhythm.

Respiratory sinus arrhythmia (RSA) reflects the functioning of the nervous heart control, predominantly of a parasympathetic nature. The study of RSA mechanisms helps to reveal the physiological patterns of regulation of cardiac activity, and the development of new approaches to its assessment is an urgent medical task. This review will examine experimental approaches that have contributed to the development of modern ideas about the autonomic nervous system’s role in the formation of RSA, as well as the connection between RSA and frequency-matched fluctuations in systemic blood pressure. In addition, we will consider new data on the phase relationships of fluctuations in heart rate and blood pressure in the frequency range of respiratory waves, obtained using wavelet analysis of these physiological signals.

We aimed to investigate the effect of 8 weeks of moderate endurance training without considerable mechanical stress on the activation of extracellular matrix (ECM) gene expression in human skeletal muscles. Mechanical stress activates ECM biogenesis in the skeletal muscles, therefore aerobic exercise on a cycling ergometer with concentric muscle contractions only was used in the study. Skeletal muscle samples from m. vastus lateralis were taken from seven young untrained men before and after 8 weeks of aerobic training. Changes in the transcriptome (RNA sequencing) and proteome (shotgun quantitative proteomics analysis) were assessed in the samples; ECM-associated proteins (or matrisome) were determined using the Matrisome DB database. After the training period, a change (mainly an increase) in the content of 14 ECM proteins and 134 mRNAs of ECM proteins was found. The largest increase in protein content was found for collagens type 1 and 3 (1.7 and 2.2 times, respectively), the main proteins of the human skeletal muscle’s ECM, which was consistent with an increase in the corresponding mRNA by 10–20 times. In addition, an increase in the expression of more than a hundred mRNAs of collagens, glycoproteins, proteoglycans, and enzymatic regulators of ECM was found, which occurs simultaneously with an increase in the expression of genes of growth factors (IGF1, PDGFs, TGFB1, MDK, etc.), which play a main role in ECM biogenesis regulation. In conclusion, 8-week aerobic exercise training without considerable mechanical stress is a powerful stimulus for the activation of ECM biogenesis in skeletal muscle.

Topic: 35. Quality of life and palliative care Background: Polycythemia vera (PV) is associated with troublesome symptoms and reduced quality of life (QoL). Although its treatment is risk-adapted and aims to minimize or improve symptoms, symptom burden is not included as a risk stratification factor for PV. Symptom burden and its impact on QoL may be underestimated in “low risk” patients (with age <60 and without prior thrombo-hemorrhagic events). Aims: The study, therefore, aimed to explore symptom burden and QoL in “low risk” PV patients and to compare such aspects with that in “high risk” PV. Methods: Patients with PV were selected from a cohort of participated in a cross-sectional nationwide survey MPN-QoL-2020 carried out in September-December 2020 in different areas of Russia. Patients aged ≥18 years with a confirmed diagnosis of PV and treated on the in-patient or outpatient basis were included in the analysis. For symptom and QoL assessment MPN10 and HM-PRO were used, respectively. The MPN10 assesses 10 of the most clinically relevant symptoms, including fatigue and generates a Total Symptom Score (TSS). The HM-PRO is a specific QoL questionnaire for patients with hematologic malignancies developed for the use in clinical practice. It consists of two scales: Part A measuring the ‘impact on patients’ QoL’; Part B – ‘signs and symptoms’ (S&S) experienced by the patients. Part A has 4 domains: physical behavior (PB), social well-being (SW), emotional behavior (EB), eating and drinking habits (ED). Higher scores indicate greater impact. Exploratory analyses were carried out applying descriptive statistics, χ2 test and Mann-Whitney U test. Results: Altogether 265 PV patients were included in the analysis: 95 patients were identified as “low risk” (mean age±SD – 48.8±11.6 yrs; 49.5% males) and 170 patients as “high risk” PV (mean age – 62.9±12.3 yrs; 45.3% males). In the “low risk” group, 69.5% received cytoreductive treatments (CT) – hydrea (64%), interferons (30%), ruxolitinib (6%); in the high risk group, 86.5% received CT – hydrea (79%), interferons (15%), ruxolitinib (6%). Among “low risk” PV, 94.7% reported at least 1 PV-related symptom. The most frequently reported symptoms of MPN10 were inactivity (83%), fatigue (81%) and itching (65%). Symptoms with the highest reported mean severity scores were fatigue (3.3±2.6), inactivity (3.3±2.6), problems concentrating (2.8±2.9) and itching (2.6±2.9). More than half of “low risk” patients (61.5%) experienced moderate-to-severe symptoms (4-10 scores). Symptom burden according to MPN10 TSS was similar to “high risk” patients: 20.4±16.5 vs 24.6±18.4 (ns). Prevalence of moderate-to-severe symptoms did not differ significantly between “low risk” (61.5%) and “high risk” (71.7%) PV (ns). In “low risk” PV, the highest impact on QoL by HM-PRO (Part A) was for EB (Table). According to HM-PRO Part A and S&S, 26.3% and 44.2% patients exhibited moderate/very large/extremely large effect on QoL and S&S, respectively (Table). In “high risk” PV these proportions were 38.2% and 52.3%, respectively (ns). QoL impact and S&S were higher in “high risk” than in “low risk” PV (p<0.05), Table. Summary/Conclusion: In conclusion, the vast majority of patients with “low risk” PV reported high PV-related symptoms/ symptom burden and impact on QoL. Further prospective studies are worthwhile to explore the determinants of symptom burden in “low risk” PV. Furthermore, the results suggest that risk profiling may not capture all aspects of disease burden in PV and this highlights the importance of using patient-reported outcomes, namely MPN10 and HM-PRO, to identify unmet patients’ needs, especially in “low risk” PV.Keywords: Risk factor, Quality of life, Polycythemia vera

Topic: 8. Chronic myeloid leukemia - Clinical Background: In Russia, within the framework of the GIPAP program in the period from 2001 to imatinib therapy was initiated in 235 patients in the chronic phase of chronic myelogenous leukemia (CML). Currently, this group of patients has the longest follow-up period after the start of treatment with imatinib and is of interest in terms of studying long-term results of survival and the effects of therapy with tyrosine kinase inhibitors (TKIs). Aims: to analyze the long-term results of therapy in patients with CML who started imatinib therapy as part of the GIPAP program in the period from 2001 to 2007 Methods: We performed a retrospective analysis of the results of therapy in 235 patients with chronic phase CML, who received imatinib under the GIPAP program from 2001 to 2007. The protocols for therapy and monitoring of the residual disease of patients at various time intervals were determined by the clinical recommendations relevant at that time in the conditions of real clinical practice. Overall survival was analyzed using the Kaplan-Meier method. The cumulative incidence of responses was calculated by «intention-to-treat» principle. The probability of CML-related and CML-unrelated death and cumulative incidence of responses was carried out by cumulative incidence function. Results: The median follow-up for alive patients at the time of analysis was 17.3 years (interquartile range (IQR) 15.5–18.5). Seventy (30%) patients died, the median time to death from the start of therapy was 7.8 years (IQR 3.7-13.6). The overall 10-year, 15-year and 20-year survival rates were 82%, 74% and 62%. The cause of death in 43 cases (61%) was CML-related death, 27 (39%) patients died from death unrelated to CML. The 20-year probability of CML-related and CML-unrelated death was 27% and 18%, respectively. The median duration of imatinib therapy was 11.4 years (0.8-21 years). Ninety two (39%) patients received at least one second-generation TKI (2nd TKI), three or more TKIs were prescribed to 43 (18%) patients. The median duration of therapy after switching to 2nd TKI was 7.8 years (0.1-15.6 years). Overall 15-year survival since switching to 2nd TKI was 59%. The 10-year and 20-year cumulative incidences of CCyR, MMR and MR4 were 79%, 63%, 56% and 81%, 73%, 69%, respectively. Summary/Conclusion: After 20 years of monitoring patients on TKI therapy, we still cannot say that survival in CML is comparable to the survival of normal populationKeywords: Chronic myeloid leukemia, Imatinib, Long-term follow-up

We studied the effects of long-term anti-orthostatic hypokinesia (head-down bed rest—BR, a model of gravitational unloading) on the dynamics of orthostasis-induced changes in the content of total (THb), deoxygenated (HHb), and oxygenated (OHb) hemoglobin in the calf at the level of the gastrocnemius muscle medial head using near-infrared spectroscopy. In seven young men, 2–4 days before and on the 19th day of BR, a passive head-up tilt test was performed (15 min in the supine position, then 15 min at 65°). After BR, there was an increase in heart rate and a decrease in stroke volume in the supine position, as well as more pronounced changes in these parameters during orthostasis. Blood pressure in the supine position and orthostasis did not change after BR. THb content increased gradually during orthostasis and reached a plateau by the end of the test; after BR, an increase in the half-rise time and a twofold increase in the plateau level were observed. Tissue HHb content by the end of the tilt test also increased after BR. The dynamics of OHb before BR was more complicated: this indicator grew, reached a maximum during a minute, and then gradually decreased to half of the maximum by the end of the test. After BR, the dynamics of OHb changed drastically: the signal increased gradually and reached a level that was twice the peak value of OHb content before BR. The results allow us to conclude that exposure to BR weakens the compensatory constriction of calf vessels during tilt test; consequently, it is followed by higher blood accumulation in calf vascular bed, which, in turn, leads to smaller SV during orthostasis.

The course of chronic myeloproliferative neoplasms (CMPN), a group of systemic hematological diseases, can be accompanied by various complications and changes in tissues and organs of the whole organism. The eye is the only organ where damage of nerve fibers and blood vessels can be directly observed and examined, and ocular symptoms can be the initial, manifest of systemic pathology, the toxic effects of modern targeted therapy, or the first manifestation of a relapse of the disease after treatment. The most frequently described manifestations are caused by hematological anomalies that cause microvascular disorders. Such changes today remain insufficiently studied in terms of the using new research methods and contemporary targeted therapy. In addition, ocular symptoms may precede more serious extraocular complications. Combined ophthalmological and hematological examination of patients with CMPN can become a preventive approach for early diagnosis and timely treatment.

COVID-19 and other infectious diseases can exacerbate the course of paroxysmal nocturnal hemoglobinuria (PNH). The efficacy and safety of the Gam-COVID-Vac vaccine in patients with PNH has not been adequately studied. A retrospective, observational, cohort, non-comparative study was performed to assess the course of COVID-19 as well as the safety and efficacy of the Gam-COVID-Vac (Sputnik V) vaccine in patients with paroxysmal nocturnal hemoglobinuria (PNH). The study included data from 52 patients with PNH aged 18 to 75 years, 38 of whom received background therapy with eculizumab (Elizaria®) between March 2020 and January 2022. COVID-19 was diagnosed according to the results of PCR testing. The patients were divided into two groups for comparison of the incidence of COVID-19. Group 1 included non-vaccinated patients with PNH, and Group 2 included patients vaccinated prior to the onset of COVID-19. According to vaccination, patients were subdivided into non-vaccinated and vaccinated groups without signs of previous COVID-19 at the beginning of the analyzed period, and patients vaccinated half a year or more after recovery from COVID-19. Testing for anti-SARS-CoV-2 IgG levels was carried out in patients with PNH in the year after their COVID-19. Tests for anti-SARS-CoV-2 RBD IgG levels were performed on vaccinated patients. In total, 28 (53.8%) of the enrolled patients had COVID-19, including asymptomatic forms in 7 (25%) and mild forms in 16 (57%) patients. A total of 22 (42.3%) patients were fully vaccinated with Gam-COVID-Vac, of which 13 (25%) patients were vaccinated without the signs of previous SARS-CoV-2infection, and 9 (17.3%) patients were vaccinated after COVID-19. The number of patients who had COVID-19 was about two times higher in Group 1 (non-vaccinated; 24) (61.5%), whereas in Group 2 (vaccinated), the number of patients with COVID-19 was only 4 (30.8%). The proportion and number of patients who did not have COVID-19 was higher in the group of vaccinated patients (9; 69.2%) than in the group of non-vaccinated patients (15; 38.5%) (p = 0.054). In patients who had been infected with COVID-19, maximum concentrations of anti-SARS-CoV-2 IgG were observed 2–3 months after the acute infection phase, followed by a gradual decline by month 9–10. The mean RBD IgG concentration was higher in the group of patients who had been infected by COVID-19 than in the group of patients without COVID-19 (p = 0.047). Therapy type, including eculizumab, did not have a significant impact on RBD IgG titers (p > 0.05). Hospitalization was required in five (18%) patients, all of whom had breakthrough hemolysis and severe lung damage on CT scans. After the first dose, adverse events (AEs) were reported in 41% of the patients (body temperature increased in 18%; headache in 13.6%; and pain in joints in 4.5%; colitis exacerbation was observed in 4.5%). After the second dose, no AEs were reported. The performed study suggests the possible efficacy and demonstrates the safety of Gam-COVID-Vac (Sputnik V) for the prophylaxis of COVID-19 in patients with PNH who experience immunosuppression due to target therapy.

NGS data can confirm disease clonal nature, assess disease prognosis, and select target therapy for patients with Ph-negative myeloproliferative neoplasms. To get new information it is possible to expand the panel of sequenced genes, as well as study other genetic mechanisms underlying disease pathogenesis (e.g., changes in gene expression level, microRNAs, or transcription factors).

Introduction Ruxolitinib (RUX), a first-in-class Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for myelofibrosis (MF). However, ~50% patients (pts) discontinue RUX after ~3 years, including a third due to lack/loss of spleen response. Targeting additional pathogenic signaling pathways may provide superior disease control and potentially address underlying causes of disease. JAK2 mutations in MF induce expression of HDM2, which degrades tumor suppressor protein p53. Siremadlin (SIR), a potent and selective HDM2 inhibitor, restores p53-mediated apoptosis, which may promote clonal regression and spleen volume reduction (SVR). ADORE (NCT04097821) is a three-part phase 1/2 platform study assessing RUX in combination with 5 novel compounds, including SIR. We report results from the Part 1 (phase 1b) dose escalation cohort of SIR added to existing stable dose of RUX after suboptimal response to RUX alone. Methods Eligible pts had a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, splenomegaly (a palpable spleen ≥5 cm from the left costal margin or spleen volume ≥450 cm3 by MRI/CT scan), hemoglobin (Hb) level <11 g/dL (earlier protocol: <10 g/dL), and platelet count ≥75 × 109/L. Pts must have received RUX for ≥12 weeks (wks) (earlier protocol: ≥24 wks) and at a stable dose for ≥4 wks (earlier protocol: ≥8 wks) prior to first combination dose. Part 1 objective was to characterize the safety, tolerability, and recommended phase 2 dose (RP2D) of SIR added to RUX. Primary endpoint was incidence and severity of dose-limiting toxicities (DLT) within first 2 cycles; secondary objectives included characterization of the pharmacokinetic (PK) profile. Preliminary efficacy (change in spleen volume by MRI/CT scan from baseline [BL]), total symptom score (TSS) by MFSAF v4.0 and biomarkers were also explored. Pts were allocated to add SIR 20mg, 30mg or 40mg (orally once daily; days 1-5/28-day cycle) to their stable RUX dose (5-25mg twice daily). Adverse events (AEs) were coded by MedDRA and graded by CTCAE v5.0. Results In Part 1 SIR 20mg, 30mg and 40mg cohorts, 1/7, 9/10 and 1/6 pts were ongoing at data cut-off (April 13, 2022) respectively. The number of pts with DLTs after 2 cycles per number of evaluable pts was 0/6 at 20mg, 1/7 at 30mg (grade [G] 4 neutropenia and G4 thrombocytopenia in same pt), and 2/5 at 40mg (G3 and G4 thrombocytopenia). The most common AEs were gastrointestinal (GI) and hematologic (Table). RP2D was SIR 30mg/day. At 30mg, 5 pts experienced SIR-related GI toxicity; all events were G≤2; all lasted ≤4 days except for 1 case controlled with medication; 2 pts required concomitant medication for nausea, however, none discontinued treatment due to GI AEs. The most common hematologic AEs at 30mg were anemia, neutropenia, and thrombocytopenia. Two pts discontinued SIR 30mg due to G3 neutropenia and thrombocytopenia (for 1 pt) and G3 neutropenia (for 1 pt). At 30mg, 4/10 pts had completed a spleen volume assessment at 24 wks at time of data cut-off and all achieved SVR ≥35% from BL. At 20mg, 1/7 pts had SVR ≥35% at 24 wks. At 40mg, 3 pts discontinued prior to or did not complete spleen volume assessment at wk 24, limiting the availability of efficacy data (Figure). Symptom burden was low at BL across cohorts and subsequent TSS changes were highly variable between pts. SIR exposure increased with dose, with no relevant PK interactions between RUX and SIR observed. SIR increased growth/differentiation factor-15 (GDF15) expression, indicating target TP53 engagement. All pts were TP53 wildtype at BL. At data cut-off, SIR treatment resulted in the emergence of TP53 mutant clones in 1/7 pts at 20mg, 0/10 pts at 30mg and 1/6 pts at 40mg, at very low variant allele frequency (0.02-0.06) with unknown clinical significance. At 24 wks, 4/7 SIR-treated pts with available data had a decrease in JAK2 V617F mutational burden from BL (range 1.85-20.0%). Conclusions The RP2D of SIR is established as 30mg orally once daily on days 1-5/28-day cycle when added to the existing stable dose of RUX in pts with suboptimal response to prior RUX treatment. The addition of SIR 30mg was well tolerated, with low-G short-duration GI toxicity in contrast to an expected HDM2 inhibitor class effect. Other AEs were consistent with known RUX safety profile. Good tolerability at 30mg allowed pts to remain on SIR + RUX and to achieve robust spleen volume responses at 24 wks. The study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

— We compared the ability to maintain a preset effort of the shoulder girdle muscles by skiers before and after three months of high-intensity training and untrained subjects before and after exposure to severe hypokinesia (21-day dry immersion). Both the athletes and untrained volunteers were tested with the incremental exercise at manual ergometry until exhaustion. The anaerobic threshold was determined by blood lactate (4 mmol/L) and precision of effort maintenance by the standard deviation of actual effort from the preset one. It was shown that precision of the preset effort maintenance gradually reduced as the load increased. Precision decreased sharply with a load increasing above the anaerobic threshold. Improvement in the training level did not modify the pattern of the relationship between the deviation and load; however, the relative deviation became much less. Exposure to dry immersion led to a slight reduction in the anaerobic threshold but not to a noticeable change in precision of the shoulder girdle movements.

Multiple myeloma (MM) patients typically receive several lines of combination therapy and first-line treatment commonly includes lenalidomide. As patients age, they become less tolerant to treatment, requiring convenient/tolerable/lenalidomide-free options. Carfilzomib and/or bortezomib-exposed/intolerant, lenalidomide-refractory MM patients with ≥2 prior lines of therapy were randomized 3:2 to ixazomib-dexamethasone (ixa-dex) ( n = 73) or pomalidomide-dexamethasone (pom-dex) ( n = 49) until progression/toxicity. Median progression-free survival (mPFS) was 7.1 vs 4.8 months with ixa-dex vs pom-dex (HR 0.847, 95% CI 0.535–1.341, P = 0.477; median follow-up: 15.3 vs 17.3 months); there was no statistically significant difference between arms. In patients with 2 and ≥3 prior lines of therapy, respectively, mPFS was 11.0 vs 5.7 months (HR 1.083, 95% CI 0.547–2.144) and 5.7 vs 3.7 months (HR 0.686, 95% CI 0.368–1.279). Among ixa-dex vs pom-dex patients, 69% vs 81% had Grade ≥3 treatment-emergent adverse events (TEAEs), 51% vs 53% had serious TEAEs, 39% vs 36% had TEAEs leading to drug discontinuation, 44% vs 32% had TEAEs leading to dose reduction, and 13% vs 13% died on study. Quality of life was similar between arms and maintained during treatment. Ixa-dex represents an important lenalidomide-free, oral option for this heavily pretreated, lenalidomide-refractory, proteasome inhibitor-exposed population. Trial registration: ClinicalTrials.gov number, NCT03170882.

Background: Not everyone with CML responds optimally to TKI-therapy, especially those with BCR::ABL1T315I. PF-114 is a 4 th-generation oral tyrosine kinase-inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1T315I. We present final results of a phase-1 study (NCT02885766).