A pilot randomised controlled trial of acceptance and commitment therapy for medication decision-making and quality of life in women with breast cancer: The ACTION trial.

OBJECTIVE: Non-adherence to adjuvant endocrine therapy (AET) in women with breast cancer is common and associated with medication side-effects and distress. We co-designed an Acceptance and Commitment Therapy intervention (ACTION) to enhance medication decision-making and quality of life (QoL). We undertook a pilot trial of ACTION to inform the feasibility of a phase III trial, and to examine intervention acceptability. METHODS: This was a multi-site, exploratory, two-arm, individually randomised external pilot trial. Women with early breast cancer prescribed AET were randomised (1:1) to receive usual care (UC) or UC + ACTION. The ACTION intervention comprised a remotely delivered one-to-one ACT session followed by three group sessions delivered by clinical psychologists, alongside a website containing ideas for the self-management of side effects. RESULTS: Of the 480 women screened for eligibility, 260 (54.2%) were approached and 79 (30.4%) randomised. 71 (89.9%) women provided data at 3-month and 70 (88.6%) at 6-month 40 women were randomised to receive UC + ACTION and 32 (80.0%) completed the intervention. Most (75.0%) accessed the website at least once. ACTION was acceptable to participants (Borkovec & Nau Scale: mean = 7.8 [SD = 2.7] out of 10). Signals of effectiveness in favour of the UC + ACTION arm were observed for medication adherence (Adherence Starts with Knowledge questionnaire-12), QoL (work and social adjustment scale), health-related QoL (functional assessment of cancer therapy[FACT] general and FACT-ES-19/23), distress (generalised anxiety disorder -7, patient health questionnaire-9) and psychological flexibility (valuing questionnaire). CONCLUSIONS: The ACTION intervention was acceptable to patients. There were promising signals for effectiveness on primary and secondary outcomes. A phase III randomised controlled trial is feasible. TRIAL REGISTRATION: ISRCTN12027752.

Maternal and newborn plasma oxytocin levels in response to maternal synthetic oxytocin administration during labour, birth and postpartum - a systematic review with implications for the function of the oxytocinergic system.

BACKGROUND: The reproductive hormone oxytocin facilitates labour, birth and postpartum adaptations for women and newborns. Synthetic oxytocin is commonly given to induce or augment labour and to decrease postpartum bleeding. AIM: To systematically review studies measuring plasma oxytocin levels in women and newborns following maternal administration of synthetic oxytocin during labour, birth and/or postpartum and to consider possible impacts on endogenous oxytocin and related systems. METHODS: Systematic searches of PubMed, CINAHL, PsycInfo and Scopus databases followed PRISMA guidelines, including all peer-reviewed studies in languages understood by the authors. Thirty-five publications met inclusion criteria, including 1373 women and 148 newborns. Studies varied substantially in design and methodology, so classical meta-analysis was not possible. Therefore, results were categorized, analysed and summarised in text and tables. RESULTS: Infusions of synthetic oxytocin increased maternal plasma oxytocin levels dose-dependently; doubling the infusion rate approximately doubled oxytocin levels. Infusions below 10 milliunits per minute (mU/min) did not raise maternal oxytocin above the range observed in physiological labour. At high intrapartum infusion rates (up to 32 mU/min) maternal plasma oxytocin reached 2-3 times physiological levels. Postpartum synthetic oxytocin regimens used comparatively higher doses with shorter duration compared to labour, giving greater but transient maternal oxytocin elevations. Total postpartum dose was comparable to total intrapartum dose following vaginal birth, but post-caesarean dosages were higher. Newborn oxytocin levels were higher in the umbilical artery vs. umbilical vein, and both were higher than maternal plasma levels, implying substantial fetal oxytocin production in labour. Newborn oxytocin levels were not further elevated following maternal intrapartum synthetic oxytocin, suggesting that synthetic oxytocin at clinical doses does not cross from mother to fetus. CONCLUSIONS: Synthetic oxytocin infusion during labour increased maternal plasma oxytocin levels 2-3-fold at the highest doses and was not associated with neonatal plasma oxytocin elevations. Therefore, direct effects from synthetic oxytocin transfer to maternal brain or fetus are unlikely. However, infusions of synthetic oxytocin in labour change uterine contraction patterns. This may influence uterine blood flow and maternal autonomic nervous system activity, potentially harming the fetus and increasing maternal pain and stress.

Retrospective analysis of pacritinib in patients with myelofibrosis and severe thrombocytopenia.

Thrombocytopenia is common in patients with myelofibrosis (MF) and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (platelet counts <50×109/L). Pacritinib, a novel JAK2/interleukin-1 receptor-associated kinase 1 inhibitor, has been studied in two phase III trials (PERSIST-1 and PERSIST- 2), both of which enrolled patients with MF and severe thrombocytopenia. In order to better characterize treatment outcomes for this population with advanced disease, we present a retrospective analysis of efficacy and safety data in the 189 patients with severe thrombocytopenia treated in the PERSIST studies. The proportion of patients in the pacritinib group meeting efficacy endpoints was greater than in the BAT group for ≥35% spleen volume reduction (23% vs. 2%, P=0.0007), ≥50% modified Total Symptom Score reduction (25% vs. 8%, P=0.044), and self-reported symptom benefit ("much" or "very much" improved; 25% vs. 8%, P=0.016) at the primary analysis time point (week 24). The adverse event profile of pacritinib was manageable, and dose modification was rarely required. There was no excess in bleeding or death in pacritinib-treated patients. These results indicate that pacritinib is a promising treatment for patients with MF who lack safe and effective therapeutic options due to severe thrombocytopenia.

Maternal plasma levels of oxytocin during physiological childbirth - a systematic review with implications for uterine contractions and central actions of oxytocin.

BACKGROUND: Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies. METHODS: An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n = 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects. RESULTS: Basal levels of oxytocin increased 3-4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin. CONCLUSIONS: Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother's brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does.

Quality of life from the perspective of the patient with acute myeloid leukemia.

BACKGROUND: Although outcomes for acute myeloid leukemia (AML) have improved over time, they remain poor overall, and toxicity from both the disease and its treatment can affect quality of life (QOL). One barrier to including QOL endpoints in clinical trials is the lack of a disease-specific QOL instrument that can efficiently capture the major QOL deficits in this population. METHODS: A cross-sectional study was performed to elicit concepts for inclusion in a new AML-specific QOL instrument called the AML-QOL. Eighty-two patients at various stages of disease were interviewed about sources of support (positive concepts) and problems and symptoms (negative concepts) experienced over the past week, and they were asked to grade how much each affected their QOL. In addition, patients were asked to complete 2 validated instruments: the Functional Assessment of Cancer Therapy with the leukemia and transplant modules and the 29-item Patient-Reported Outcomes Measurement Information System questionnaire. RESULTS: With data from the open-ended and questionnaire-based portions of the interview, 7 positive concepts and 64 negative concepts were elicited. From these, 5 positive concepts and 21 negative concepts were selected for inclusion in the preliminary AML-QOL on the basis of concept prevalence and the impact on QOL. CONCLUSIONS: These concepts will form the basis of a new QOL instrument specific to AML. Cancer 2018;124:145-52. © 2017 American Cancer Society.

PROMIS measures can be used to assess symptoms and function in long-term hematopoietic cell transplantation survivors.

BACKGROUND: Patient-reported outcomes for hematopoietic cell transplantation (HCT) survivors are well characterized with established measures; however, there is little experience with the new, freely available Patient-Reported Outcomes Measurement Information System (PROMIS) measures in this population. The aim of this study was to compare the performance of the PROMIS measures in the HCT setting with the performance of the commonly used 36-Item Short Form Health Survey (SF-36). METHODS: Adult HCT survivors from the Fred Hutchinson Cancer Research Center (n = 4446) were mailed a survey that included the following as part of an annual follow-up survey: the Patient-Reported Outcomes Measurement Information System-Global Health (PROMIS-GH; 10 questions), the 29-Item Patient-Reported Outcomes Measurement Information System Profile (PROMIS-29), and the SF-36. RESULTS: Both the SF-36 and PROMIS measures were available for 1634 HCT recipients (503 autologous recipients and 1131 allogeneic recipients). The overall response rate was 46%. The median time after transplantation for allogeneic and autologous recipients was 12.0 years (range, 0.4-44.1 years) and 6.1 years (range, 0.4-30.1 years), respectively. With the SF-36 or PROMIS-GH, overall physical functioning was somewhat lower in comparison with the general population, but mental functioning was similar. Component and domain scores with similar contents were strongly correlated by Pearson correlation coefficients: the Global Health-Physical and SF-36 Physical Component Summary scores for autologous (r = 0.82) and allogeneic recipients (r = 0.83) and the PROMIS-29 and SF-36 physical function, pain, and vitality/fatigue scores for allogeneic (0.87, -0.82, and -0.82, respectively) and autologous recipients (0.84, -0.82, and -0.81, respectively). The correlation between the Global Health-Mental and SF-36 Mental Component Summary scores was lower (0.70 for autologous recipients and 0.72 for allogeneic recipients). CONCLUSIONS: Physical and mental symptoms and function in autologous and allogeneic HCT survivors can be adequately assessed with PROMIS-29 and PROMIS-GH. Cancer 2018;124:841-9. © 2017 American Cancer Society.

Patient-reported outcomes and health status associated with chronic graft-versus-host disease.

Chronic graft-versus-host disease occurs in 20-50% of allogeneic hematopoietic cell transplant survivors. We surveyed patients about their quality of life, symptoms, health status, comorbid conditions and medications. Instruments included the Short-Form-36 (SF-36), the Patient-Reported Outcomes Measurement Information System (PROMIS) Global and PROMIS-29 scales and the Lee Chronic Graft-versus-Host Disease Symptom Scale. Functional status was measured by self-reported Karnofsky performance status and work status. Of 3027 surveys sent to recipients surviving one or more years after transplantation, 1377 (45%) were returned. Among these, patients reported that their chronic graft-versus-host disease was mild (n=257, 18.7%), moderate (n=110, 8.0%) or severe (n=25, 1.8%). Another 377 (27.4%) had never had chronic graft-versus-host disease and 280 (20.3%) had had chronic graft-versus-host disease but it had resolved. We excluded 328 (23.8%) patients who did not answer the questions about chronic graft-versus-host disease. Patients who reported moderate or severe chronic graft-versus-host disease reported worse quality of life, lower performance status, a higher symptom burden and were more likely to be taking prescription medications for pain, anxiety and depression compared to those with resolved chronic graft-versus-host disease. Self-reported measures were similar between patients with resolved chronic graft-versus-host disease and those who had never had it. Our data suggest that the PROMIS measures may be able to replace the SF-36 in the assessment of chronic graft-versus-host disease. Between 26.7-39.4% of people with active chronic graft-versus-host disease were unable to work due to health reasons, compared with 12.1% whose chronic graft-versus-host disease had resolved and 15.4% who had never had chronic graft-versus-host disease. Mouth, eye and nutritional symptoms persisted after resolution of chronic graft-versus-host disease. These results show that better prevention of and treatment for chronic graft-versus-host disease are needed to improve survivorship after allogeneic transplantation.

No. 355-Physiologic Basis of Pain in Labour and Delivery: An Evidence-Based Approach to its Management.

OBJECTIVE: To review the evidence relating to nonpharmacological approaches in the management of pain during labour and delivery. To formulate recommendations for the usage of nonpharmacological approaches to pain management. OPTIONS: Nonpharmacological methods available for pain management during labour and delivery exist. These should be included in the counselling and care of women. EVIDENCE: PubMed and Medline were searched for articles in French and English on subjects related to "breastfeeding," "pain," "epidural," "anaesthesia," "analgesia," "labour," "labor," and combined with "gate control theory," "alternative therapies," "massage," "position," "mobility," "TENS," "bathing," "DNIC," "acupuncture," "acupressure," "sterile water injection," "higher center," "control mind," "cognitive structuring," "holistic health," "complementary therapy(ies)," "breathing," "relaxation," "mental imagery," "visualization," "mind focusing," "hypnosis," "auto-hypnosis," "sophrology," "mind and body interventions," "music," "odors," "biofeedback," "Lamaze," "Bonapace," "prenatal training," "gymnastic," "chanting," "haptonomy," "environment," "transcutaneous electrical stimulus-stimulation," "antenatal education," "support," "continuous support," "psychosocial support," "psychosomatic medicine," "supportive care," "companion," "intrapartum care," "nurse," "midwife(ves)," "father," "doula," "caregiver," " hormones," "oxytocin," "endorphin," "prolactin," "catecholamine," "adrenaline," and "noradrenaline" from 1990 to December 2015. Additional studies were identified by screening reference lists from selected studies and from expert suggestions. No language restrictions were applied. VALIDATION METHODS: The quality of the evidence is rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice are ranked according to the method described in this report. BENEFITS, RISKS, AND COST: The nonpharmacological method encourages an incremental approach to pain management that contributes to reduced interventions through optimal use of the woman's neurophysiologic and endocrine resources and a better understanding of the physiology of stress and pain during labour. GUIDELINE UPDATE: The guideline will be reviewed 5 years after publication to decide whether all of part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycles, the review process may be accelerated for a more rapid update of some recommendations. SPONSORS: This guideline was developed with resources funded by The Society of Obstetricians and Gynaecologists of Canada. SUMMARY STATEMENTS: RECOMMENDATIONS.

Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis.

Minimal residual disease prior to allogeneic hematopoietic cell transplantation has been associated with increased risk of relapse and death in patients with acute myeloid leukemia, but detection methodologies and results vary widely. We performed a systematic review and meta-analysis evaluating the prognostic role of minimal residual disease detected by polymerase chain reaction or multiparametric flow cytometry before transplant. We identified 19 articles published between January 2005 and June 2016 and extracted hazard ratios for leukemia-free survival, overall survival, and cumulative incidences of relapse and non-relapse mortality. Pre-transplant minimal residual disease was associated with worse leukemia-free survival (hazard ratio=2.76 [1.90-4.00]), overall survival (hazard ratio=2.36 [1.73-3.22]), and cumulative incidence of relapse (hazard ratio=3.65 [2.53-5.27]), but not non-relapse mortality (hazard ratio=1.12 [0.81-1.55]). These associations held regardless of detection method, conditioning intensity, and patient age. Adverse cytogenetics was not an independent risk factor for death or relapse. There was more heterogeneity among studies using flow cytometry-based than WT1 polymerase chain reaction-based detection (I2=75.1% vs. <0.1% for leukemia-free survival, 67.8% vs. <0.1% for overall survival, and 22.1% vs. <0.1% for cumulative incidence of relapse). These results demonstrate a strong relationship between pre-transplant minimal residual disease and post-transplant relapse and survival. Outcome heterogeneity among studies using flow-based methods may underscore site-specific methodological differences or differences in test performance and interpretation.

Historical spatial reconstruction of a spawning-aggregation fishery.

Aggregations of individual animals that form for breeding purposes are a critical ecological process for many species, yet these aggregations are inherently vulnerable to exploitation. Studies of the decline of exploited populations that form breeding aggregations tend to focus on catch rate and thus often overlook reductions in geographic range. We tested the hypothesis that catch rate and site occupancy of exploited fish-spawning aggregations (FSAs) decline in synchrony over time. We used the Spanish mackerel (Scomberomorus commerson) spawning-aggregation fishery in the Great Barrier Reef as a case study. Data were compiled from historical newspaper archives, fisher knowledge, and contemporary fishery logbooks to reconstruct catch rates and exploitation trends from the inception of the fishery. Our fine-scale analysis of catch and effort data spanned 103 years (1911-2013) and revealed a spatial expansion of fishing effort. Effort shifted offshore at a rate of 9.4 nm/decade, and 2.9 newly targeted FSAs were reported/decade. Spatial expansion of effort masked the sequential exploitation, commercial extinction, and loss of 70% of exploited FSAs. After standardizing for improvements in technological innovations, average catch rates declined by 90.5% from 1934 to 2011 (from 119.4 to 11.41 fish/vessel/trip). Mean catch rate of Spanish mackerel and occupancy of exploited mackerel FSAs were not significantly related. Our study revealed a special kind of shifting spatial baseline in which a contraction in exploited FSAs occurred undetected. Knowledge of temporally and spatially explicit information on FSAs can be relevant for the conservation and management of FSA species.

Number of courses of induction therapy independently predicts outcome after allogeneic transplantation for acute myeloid leukemia in first morphological remission.

Whether the number of chemotherapy cycles required to obtain a first morphological remission affects prognosis of patients with acute myeloid leukemia (AML) remains controversial. To clarify how achievement of early remission might influence outcome of allogeneic hematopoietic cell transplantation (HCT), we studied 220 consecutive adults with AML in first morphological remission who underwent transplantation after myeloablative or nonmyeloablative conditioning to investigate how the number of standard- or high-dose induction courses required to achieve remission impacted post-HCT outcome. Three-year estimates of overall survival were 65% (95% confidence interval [CI] 56% to 73%), 56% (95% CI, 43% to 67%), and 23% (95% CI, 6% to 46%) for patients requiring 1 course, 2 courses, or >2 courses of induction therapy; corresponding relapse estimates were 24% (95% CI, 17% to 31%), 43% (95% CI, 31% to 55%), and 58% (95% CI, 30% to 78%), respectively. After covariate adjustment (minimal residual disease status, conditioning, age, cytogenetic disease risk, type of consolidation chemotherapy, pre-HCT karyotype, and pre-HCT peripheral blood count recovery), the hazard ratios for 2 or >2 induction courses versus 1 induction were 1.16 (95% CI, .73 to 1.85, P = .53) and 2.63 (95% CI, 1.24 to 5.57, P = .011) for overall mortality, and 2.10 (95% CI, 1.27 to 3.48, P = .004) and 3.32 (95% CI, 1.42 to 7.78, P = .006), respectively, for relapse. These findings indicate that the number of induction courses required to achieve morphological remission in AML adds prognostic information for post-HCT outcome that is independent of other prognostic factors.

A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age.

Outcomes for older adults with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are generally poor, and new effective therapies are needed. We investigated oral clofarabine combined with low-dose cytarabine (LDAC) in patients aged 60 years and above with relapsed or refractory AML or high-risk MDS in a phase I/II trial. A 3 + 3 dose escalation of oral clofarabine was followed by a phase II expansion with the aim of obtaining a complete response (CR) rate ≥30%. We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. A total of 35 patients, with a median age of 72 years, were treated. Of 26 patients enrolled at the MTD, 4 had treatment-related grade 3-4 non-haematological toxicities, but none died within 28 d. The observed CR rate and median survival were 34% [95% confidence interval (CI), 18-50%] and 6.8 months overall and 38% [95% CI, 19-57%] and 7.2 months at the MTD. The median disease-free survival was 7.4 months. Fifty-two percent (23/44) of cycles administered at the MTD were done without hospital admission. This combination of oral clofarabine and LDAC demonstrated efficacy with a CR rate of >30% and acceptable toxicity in older patients.

Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission.

Minimal residual disease (MRD) before myeloablative hematopoietic cell transplantation (HCT) is associated with adverse outcome in acute myeloid leukemia (AML) in first complete remission (CR1). To compare this association with that for patients in second complete remission (CR2) and to examine the quantitative impact of MRD, we studied 253 consecutive patients receiving myeloablative HCT for AML in CR1 (n = 183) or CR2 (n = 70) who had pre-HCT marrow aspirates analyzed by 10-color flow cytometry. Three-year estimates of overall survival were 73% (64%-79%) and 32% (17%-48%) for MRDneg and MRDpos CR1 patients, respectively, and 73% (57%-83%) and 44% (21%-65%) for MRDneg and MRDpos CR2 patients, respectively. Similar estimates of relapse were 21% (14%-28%) and 58% (41%-72%) for MRDneg and MRDpos CR1 patients, respectively, and 19% (9%-31%) and 68% (41%-85%) for MRDneg and MRDpos CR2 patients, respectively. Among the MRDpos patients, there was no statistically significant evidence that increasing levels of MRD were associated with increasing risks of relapse and death. After multivariable adjustment, risks of death and relapse were 2.61 times and 4.90 times higher for MRD(pos) patients (P < .001). Together, our findings indicate that the negative impact of pre-HCT MRD is similar for AML in CR1 and CR2 with even minute levels (≤ 0.1%) as being associated with adverse outcome.

Prediction of adverse events during intensive induction chemotherapy for acute myeloid leukemia or high-grade myelodysplastic syndromes.

Intensive chemotherapy for newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) is associated with significant treatment-related morbidity and mortality. Herein, we investigate how pretreatment characteristics relate to early adverse outcomes in such patients, studying 205 consecutive individuals receiving curative-intent induction chemotherapy with cytarabine and an anthracycline ("7 + 3"; n = 175) or a "7 + 3"-like regimen (n = 30). Among the entire cohort, baseline grade 4 neutropenia (i.e., absolute neutrophil count <500 cells/µL) was associated with development of fever (P = 0.04), documented infection (P < 0.0001), and bacteremia (P = 0.002) but not requirement for intensive care unit-level care; after exclusion of the 30 patients who received "7 + 3"-like induction, baseline grade 4 neutropenia remained associated with documented infection (P < 0.0001) and bacteremia (P = 0.0005). Among patients achieving a complete remission with the initial treatment cycle, grade 4 neutropenia was associated with delayed neutrophil count recovery (P < 0.0001). Low monocyte and lymphocyte counts at baseline were similarly associated with increased risk of documented infection or bacteremia. After adjustment for age, gender, disease type, cytogenetic/molecular risk, and performance status, the risk of fever, documented infection, or bacteremia was 1.87 (95% confidence interval: 1.04-3.34; P=0.04)-fold, 4.95 (2.20-11.16; P<0.001)-fold, and 3.14 (0.99-9.98; P=0.05)-fold higher in patients with initial grade 4 neutropenia. Together, our studies identify severe baseline neutropenia as a risk factor for infection-associated adverse events after induction chemotherapy and may provide the rationale for the risk-adapted testing of myeloid growth factor support in this high-risk AML/MDS patient subset.

Pacritinib is a potent ACVR1 inhibitor with significant anemia benefit in patients with myelofibrosis.

In patients with cytopenic myelofibrosis, treatment with the JAK2/IRAK1 inhibitor pacritinib was associated with anemia benefit in the phase 3 PERSIST-2 study. The impact of pacritinib on transfusion independence (TI) has not been previously described, nor has the mechanism by which pacritinib improves anemia been elucidated. Because it has been previously postulated that inhibition of activin A receptor, type 1 (ACVR1)/activin receptor-like kinase-2 improves anemia in patients with myelofibrosis via suppression of hepcidin production, we assessed the relative inhibitory potency of pacritinib compared with other JAK2 inhibitors against ACVR1. Pacritinib inhibited ACVR1 with greater potency (half-maximal inhibitory concentration [IC50] = 16.7 nM; Cmax:IC50 = 12.7) than momelotinib (IC50 = 52.5 nM; Cmax:IC50 = 3.2), fedratinib (IC50 = 273 nM; Cmax:IC50 = 1.0), or ruxolitinib (IC50 > 1000; Cmax:IC50 < 0.01). Pacritinib's inhibitory activity against ACVR1 was corroborated via inhibition of downstream SMAD signaling in conjunction with marked suppression of hepcidin production. Among patients on PERSIST-2 who were not transfusion independent at baseline based on Gale criteria, a significantly greater proportion achieved TI on pacritinib compared with those treated on best available therapy (37% vs 7%, P = .001), and significantly more had a ≥50% reduction in transfusion burden (49% vs 9%, P < .0001). These data indicate that the anemia benefit of the JAK2/IRAK1 inhibitor pacritinib may be a function of potent ACVR1 inhibition.

Risk-adjusted safety analysis of the oral JAK2/IRAK1 inhibitor pacritinib in patients with myelofibrosis.

The safety profile of the novel oral JAK2/IRAK1 inhibitor pacritinib in patients with cytopenic myelofibrosis was described in the Phase 2 PAC203 and Phase 3 PERSIST-2 studies. To account for longer treatment durations on the pacritinib arms compared to best available therapy (BAT), we present a risk-adjusted safety analysis of event rates accounting for different time on treatment. While the rate of overall events was higher on pacritinib compared to BAT, the rate of fatal events was lower, and there was no excess in bleeding, cardiac events, secondary malignancy, or thrombosis on pacritinib, including in patients with severe thrombocytopenia.