Risk and adverse clinical outcomes of thrombocytopenia among patients with solid tumors-a Danish population-based cohort study.

BACKGROUND: Knowledge about thrombocytopenia among patients with solid tumors is scarce. We examined the risk of thrombocytopenia among patients with solid tumors and its association with adverse outcomes. METHODS: Using Danish health registries, we identified all patients with incident solid tumors from 2015-2018 (n = 52,380) and a platelet count measurement within 2 weeks prior to or on their cancer diagnosis date. The risk of thrombocytopenia was categorized as grades 0 (any platelet count × 109/L): <150; 1: <100; 2: <75; 3: <50; 4: <25, and 5: <10. To study the outcomes, each patient with thrombocytopenia was matched with up to five cancer patients without thrombocytopenia by age, sex, cancer type, and stage. Cox regression was used to compute hazard ratios (HRs) of bleeding, transfusion, or death, adjusting for confounding factors. RESULTS: The 1-year risk of thrombocytopenia was 23%, increasing to 30% at 4 years. This risk was higher in patients receiving chemotherapy (43% at 1 year and 49% at 4 years). Overall, patients with thrombocytopenia had higher 30-days rates of bleeding (HR = 1.72 [95% confidence interval, CI: 1.41-2.11]). Thrombocytopenia was also associated with an increased rate of transfusion, and death, but some of the risk estimates were imprecise. CONCLUSIONS: The risk of thrombocytopenia was substantial among patients with solid tumors and associated with adverse outcomes.

Romiplostim use in pregnant women with immune thrombocytopenia.

Treatment for immune thrombocytopenia (ITP) in pregnancy is hampered by the lack of fetal safety evidence of maternally-administered medications. The Pregnancy Surveillance Program (PSP) collected patient information from 2017-2020 for pregnancy, birth outcomes, and adverse events (AEs) for 186 women exposed to romiplostim from 20 days before pregnancy to the end of pregnancy. Timing of exposure was available in 128 women. Seventy-one mothers (38%) had prepregnancy exposure to romiplostim; intrapartum exposure was known for the first (for many mothers when they discovered their pregnancy), second, and third trimesters for 74 (40%), 22 (12%), and 44 (24%) mothers, respectively, with 15 mothers exposed during >1 trimester. Among the 86 mothers with known pregnancy outcomes, 46 (53%) had at least one pregnancy-related serious AE (SAE); approximately 2/3 of SAEs were due to underlying ITP. Of 92 mothers with known birth outcomes, 60 (65%) had a normal pregnancy and 16 (17%) had complications, with both categories including term and preterm births; there were 12 (14%) spontaneous miscarriages/stillbirths, 3 (3%) ectopic pregnancies, and 1 (1%) molar pregnancy. Most abnormal births resulted from abnormal pregnancies. There were five neonatal/postnatal AEs of note: inguinal hernia, cytomegalovirus infection, trisomy 8 (third trimester single-dose romiplostim exposure), single umbilical artery without known anomalies, and development of autism at age 2 years. Seven of 12 infants with neonatal thrombocytopenia had resolution of thrombocytopenia before discharge; all 12 were discharged. Review of pregnancies in women exposed to romiplostim did not reveal any specific safety concerns for mothers, fetuses, or infants.

Assessment of Bone Health Awareness and Education in Breast Cancer Patients with Bone Metastasis in the USA.

Bone metastases are common in advanced breast cancer (BC) patients and increase the risk for skeletal-related events (SREs), which present a significant health and economic burden. Bone targeting agents (BTAs) can improve health-related quality of life by delaying or preventing SREs; nevertheless, a significant portion of eligible BC patients are not receiving this therapy. A bone health education needs assessment survey was conducted to examine cancer-related bone health awareness and to identify opportunities to improve bone health education. Direct-to-patient outreach was used to recruit adult BC patients in the USA self-reporting a diagnosis of bone metastasis within the past 3 years. Of the 200 patients, 59% experienced at least one SRE prior to survey participation (44% radiation to bone, 29% bone fracture, 17% spinal cord compression, 15% surgery to bone), and 83% were currently receiving a BTA. Awareness of general cancer bone health, protection strategies against SREs, and screening tests were low to moderate. Patients currently not receiving a BTA were least knowledgeable about cancer bone health, with only 40% aware of BTAs as a protective strategy, and only 26% were very or extremely satisfied with the information received from healthcare providers. Sixty-two percent of patients wanted to receive information by more than one mode of communication. Notable gaps in bone health education were observed in bone metastatic BC patients at risk for SREs, suggesting the need for earlier and more effective communication and education strategies to promote appropriate BTA use and better health outcomes.

Relative Dose Intensity of Chemotherapy and Survival in Patients with Advanced Stage Solid Tumor Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Chemotherapy-induced toxicities lead to therapy dose reduction or delay, affecting patient outcomes. This systematic review and meta-analysis evaluated the impact of relative dose intensity (RDI) on survival in adult patients with solid tumor cancer on nonadjuvant-based chemotherapy regimens. METHODS: PubMed, Embase, and Web of Science databases were searched for peer-reviewed English journal articles or congress abstracts evaluating association between RDI and survival; observational studies, case series of ≥20 patients, and clinical trials published between 2013 and 2020 were eligible. Meta-analyses were conducted to quantify the association between RDI levels and overall survival (OS) among studies reporting a hazard ratio (HR) for OS by similar tumor types, regimens, and RDI. Forest plots represented summary HR and 95% confidence interval (CI); Cochran's Q and I2 tests evaluated study heterogeneity. RESULTS: Overall, 919 articles were reviewed and 22 included; seven were eligible for meta-analysis. Significantly shorter OS at RDI <80% versus ≥80% and <85% versus ≥85% was observed upon meta-analysis of four carboplatin-based studies for breast, non-small cell lung, or ovarian cancer (HR 1.17; 95% CI: 1.07-1.27) and three FOLFOX-, FOLFIRI-, or FOLFIRINOX-based studies for colorectal or pancreatic cancer (HR 1.39; 95% CI: 1.03-1.89). Grade 3 or higher hematologic toxicities were higher for carboplatin-based regimens (thrombocytopenia: 14%-22%; anemia: 15%-19%; neutropenia: 24%-58%) than FOLFOX-, FOLFIRI-, or FOLFIRINOX-based regimens (thrombocytopenia: 1%-4%; anemia: 5%-19%; neutropenia: 19%-47%). CONCLUSION: The results suggested longer OS with RDI ≥80% or ≥85% for both regimens, indicating that management of toxicities across treatment modalities may contribute to maintenance of higher RDI and benefit survival for patients with advanced solid tumors. IMPLICATIONS FOR PRACTICE: Chemotherapy-induced toxicities lead to dose reduction and/or treatment delay, thus affecting patient outcomes. Results of this systematic review and meta-analysis, evaluating the impact of relative dose intensity (RDI) on survival of patients with solid tumors on nonadjuvant-based chemotherapy regimens, demonstrate a longer overall survival with RDI levels of at least 80% for patients with solid tumors on carboplatin-based and FOLFOX-, FOLFIRI-, or FOLFIRINOX-based chemotherapy regimens, suggesting a protective effect of maintaining RDI ≥80% or ≥ -85%. Although grade 3 or higher hematologic toxicities occurred more in carboplatin-based studies, managing toxicities across treatment regimens may contribute to maintenance of higher RDI and ultimately benefit overall survival.

Identified unmet needs and proposed solutions in mild-to-moderate haemophilia: A summary of opinions from a roundtable of haemophilia experts.

INTRODUCTION: The experiences of patients with mild-to-moderate haemophilia differ from those of patients with severe haemophilia or those without a bleeding disorder and include a challenging diagnosis and variability in bleeding symptoms and treatment needs. In addition, there is a significant lack of data on mild-to-moderate haemophilia, and many unmet needs remain to be identified and addressed in this group of patients. METHODS: Challenges for these patients, including women with haemophilia, were identified during a roundtable meeting attended by a group of US-based experts including healthcare professionals (e.g., physicians, nurses, and physical therapists) and patients who live with a bleeding disorder. RESULTS: Identified unmet needs included a lack of proper education on the management of their disorder and prompt treatment of bleeds, absenteeism from school and work, and challenges with personal relationships. Initiatives to assist with alleviating these unmet needs were proposed and include suggestions for healthcare professionals, haemophilia treatment centres (HTCs) and national and local organizations within the bleeding disorders community. These included HTC and community engagement programmes for patients with mild-to-moderate haemophilia, revised transition guidelines for these patients as they approach adulthood and revised diagnostic classification of mild and moderate haemophilia. Challenges unique to women with haemophilia and ways to address these issues were also discussed. CONCLUSION: This paper summarizes the challenges, initiatives and suggestions that were identified by the haemophilia experts during the roundtable meeting.

Immune thrombocytopenia: Pathophysiology and impacts of Romiplostim treatment.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disease caused by immune-mediated platelet destruction and decreased platelet production. ITP is characterized by an isolated thrombocytopenia (<100 × 109/L) and increased risk of bleeding. The disease has a complex pathophysiology wherein immune tolerance breakdown leads to platelet and megakaryocyte destruction. Therapeutics such as corticosteroids, intravenous immunoglobulins (IVIg), rituximab, and thrombopoietin receptor agonists (TPO-RAs) aim to increase platelet counts to prevent hemorrhage and increase quality of life. TPO-RAs act via stimulation of TPO receptors on megakaryocytes to directly stimulate platelet production. Romiplostim is a TPO-RA that has become a mainstay in the treatment of ITP. Treatment significantly increases megakaryocyte maturation and growth leading to improved platelet production and it has recently been shown to have additional immunomodulatory effects in treated patients. This review will highlight the complex pathophysiology of ITP and discuss the usage of Romiplostim in ITP and its ability to potentially immunomodulate autoimmunity.

Treatment Patterns of Bone-targeting Agents Among Solid Tumor Patients With Bone Metastases: An Analysis of Electronic Health Record Data in the United States From 2014 to 2018.

OBJECTIVES: This study evaluated real-world treatment patterns of approved bone-targeting agents (BTAs) with various mechanisms of action-pamidronate, zoledronic acid, and denosumab-for the prevention of skeletal-related events in patients with bone metastases (BM) from solid tumors. METHODS: Adult patients with BM secondary to solid tumors between January 1, 2014, and December 31, 2018, were identified from the Flatiron Health Oncology Services Comprehensive Electronic Records database and categorized by BTA use and therapy type. Time from diagnosis to initiation, persistence (mean time on treatment), and compliance (≥12 administrations/year) with BTA with up to 4 years of follow-up were examined. RESULTS: This study included 27,268 patients with BM (breast cancer, 32.7%; lung cancer, 16.5%; prostate cancer, 17.2%; and other solid tumors, 33.6%); of these, 41.4% initiated denosumab after BM diagnosis; 21.3%, zoledronic acid; 0.6%, pamidronate; and 36.7% had no treatment record. Mean (SD) time to initiation for denosumab or zoledronic acid was 68.6 (157.0) days (denosumab, 70.3 (160.4) days; zoledronic acid, 65.2 [150.2] days). Mean persistence and compliance (first year of treatment) were significantly higher for denosumab than for zoledronic acid (22.0 vs. 14.9 mo [ P <0.0001] and 42.3% vs. 34.8% [ P <0.0001], respectively). Treatment compliance was the highest in patients with breast cancer (denosumab, 48.2%; zoledronic acid, 39.1%). CONCLUSION: Real-world BTA treatment patterns in the United States suggest that over one-third of patients with BM secondary to solid tumors remain untreated and less than 50% of the patients received ≥12 administrations/year of BTA therapy.

Accurate Posterior Fossa Decompression Technique for Chiari Malformation Type I and a Syringomyelia With Navigation: A Technical Note.

BACKGROUND: Posterior fossa decompression (PFD) has been widely accepted for the surgical treatment for Chiari malformation type I (CM1). However, inadequate decompression causes surgical mortality and complications such as cerebrospinal fluid leakage, meningitis, or progression of syrinx and symptoms. The authors report a novel technique of PFD under navigation. METHODS: Five female patients with CM1 who developed severe symptoms and underwent surgical treatment were evaluated (mean age 14.0 years; mean follow-up 1.3 years). Surgical outcomes, surgical time, intraoperative blood loss, and operative complications were assessed. RESULTS: Four patients with CM1 who developed severe symptoms and underwent surgery were evaluated (mean age 14 years; mean follow-up 1.2 years). All patients were treated with PFD, C1 (and partial C2) laminoplasty to decompress the spinal cord under navigation guidance. Suboccipital craniectomy with 3 cm in diameter around the foramen magnum was performed. The postoperative radiograms and computed tomographic images showed adequate bony resection for CM1. Average surgical time was 114 minutes and average blood loss was 82 mL. There were no postoperative complications. After surgery, the numbness and muscle weakness of the patients were improved. The final follow-up magnetic resonance imaging displayed a good decompression of cerebral tonsile, and cervical syringomyelia was decreased. CONCLUSIONS: PFD under navigation guidance can reduce inappropriate decompression and may decrease a revision surgery. During decompression surgery, cerebrospinal fluid leakage can be prevented using an ultrasonic bone cutter and navigation.

Risk factors associated with skeletal-related events following discontinuation of denosumab treatment among patients with bone metastases from solid tumors: A real-world machine learning approach.

Background: Clinical practice guidelines recommend the use of bone-targeting agents for preventing skeletal-related events (SREs) among patients with bone metastases from solid tumors. The anti-RANKL monoclonal antibody denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors. However, real-world data are lacking on the impact of individual risk factors for SREs, specifically in the context of denosumab discontinuation. Purpose: We aim to identify risk factors associated with SRE incidence following denosumab discontinuation using a machine learning approach to help profile patients at a higher risk of developing SREs following discontinuation of denosumab treatment. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. Results: A total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19-89) years with a median duration of denosumab treatment of 253 (range, 88-2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer. Conclusion: This analysis showed a higher cumulative number of SREs, prior SREs relative to denosumab initiation, a higher number of hospital visits, and a shorter denosumab treatment duration as significant factors that are associated with an increased SRE risk after discontinuation of denosumab, in both the tumor-agnostic and tumor-specific models. Our machine learning approach to SRE risk factor identification reinforces treatment guidance on the persistent use of denosumab and has the potential to help clinicians better assess a patient's need to continue denosumab treatment and improve patient outcomes.

Disease Burden in Patients with Glanzmann's Thrombasthenia: Perspectives from the Glanzmann's Thrombasthenia Patient/Caregiver Questionnaire.

PURPOSE: Glanzmann's thrombasthenia (GT) is a rare bleeding disorder caused by a mutation in the αIIbß3 integrin essential for optimal platelet function and hemostasis. The aim of this study was to identify the burden of GT on patients and caregivers through better understanding of the management and psychosocial impact of this disorder. PATIENTS AND METHODS: Participants for this online survey were recruited using a rare disease specialty recruiter from Comprehensive Health Education Services. Data were collected from January 31 through March 12, 2019. The questionnaire was designed to collect information regarding demographics, diagnosis, treatment, and psychosocial impact. RESULTS: Of the 45 respondents (24 patients and 21 caregivers), the majority were female (58%), white (64%), and employed full-time (53%) and had no family history of GT (64%). Many patients reported significant bruising at birth (76%), and the mean age at diagnosis was 2.6 years. About half of the patients experienced 1 bleed per day, and 13% had over 500 bleeds of any severity per year. Most bleeds were skin bruising or mouth bleeds, but patients also reported joint/muscle and gastrointestinal bleeds. Most patients reported receiving a platelet transfusion (82%), and some had developed platelet refractoriness (38%) or antibodies (32%). Common treatments were antifibrinolytics (82%) and recombinant activated factor VII (rFVIIa) (42%), likely due to the presence of antibodies. Many (58%) patients experienced issues with excessive bleeding at school; 38% reported missing school as a result. Female patients struggled to find a gynecologist with knowledge of the management of GT. Most patients were satisfied with the support they receive from their current partner (65%) and their friends (76%). CONCLUSION: Most patients with GT are diagnosed early. Patients experience considerable psychosocial impact. Patient and physician education concerning treatment alternatives and the support of the GT community are critical.

Psychosocial Impact and Disease Management in Patients with Congenital Factor VII Deficiency.

PURPOSE: Congenital factor VII (FVII) deficiency is a rare bleeding disorder of variable phenotype with predominantly mucocutaneous bleeding. The aim of this study was to identify the burden of FVII deficiency on patients and caregivers through a better understanding of the management and psychosocial impact of this disease. MATERIALS AND METHODS: A rare disease specialty recruiter from Comprehensive Health Education Services recruited participants for this online survey, which was conducted from January 31 to March 12, 2019. A moderator-assisted questionnaire was used to collect data on demographics, diagnosis, treatment, and psychosocial impact. RESULTS: Of the 45 respondents (25 patients and 20 caregivers), the majority were female (56%). Respondents reported a wide variety of initial bleeding symptoms, including bruising (58%), epistaxis (56%), and menorrhagia (36% of females). Because symptoms varied between individuals and were not always severe, diagnosis was often delayed. Mean time to obtain a diagnosis was 6.5 years and mean age at first diagnosis was 12.9 years. One-quarter (24%) of the respondents reported more than 100 bleeds of any severity over the previous year. When treating bleeds, 44% of patients reported using antifibrinolytics, and 42% reported using recombinant activated factor VII. Almost 31% of respondents reported missing schooldays as children, and 16% reported losing or resigning from a job in adulthood as a direct result of their disease. Notably, 29% of caregivers and 10% of their partners had also experienced issues with employment. Forty percent of respondents reported not participating in contact sports during childhood, and 22% continued to avoid contact sports in adulthood. CONCLUSION: Overall, FVII deficiency has a substantial psychosocial impact, but most patients are satisfied with their disease management and are optimistic about their future. Patients desire additional educational, social, and financial support.

Hemophilia and sexual health: results from the HERO and B-HERO-S studies.

BACKGROUND: Sexual health plays a primary role in quality of life (QoL) for many people, including those with hemophilia; however, there is little information available about sexual relationships and satisfaction in patients with hemophilia. METHODS: To address this issue, the Hemophilia Experiences, Results and Opportunities (HERO) and the Bridging Hemophilia B Experiences, Results and Opportunities into Solutions (B-HERO-S) studies included questions from the Male Sexual Health Questionnaire (MSHQ). RESULTS: Although these data were not statistically analyzed for comparisons between the 3 populations (HERO, HERO US only, and B-HERO-S), in general, participants in the HERO survey appeared to be more satisfied with their sexual relationship than participants in the B-HERO-S survey. In addition, many patients, especially those outside the United States, reported that they had not discussed sexual health with their doctor or other members of the hemophilia treatment center team. While the topic of sexual health has been infrequently explored in men with hemophilia, this is the first time it has been investigated in women with hemophilia. CONCLUSION: The results of these studies demonstrate that the impact of hemophilia extends to intimacy and suggest the need for large-scale studies in additional countries to explore further the factors associated with sexual health issues in people with hemophilia.

HAEMOcare: The First International Epidemiological Study Measuring Burden of Hemophilia in Developing Countries.

Introduction Optimizing hemophilia care remains challenging in developing countries. Burden-of-disease studies are important to develop strategies for improving hemophilia care. Aim The HAEMOcare study evaluated the factors contributing to hemophilia-related orthopedic disease burden in developing countries. Methods HAEMOcare was a noninterventional, cross-sectional, epidemiological study conducted in Algeria, India, Morocco, Oman, and South Africa. Male patients with severe hemophilia ( N = 282) aged ≥6 years, without or with inhibitors, being treated on-demand for bleeding were included. Hemophilia-related orthopedic clinical and functional status was assessed using the Hemophilia Joint Health Score (HJHS), radiological status with the Pettersson Score, and quality of life with the EuroQol five-dimension questionnaire (EQ-5D-3L). Direct and indirect economic costs of hemophilia care were also calculated. Results Patients (mean [standard deviation, SD] age: 20.8 [10.6] years) experienced a mean annualized bleeding rate of 25.8. Overall mean (SD) HJHS and Pettersson score were 17.9 (12.8) and 15.0 (13.5), respectively; scores were similar between patients without or with inhibitors ( p = 0.21 and 0.76, respectively). Approximately 70% of adults reported problems relating to pain/discomfort and mobility parameters in the EQ-5D-3L. Mean distance to a hemophilia treatment center (HTC) was 79.4 km. As expected, total costs of hemophilia were statistically significantly higher in patients with inhibitors versus without inhibitors ( p = 0.002). Conclusion Inadequate access to HTCs and expert care, along with high bleeding rates, led to equivalent hemophilia-related orthopedic morbidity between hemophilia patients without and with inhibitors. HAEMOcare documented the economic and disease burdens associated with suboptimal hemophilia care in developing countries.

Home treatment of haemarthrosis with recombinant activated factor VII in patients with haemophilia A or B and inhibitors: experience from developing countries.

Home therapy for uncomplicated mild/moderate bleeding can decrease healthcare burden, promote self-esteem, reduce complications, and provide near-normal quality of life. To evaluate recombinant activated factor VII (rFVIIa) as home therapy for joint bleeds in Algeria, Morocco, Oman, Saudi Arabia, and United Arab Emirates. Twenty-seven patients aged more than 2 years with congenital haemophilia and inhibitors were monitored for up to 8 months after a first haemarthrosis episode treated with rFVIIa. Assessments were made by patients/caregivers with a standardized diary. The main measures included home-managed bleeds, haemostasis, and pain relief within 9 h after first injection. Additional analyses included convenience, time to pain resolution, and doses given within 48 h. Of 132 bleeds, 84 (63.6%) were managed at home. Of these, successful haemostasis (partial or complete) was achieved at 9 h in 87.8%, with pain relief for 84.0%. For all treatment settings, successful haemostasis at 9 h was achieved for 86.3% of bleeds, with pain relief achieved for 74.8% of bleeds. Higher initial dosing was associated with fewer injections. Median time to complete haemostasis was 48 h (spontaneous bleeds) and 24 h (traumatic bleeds). Median time to complete pain relief was 24 h for both bleed types. Satisfaction with treatment was high. No safety concerns were reported. Results from this observational study agree with previous data on the safety and efficacy of home treatment with rFVIIa and will help to increase awareness and aggregate experience, fostering confidence in home management of haemophilia patients with inhibitors in developing countries.