Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years.

BACKGROUND: Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality. PROCEDURE: The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6 months to 17 years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11 years who received voxelotor treatment for up to 48 weeks are reported. RESULTS: Hemoglobin (Hb) response, defined as a >1.0 g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5 g/dl increase and a >2.0 g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed. Voxelotor was well tolerated in this young cohort, with no newly emerging safety signals. CONCLUSIONS: Based on its mechanism as an HbS polymerization inhibitor, voxelotor improves Hb levels and markers of hemolysis and has the potential to mitigate SCD-related complications; these results support its use in patients aged ≥4 years.

A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease.

New treatments directly targeting polymerization of sickle hemoglobin (HbS), the proximate event in the pathophysiology of sickle cell disease (SCD), are needed to address the severe morbidity and early mortality associated with the disease. Voxelotor (GBT440) is a first-in-class oral therapy specifically developed to treat SCD by modulating the affinity of hemoglobin (Hb) for oxygen, thus inhibiting HbS polymerization and downstream adverse effects of hemolytic anemia and vaso-occlusion. GBT440-001 was a phase 1/2 randomized, double-blind, placebo-controlled, single and multiple ascending dose study of voxelotor in adult healthy volunteers and patients with SCD, followed by a single-arm, open-label extension study. This report describes results of voxelotor (500-1000 mg per day) in patients with sickle cell anemia. The study evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of voxelotor and established proof of concept by improving clinical measures of anemia, hemolysis, and sickling. Thirty-eight patients with SCD received 28 days of voxelotor 500, 700, or 1000 mg per day or placebo; 16 patients received 90 days of voxelotor 700 or 900 mg per day or placebo. Four patients from the 90-day cohort were subsequently enrolled in an extension study and treated with voxelotor 900 mg per day for 6 months. All patients who received multiple doses of voxelotor for ≥28 days experienced hematologic improvements including increased Hb and reduction in hemolysis and percentage of sickled red cells, supporting the potential of voxelotor to serve as a disease-modifying therapy for SCD. Voxelotor was well tolerated with no treatment-related serious adverse events and no evidence of tissue hypoxia. These trials were registered at www.clinicaltrials.gov as #NCT02285088 and #NCT03041909.

Multicentre review of readmission rates within 30 days of discharge following lung cancer surgery.

Postoperative complications following curative lung cancer surgery are well recognised, but there is limited data on 30-day readmission rates. The UK Thoracic Surgery Group conducted a multicentre review over a 3-month period to assess readmission rates. Overall readmission among the 268 patients who had undergone primary lung cancer surgery was 30 (11%); 14/30 of readmissions occurred within 7 days of discharge, with 13/30 patients readmitted to a hospital that had not performed the surgery. The causes of readmission were mainly pulmonary related (16/30). Readmission was associated with being discharged with a pleural drain 11/30 (P<0.01), having two or more postoperative complications 11/30 (P<0.01) and a patient's readiness for discharge 9/30 (P=0.001). There was a trend toward an association with smoking 13/30 (P=0.18). The authors suggest that a greater focus on patients presenting with characteristics associated with readmission, and incorporating a patient's readiness for discharge, may reduce readmission, although more studies are needed.

CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma.

Carfilzomib, a proteasome inhibitor, is approved in the United States as a single agent, and in combination with dexamethasone or lenalidomide/dexamethasone (KRd) for relapsed or refractory multiple myeloma (MM). Under the single-agent and KRd approvals, carfilzomib is administered as a 10-minute IV infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (20 mg/m(2) [cycle 1, days 1-2]; 27 mg/m(2) thereafter). This multicenter, single-arm, phase 1/2 study, Community Harmonized Assessment of Myeloma Patients via an Integrated Oncology Network-1 (CHAMPION-1), evaluated once-weekly carfilzomib with dexamethasone in relapsed, or relapsed and refractory MM (1-3 prior therapies). Patients received carfilzomib (30-minute IV infusion) on days 1, 8, and 15 of 28-day cycles. The phase 1 portion used a 3 + 3 dose-escalation scheme to determine the maximum tolerated dose (MTD) of carfilzomib. During phase 2, patients received carfilzomib on the same schedule at the MTD. Patients received dexamethasone (40 mg) on days 1, 8, 15, and 22; dexamethasone was omitted on day 22 for cycles 9+. A total of 116 patients were enrolled. The MTD was 70 mg/m(2), and 104 patients (phase 1/2) received carfilzomib 70 mg/m(2) At 70 mg/m(2), the median number of prior regimens was 1; and 52% were bortezomib-refractory. At 70 mg/m(2), the most common grade ≥3 adverse events were fatigue (11%) and hypertension (7%). Overall response rate at 70 mg/m(2) was 77%. Median progression-free survival was 12.6 months. These findings merit additional evaluation of the once-weekly dosing regimen. This trial was registered at www.clinicaltrials.gov as #NCT01677858.

Fc gamma receptor IIb on target B cells promotes rituximab internalization and reduces clinical efficacy.

The anti-CD20 mAb rituximab is central to the treatment of B-cell malignancies, but resistance remains a significant problem. We recently reported that resistance could be explained, in part, by internalization of rituximab (type I anti-CD20) from the surface of certain B-cell malignancies, thus limiting engagement of natural effectors and increasing mAb consumption. Internalization of rituximab was most evident in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but the extent of internalization was heterogeneous within each disease. Here, we show that the inhibitory FcγRIIb on target B cells promotes this process and is largely responsible for the observed heterogeneity across a range of B-cell malignancies. Internalization correlated strongly with FcγRIIb expression on normal and malignant B cells, and resulted in reduced macrophage phagocytosis of mAb-coated targets. Furthermore, transfection of FcγRIIb into FcγRIIb negative Ramos cells increased internalization of rituximab in a dose-dependent manner. Target-cell FcγRIIb promoted rituximab internalization in a cis fashion and was independent of FcγRIIb on neighboring cells. It became phosphorylated and internalized along with CD20:anti-CD20 complexes before lysosomal degradation. In MCL patients, high FcγRIIb expression predicted less durable responses after rituximab-containing regimens. Therefore, target-cell FcγRIIb provides a potential biomarker of response to type I anti-CD20 mAb.

Interaction with FcγRIIB is critical for the agonistic activity of anti-CD40 monoclonal antibody.

A high activatory/inhibitory FcγR binding ratio is critical for the activity of mAb such as rituximab and alemtuzumab that attack cancer cells directly and eliminate them by recruiting immune effectors. Optimal FcγR binding profiles of other anti-cancer mAb, such as immunostimulatory mAb that stimulate or block immune receptors, are less clear. In this study, we analyzed the importance of isotype and FcγR interactions in controlling the agonistic activity of the anti-mouse CD40 mAb 3/23. Mouse IgG1 (m1) and IgG2a (m2a) variants of the parental 3/23 (rat IgG2a) were engineered and used to promote humoral and cellular responses against OVA. The mouse IgG1 3/23 was highly agonistic and outperformed the parental Ab when promoting Ab (10-100-fold) and T cell (OTI and OTII) responses (2- to >10-fold). In contrast, m2a was almost completely inactive. Studies in FcγR knockout mice demonstrated a critical role for the inhibitory FcγRIIB in 3/23 activity, whereas activatory FcγR (FcγRI, -III, and -IV) was dispensable. In vitro experiments established that the stimulatory effect of FcγRIIB was mediated through Ab cross-linking delivered in trans between neighboring cells and did not require intracellular signaling. Intriguingly, activatory FcγR provided effective cross-linking of 3/23 m2a in vitro, suggesting the critical role of FcγRIIB in vivo reflects its cellular distribution and bioavailability as much as its affinity for a particular Ab isotype. In conclusion, we demonstrate an essential cross-linking role for the inhibitory FcγRIIB in anti-CD40 immunostimulatory activity and suggest that isotype will be an important issue when optimizing reagents for clinical use.

Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection.

Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fcgamma receptor-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

Ligation of CD11c during vaccination promotes germinal centre induction and robust humoral responses without adjuvant.

In this study, we investigated the mouse dendritic cell (DC) receptor, complement receptor 4 (CR4; CD11c/CD18), as an immunotarget for triggering humoral immunity. Comparison of antibody titres generated against a panel of 13 anti-antigen-presenting cell receptor monoclonal antibodies, with or without conjugated ovalbumin (OVA), revealed uniquely rapid and robust responses following CR4 targeting, with antibody titres approaching 1 : 100 000 7 days after a single dose of antigen. Furthermore, using just 100 ng OVA conjugated to anti-CD11c Fab', we generated anti-OVA titres greater than those produced by a 100-fold higher dose of OVA in complete Freund's adjuvant at day 28. These anti-OVA antibody titres were sustained and could be boosted further with targeted OVA on day 21. Investigations to explain this vaccine potency showed that, in addition to targeting splenic DC, anti-CDl1c antibodies delivered a powerful adjuvant effect and could boost humoral immunity against OVA even when the OVA was targeted to other molecules on DC, such as major histocompatibility complex class II, CD11a and CD11b. However, interestingly, this adjuvant effect was lost if OVA was targeted to other cells such as B cells via CD21 or CD19. The adjuvant effect was mediated through a marked enhancement of both germinal centre and extrafollicular plasma cell formation in responding spleens. These results demonstrate that anti-CD11c monoclonal antibody can both target antigen and act as a powerful adjuvant for rapid and sustained antibody responses. They also point to an interesting role for CR4 on DC in triggering B cells during humoral immunity.

Intersectionality of Cultural Identities in Health Psychology: Key Recommendations for Working With African-Caribbean Immigrant Women.

While the field of health psychology has progressed over the years, much work still needs to be done when considering immigrants' health care and well-being. Particularly, for African-Caribbean immigrants, the intersectionality of their cultural identities in the health care system require much attention moving forward. Therefore, this article is particularly relevant for Canada's multicultural society; it describes cultural identity reconstruction within health psychology as a common issue for diverse groups, particularly African-Caribbean immigrant women. The article speaks to the holistic worldview that is required in a paradigm shift which engages a pluralistic society that is Canada. The author presents a key cultural identity model and assessment tool that should be integrated into the health care system to ensure culturally-sensitive and inclusive care for immigrants, especially women. As is argued in the article, contemporary research, advocacy, and social movements speak to invoking alternative ways to complement the prevailing downstream approach to health psychology. In a growing multicultural society that should strive on honoring and respecting the pluralistic cultural worldviews of all people in the health care system, many immigrant women struggle to cope with the social determinants of health post-migration. Their concerns are often pushed to the margins of health care services, with several individuals relying on their faith for coping strategies. This article concludes with culturally-informed and socially-just recommendations for health care professionals working with immigrant populations, particularly African Caribbean immigrant women.

Vaccine programme stakeholder perspectives on a hypothetical single-dose human papillomavirus (HPV) vaccine schedule in low and middle-income countries.

BACKGROUND: The World Health Organization (WHO) recommends a 2-dose HPV vaccine schedule for girls aged 9-14 years. As randomised controlled trials assessing the immunogenicity and efficacy of a 1-dose schedule are ongoing, we interviewed immunisation programme managers and advisors in low and middle-income countries (LMIC) about a hypothetical, future reduction in the HPV vaccine schedule. METHODS: We conducted semi-structured interviews with LMIC immunisation programme managers and national immunisation technical advisory group members (key informants; KIs) in 2017, recruited for their knowledge/experience in national HPV vaccine policy and provision. Data were analysed thematically. RESULTS: We conducted 30 interviews with KIs from 18 countries. Perceived advantages of a 1-dose schedule included reduced logistical and financial resources needed for vaccine delivery, fewer cold chain requirements and easier integration into routine immunisation services. Perceived challenges included health worker hesitancy, resources needed to re-mobilise communities and re-train health workers, potential misrepresentation of schedule changes by anti-vaccine groups or the media. Half of interviewees suggested a WHO recommendation would be necessary prior to policy change. CONCLUSIONS: We found wide-ranging support among LMIC immunisation managers and advisors for a 1-dose vaccine schedule if research demonstrated immunological and clinical evidence of efficacy, and WHO provided a formal recommendation.

Poor preoperative patient-reported quality of life is associated with complications following pulmonary lobectomy for lung cancer.

Objectives: To assess whether quality of life (QOL) was associated with cardiopulmonary complications following pulmonary lobectomy for lung cancer. Methods: Retrospective analysis of 200 consecutive patients who had pulmonary lobectomy for lung cancer (September 2014-October 2015). QOL was assessed by the self-administration of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire within 2 weeks before the operation. The individual QOL scales were tested for a possible association with cardiopulmonary complications along with other objective baseline and surgical parameters by univariable and multivariable analyses. Results: Forty-three patients (21.5%) developed postoperative cardiopulmonary complications; 4 of them died within 30 days (2%). Univariable analysis showed that, compared to patients without complications, those with complications reported a lower global health status (GHS) [59.1; standard deviation (SD) 27.2 vs 69.6; SD 20.6, P = 0.02], were older (71.2; SD 8.4 vs 67.7; SD 9.4, P = 0.03), had lower values of forced expiratory volume in one second (FEV1) (83.9; SD 27.2 vs 91.4; SD 20.9), P = 0.06) and carbon monoxide lung diffusion capacity (DLCO) (67.9; SD 20.9 vs 74.2; SD 17.6, P = 0.02) and higher performance score (0.76; SD 0.63 vs 0.53; SD 0.64, P = 0.02). Stepwise logistic regression analysis showed that factors independently associated with cardiopulmonary complications were age [odds ratio (OR) 1.04, 95% CI 1.0-1.09, P = 0.02] and patient-reported GHS [OR 0.98, 95% confidence interval (CI) 0.96-0.99, P = 0.006], whereas other objective parameters (i.e. FEV1, DLCO) were not. The best cut-off value for GHS to discriminate patients with complications after surgery was 50 (c-index 0.65, 95% CI 0.58-0.72). Conclusions: A poor GHS perceived by the patient was associated with postoperative cardiopulmonary morbidity. Patient perceptions and values should be included in the risk stratification process to tailor cancer treatment.

Nurse led Patient Education Programme for patients undergoing a lung resection for primary lung cancer.

There has been an increase in the number of patients undergoing lung resection for primary or suspected primary lung cancer in the UK due to improved staging techniques, dedicated thoracic surgeons and other initiatives such as preoperative pulmonary rehabilitation. This has had an impact on local healthcare resources requiring new ways of delivering thoracic surgical services. When considering service changes, patient reported outcomes are pivotal in terms of ensuring that the experience of care is enhanced and may include elements such as involving patients in their care, reducing the length of inpatient stay and reducing postoperative complications. The implementation of a thoracic surgical Patient Education Programme (PEP) has the potential to address these measures and improve the psychological and physical wellbeing of patients who require a lung resection. It may also assist in their care as an inpatient and to enhance recovery after surgery both in the short and long term.

Protection against UVR involves MC1R-mediated non-pigmentary and pigmentary mechanisms in vivo.

Individuals with red hair and fair skin due to MC1R gene variants are at higher risk of cutaneous neoplasia, consistent with MC1R having a role in photoprotection. The exact reasons for greater UVR susceptibility as a result of compromised MC1R function are unclear, but hypotheses include reduced photoprotection due to less eumelanin, pheomelanin-induced phototoxicity, and lower protection by "non-pigmentary" MC1R effects. To determine how MC1R photoprotects, an in vivo hairless MC1R model containing Mc1r(-/-) albino, MC1R(+)Mc1r(-/-) albino, Mc1r(-/-) pigmented, and MC1R(+)Mc1r(-/-) pigmented mice was generated. After single doses of UVR, no significant differences in epidermal cyclobutane pyrimidine dimers or sunburn cell (SBC) formation were observed between pigmented and albino groups. However, after repeated UVR exposure, the number of p53 clones in albino skin was significantly elevated when this was null for MC1R. Furthermore, in the absence of functional MC1R, fewer p53 clones were observed in pigmented than in albino skin. The results indicate that MC1R protects by a combination of pigmentary and non-pigmentary effects in vivo and that when MC1R function is compromised the melanin type in skin is still protective against UVR.