Incidence of Post-Operative Complications and Factors Influencing Their Occurrence in Patients with Sickle Cell Disease in a Low-Income Country: A Case Study of Cameroon.

This study aimed to analyse post-operative complications and possible factors influencing their occurrence in the management of patients with sickle cell disease in a low-income country. We prospectively collected data regarding the management of patients with sickle cell disease requiring anesthesia for surgery in 11 Cameroonian hospitals from 1 May 2019 to 30 April 2021. The data were analysed using descriptive statistics and a binary logistic regression was used to determine the dependence between the variables. A total of 124 patients with sickle cell disease were enrolled; 64 were male and 60 female, giving a sex ratio of 0.93. The rate of post-operative complications was 23.4% (29/124) and the death rate was 3.2% (4/124). The female subjects had more complications than the male subjects p < 0.05. The number of vaso-occlusive crises experienced per year showed a significant impact on the occurrence of post-operative complications p < 0.05. Laparoscopic surgery had fewer post-operative complications 5/46 (10.9%) than laparotomy 14/43 (32.5%). The surgical technique for the abdominal procedures had a significant impact on the occurrence of post-operative complications p < 0.05. The type of surgery (p = 0.198) and the anaesthesia technique (p = 0.225) did not show a significant impact on the occurrence of post-operative complications. Particular attention should be paid to female patients with sickle cell disease as they are more likely to experience post-operative complications, as well as to the frequency of vaso-occlusive crises, which are also predictive of post-operative complications. Opting for laparoscopic surgery whenever possible would help to reduce post-operative complications.

Updated recommendations on the use of ruxolitinib for the treatment of myelofibrosis.

OBJECTIVES: Myelofibrosis is a rare bone marrow disorder associated with a high symptom burden, poor prognosis, and shortened survival. While allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis, the only approved and reimbursed pharmacotherapy for non-HSCT candidates in Belgium is ruxolitinib. METHODS: These updated recommendations are based on a consensus reached during two meetings and provide guidance for ruxolitinib administration in myelofibrosis patients considering the particularities of Belgian reimbursement criteria. RESULTS AND DISCUSSION: In Belgium, ruxolitinib is indicated and reimbursed for transplant-ineligible myelofibrosis patients from intermediate-2- and high-risk groups and from the intermediate-1-risk group with splenomegaly. Our recommendation is to also make ruxolitinib available in the pre-transplant setting for myelofibrosis patients with splenomegaly or heavy symptom burden. Before ruxolitinib initiation, complete blood cell counts are recommended, and the decision on the optimal dosage should be based on platelet count and clinical parameters. In anemic patients, we recommend starting doses of ruxolitinib of 10 mg twice daily for 12 weeks and we propose the use of erythropoiesis-stimulating agents in patients with endogenous erythropoietin levels ≤500 mU/mL. Increased vigilance for opportunistic infections and second primary malignancies is needed in ruxolitinib-treated myelofibrosis patients. Ruxolitinib treatment should be continued as long as there is clinical benefit (reduced splenomegaly or symptoms), and we recommend progressive dose tapering when stopping ruxolitinib. CONCLUSION: Based on new data and clinical experience, the panel of experts discussed ruxolitinib treatment in Belgian myelofibrosis patients with a focus on dose optimization/monitoring, adverse events, and interruption/rechallenge management.

Clinical outcomes in patients with Philadelphia chromosome-positive leukemia treated with ponatinib in routine clinical practice-data from a Belgian registry.

Data on clinical use of ponatinib are limited. This prospective registry aimed to evaluate outcomes of ponatinib treatment in routine practice over 3 years (2016-2019) in Belgium (NCT03678454). Patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were treated with ponatinib per current label. Fifty patients (33 CML and 17 Ph+ ALL) were enrolled. Fifty-five percent of CML and 29% of Ph+ ALL patients had received ≥3 prior tyrosine kinase inhibitors (TKIs). Reasons for starting ponatinib were intolerance (40%), relapse or refractoriness (28%) to previous TKIs, progression (16%), or T315I mutation (16%). Median follow-up was 15 months for CML and 4.5 months for Ph+ ALL patients. Best response was a major molecular response in 58% of CML and 41% of Ph+ ALL patients. Of 20 patients who started ponatinib due to intolerance to previous TKIs, 9 (64%) CML and 4 (67%) Ph+ ALL achieved a major molecular response. Three-year estimates of overall survival were 85.3% and 85.6%, respectively, in CML and Ph+ ALL patients; estimated progression-free survival was 81.6% and 48.9%. Adverse reactions were reported in 34 patients (68%); rash (26%) and dry skin (10%) were most common. Reported cardiovascular adverse reactions included vascular stenosis (3), arterial hypertension (2), chest pain (1), palpitations (1), and vascular occlusion (1). This Belgian registry confirms results from the PACE clinical trial and supports routine ponatinib use in CML and Ph+ ALL patients who are resistant or intolerant to previous TKIs or with the T315I mutation.

Interruption or Discontinuation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukaemia: A Retrospective Cohort Study (SPARKLE) in Belgium.

OBJECTIVES: To assess interruptions/discontinuations of tyrosine kinase inhibitor (TKI) treatment in Belgian patients with chronic myeloid leukaemia (CML). METHODS: This retrospective study included patients with TKI interruptions/discontinuations of ≥4 continuous weeks (no clinical trial context) between May 2013 and May 2016. Data collection took place between October 2016 and February 2017. RESULTS: All 60 participants (69 interruptions/discontinuations) had chronic-phase CML and 75% had at least a major molecular response (≥MMR) at interruption/discontinuation. Most interruptions/discontinuations occurred while on imatinib (36/69; 49%) and dasatinib (20/69; 29%). Most interruptions/discontinuations occurred due to side effects/intolerance (46/69; 67%); other reasons included a wish to conceive (6/69; 9%) and attempts to achieve treatment-free remission (TFR) (6/69; 9%). Interruptions due to side effects occurred later for imatinib- or dasatinib-treated patients than for those on nilotinib or ponatinib. Treatment was re-initiated in 62% (43/69) of cases. Most interruptions caused by side effects/intolerance were followed by treatment changes. All 4 patients with ≥MR 4.5 at interruption/discontinuation and ≥11-month follow-up who had not restarted treatment maintained the response. CONCLUSION: Although TKIs are used for long-term CML treatment, physicians sometimes recommend interruptions/discontinuations. In this study, interruptions/discontinuations were mainly caused by side effects or intolerance, rather than TFR attempts.

Disease and treatment characteristics of polycythemia vera patients in Belgium: Results from a scientific survey.

OBJECTIVE: The current survey aimed to gather predefined disease parameters and treatment strategies to characterize the polycythemia vera (PV) patient population in Belgium. METHODS: Cross-sectional data from PV patients, seen at least once between May 2014 and May 2015 at 10 sites in Belgium, were collected in aggregated form and analyzed descriptively and quantitatively. RESULTS: Data from 343 PV patients were collected. Of these, 174 (50.7%) were male and 256 (74.6%) were ≥60 years of age. Ninety-two (26.8%) had a prior history of thrombotic events. Considerable proportions of patients had increased hematological parameters (hematocrit > 45% [31.2%], leukocytes > 10 × 109 /L [33.3%], and platelet > 400 × 109 /L [38.2%]). Most patients had non-palpable spleen (284, 87.7%) and no phlebotomies during the past 6 months (197, 57.4%). Low-dose aspirin was given as thrombosis prophylaxis in 249 (72.6%) patients, while 232 (67.6%) received hydroxyurea (HU) as cytoreductive treatment. Forty-one patients (12.0%) were reported as resistant and/or intolerant to HU. Seventeen patients (5.0%) received ruxolitinib in the context of clinical trials. CONCLUSION: This survey provides better insight into the characteristics of Belgian PV patients and currently used treatment strategies. It shows that 232 (67.6%) PV patients continue to receive HU despite being potentially HU-resistant.

Recommendations on the use of ruxolitinib for the treatment of myelofibrosis.

OBJECTIVES: Myelofibrosis (MF) is a severe disease, with decreased life expectancy and heavy symptom burden. Ruxolitinib is the only approved pharmacotherapy for the treatment of MF patients. In Belgium, ruxolitinib is only reimbursed for MF patients with splenomegaly for whom the disease is categorized as intermediate-2 or high risk. The improvement of symptoms without spleen volume reduction is not considered sufficient to continue treatment. The aim of this manuscript is to provide guidance for the safe and effective administration of ruxolitinib, considering the particularities of the Belgian reimbursement criteria. METHODS: Our recommendations are based on a consensus reached during two meetings, where available data and observations derived from clinical experience were discussed. RESULTS AND DISCUSSION: We recommend changing the current Belgian reimbursement conditions to include the evaluation of disease-related symptoms along with splenomegaly to decide whether ruxolitinib treatment should be continued or not. Indeed, the decrease in disease-related symptoms seems to be an equally important parameter as the decrease in splenic volume in the evaluation of the response to ruxolitinib. We also advocate for the treatment with ruxolitinib of MF patients in lower-risk categories with severe disease-related symptoms, as this drug could greatly improve their quality of life. Optimization of the ruxolitinib dose is recommended to avoid an unnecessary decrease in platelet count or hemoglobin that may jeopardize treatment continuation. CONCLUSION: With the aim to optimize the treatment of MF patients, the Belgian regulation for ruxolitinib should be revised in terms of reimbursement criteria, dose titration, stopping rules, and patient follow-up.

Targeted Treatment Options in Mastocytosis.

Mastocytosis refers to a heterogeneous group of disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin (cutaneous mastocytosis when only in the skin, CM) or in various organs (systemic mastocytosis, SM). This leads to a wide variety of clinical manifestations resulting from excessive mediator release in CM and benign forms of SM (indolent SM, ISM) and from tissue mast cell infiltration causing multiorgan dysfunction and failure in more aggressive subtypes (aggressive SM, ASM, or mast cell leukemia). In addition, SM may be associated with hematological neoplasms (AHN). While treatment of ISM primarily aims at symptom management with anti-mediator therapies, cytoreductive and targeted therapies are needed to control the expansion of neoplastic mast cells in advanced forms of SM, in order to improve overall survival. Mast cell accumulation results from a gain-of-function mutation (mostly the D816V mutation) within the KIT tyrosine kinase domain expressed by mast cells and additional genetic and epigenetic mutations may further determine the features of the disease (ASM and AHN). Consequently, tyrosine kinase inhibitors and targeted therapies directed against the oncogenic signaling machinery downstream of KIT are attractive therapeutic approaches. A better understanding of the relative contribution of these genetic and epigenetic events to the molecular pathogenesis of mastocytosis is of particular interest for the development of targeted therapies and therefore to better choose patient subgroups that would best benefit from a given therapeutic strategy.

Survival among children and adults with sickle cell disease in Belgium: Benefit from hydroxyurea treatment.

OBJECTIVE: To evaluate the survival of patients with sickle cell disease (SCD) recorded in the Belgian SCD Registry and to assess the impact of disease-modifying treatments (DMT). METHOD: The Registry created in 2008 included patients of eight centers. All available data in 2008 were retrospectively encoded in the database. After 2008 and until 2012, all data were recorded prospectively for already registered patients as well as newly diagnosed subjects. Data were registered from neonatal screening or from diagnosis (first contact) until last follow-up or death. Data included diagnosis, demography, and outcome data. RESULTS: We collected data from 469 patients over a 5,110 patient years (PY) follow-up period. The global mortality rate was low (0.25/100 PY), although 13 patients died (2.8%) and was similar between children, adolescents (10-18 years), and young adults (P = 0.76). Out of the cohort, 185 patients received hydroxyurea at last follow-up (median duration of treatment: 10.3 years), 90 underwent hematopoietic stem cell transplantation (HSCT), 24 were chronically transfused, and 170 had never had any DMT. Hydroxyurea showed significant benefit on patients outcome as reflected by a lower mortality rate compared to transplanted individuals or people without DMT (0.14, 0.36, and 0.38 per 100 PY, respectively) and by higher Kaplan-Meier estimates of 15 year survival (99.4%) compared to HSCT (93.8%; P = 0.01) or no DMT groups (95.4%; P = 0.04). CONCLUSION: SCD mortality in Belgium is low with no increase observed in young adults. Patients treated with hydroxyurea demonstrate a significant benefit in survival when compared to those without DMT or transplanted.

IL-17 production elicited by allo-major histocompatibility complex class II recognition depends on CD25posCD4pos T cells.

BACKGROUND: Interleukin (IL)-17 is involved in autoimmune inflammatory disorders and naturally occurring CD25pos regulatory T cells were shown to promote IL-17 synthesis. Because IL-17 is overproduced in certain types of allograft rejection, it is important to characterize the cells responsible for IL-17 synthesis and to define how IL-17 is regulated during alloimmune responses. METHODS: Splenic CD4pos T cells were isolated from C57BL/6 mice and fractionated according to CD25 expression. T cells were stimulated by major histocompatibility complex class II-mismatched bone marrow-derived dendritic cells from bm12 mice, either immature or made mature by exposure to lipopolysaccharide. To track T cell populations, CD25negCD4pos and CD25posCD4pos were isolated from Thy1.1 and congenic Thy1.2 mice, respectively. Cell proliferation was quantified by CFSE dilution. IL-17-producing cells and FOXP3pos cells were enumerated by intracytoplasmic staining and cytokine levels in culture supernatants were measured by ELISA. RESULTS: Addition of CD25posCD4pos T cells to CD25negCD4pos T cells inhibited IL-2, interferon-[gamma], and IL-13 production but promoted IL-17 synthesis on stimulation by allogenic immature DC. In this setting, IL-17 originated from CD25intCD4posFOXP3neg memory T cells, which depend on IL-2 to produce IL-17. Alloreactive CD25negCD4pos T cells were also induced to produce IL-17 when stimulated by mature DC in the presence of CD25highCD4posFOXP3pos T cells. CONCLUSIONS: We conclude that (1) the cellular source of IL-17 during an antiallo major histocompatibility complex class II response depends on the maturation status of allogenic DC, (2) whereas suppressing Th1 and Th2 cytokine synthesis, naturally occurring regulatory T cells, allow IL-17 production by alloreactive CD4pos T cells.

Endotoxin hyperresponsiveness upon CD4+ T cell reconstitution in lymphopenic mice: control by natural regulatory T cells.

Natural CD4(+)CD25(+) regulatory T cells (nTreg) have been shown to control graft-versus-host disease after hematopoietic stem cell transplantation (HSCT). Herein, we considered the possibility that the beneficial action of nTreg upon immune reconstitution in lymphopenic hosts involves dampening of the inflammatory response induced by bacterial products. We first observed that transfer of syngeneic CD4(+)CD25(-) T cells in RAG-deficient mice dramatically enhanced release of inflammatory cytokines and associated pathology upon endotoxin injection. Interferon (IFN)-gamma produced by T cells undergoing homeostatic proliferation was shown to be involved in the endotoxin hyperresponsiveness induced by CD4(+) T cell reconstitution. Co-transfer of CD4(+)CD25(+) nTreg with CD4(+)CD25(-) T cells inhibited the expansion of IFN-gamma-producing T cells and reduced endotoxin responses in RAG(-/-) mice. We conclude that (1) CD4(+) T cell reconstitution sensitizes lymphopenic hosts to endotoxin-induced pathology and (2) nTreg prevent this process by limiting the emergence of IFN-gamma-producing cells.