Sickle cell disease in Australia: a snapshot from the Australian Haemoglobinopathy Registry.

BACKGROUND: Sickle cell disease (SCD) is the most common monogenic disorder worldwide. In deoxygenated conditions, the altered beta chain (haemoglobin S [HbS]) polymerises and distorts the erythrocyte, resulting in pain crises, vasculopathy and end-organ damage. Clinical complications of SCD cause substantial morbidity, and therapy demands expertise and resources. Optimising care for patients and planning resource allocation for the future requires an understanding of the disease in the Australian population. The Australian Haemoglobinopathy Registry (HbR) is a collaborative initiative of specialist centres collating and analysing data on patients with haemoglobin disorders. AIMS: To provide a snapshot of SCD in Australia over a 12-month period based on data from the HbR. METHODS: Patients with a clinically significant sickling disorder across 12 clinical sites were included for analysis. Data include demographic and diagnostic details, as well as details of the clinical management of the condition over a 12-month period. RESULTS: Data on 359 SCD patients demonstrate a shift in the demographic of patients in Australia, with a growing proportion of sub-Saharan African ethnicities associated with the HbSS genotype. Acute and chronic complications are common, and patients require significant outpatient and inpatient support. Prevalence of disease complications and therapeutic trends are in keeping with other high-income countries. CONCLUSIONS: This study provides the first national picture of SCD in Australia, describing the characteristics and needs of SCD patients, elucidating demand for current and novel therapy and facilitating the planning of services for this vulnerable population.

Bilateral Central Retinal Vein Occlusion Secondary to Leukostasis in the Setting of Diffuse Large-B Cell Lymphoma: Case Report.

A woman in her 50's was diagnosed diffuse large B-cell lymphoma (DLBCL) after presenting to hospital in a critical condition, characterised by marked hyperleukocytosis (white cell count 290 x109/L). She subsequently developed painless blurred vision bilaterally, and was diagnosed with bilateral central retinal vein occlusion secondary to leukostasis. She was managed with non-Hodgkin lymphoma R-CHOEP14 (rituximab, cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone) immunochemotherapy, with her ocular signs and symptoms improving following treatment. Optical coherence tomography and funduscopic examination demonstrated no evidence of intraocular lymphoma. Visual acuity returned to 6/6 in each eye with subsequent resolution of her symptoms. Repeat examination demonstrated stable appearance of her ocular disease.

Immunochemotherapy for life-threatening haematological malignancies in pregnancy: a systematic review of the literature and cross-sectional analysis of clinical trial eligibility.

The management of potentially life-threatening malignancies in pregnancy is complicated by a lack of robust safety and efficacy evidence. This data shortage stems from a historical exclusion of women of childbearing potential from prospective clinical trials due to concerns around potential teratogenicity and toxicity of investigational agents. We conducted a systematic review of published data on immunochemotherapeutic treatment of life-threatening haematological malignancies in pregnancy between 2010 and 2022, and the maternal and neonatal outcomes. We then performed a cross-sectional observational study of clinical trial protocols on ClinicalTrials.gov, between 2016 and 2022, recruiting women of childbearing potential with potentially life-threatening haematological malignancies, collecting trial demographic data, and documenting whether pregnant or lactating women were explicitly excluded, along with the type and duration of contraception required for women of childbearing potential. We included 17 studies for analysis in our systematic review. A total of 595 women were treated with immunochemotherapy during pregnancy, with a median age of 29 years (range 14-48). Of these, 81 women (14%) were treated in the first trimester, and 514 (86%) were treated in the second and third trimesters collectively. In total, 68 trials for acute myeloid leukaemia, acute lymphocytic leukaemia, high-grade non-Hodgkin lymphoma, and Hodgkin lymphoma (40%, 26%, 21%, and 13%, respectively) were included in our ClinicalTrials.gov analysis. Most protocols (66 [97%]) explicitly excluded pregnant women, with 40 (69%) not providing a rationale for exclusion. The potential harm to the fetus from anti-cancer therapy has historically been given greater moral precedence than a pregnant woman's autonomy. This pattern is reflected in the lack of rigorous evidence for immunochemotherapy in pregnancy and a universal exclusion of pregnant and lactating women from clinical trial protocols in this study. Nonetheless, the administration of systemic chemotherapy in the second and third trimesters was not associated with an increased rate of congenital malformations or perinatal mortality in our systematic review cohort, with maternal outcomes broadly comparable to those of the non-pregnant population.

The clinical features, management and outcomes of lymphoma in pregnancy: A multicentre study by the Australasian Lymphoma Alliance.

Lymphoma in pregnancy (LIP) presents unique clinical, social and ethical challenges; however, the evidence regarding this clinical scenario is limited. We conducted a multicentre retrospective observational study reporting on the features, management, and outcomes of LIP in patients diagnosed between January 2009 and December 2020 at 16 sites in Australia and New Zealand for the first time. We included diagnoses occurring either during pregnancy or within the first 12 months following delivery. A total of 73 patients were included, 41 diagnosed antenatally (AN cohort) and 32 postnatally (PN cohort). The most common diagnoses were Hodgkin lymphoma (HL; 40 patients), diffuse large B-cell lymphoma (DLBCL; 11) and primary mediastinal B-cell lymphoma (PMBCL; six). At a median follow up of 2.37 years, the 2- and 5-year overall survival (OS) for patients with HL were 91% and 82%. For the combined DLBCL and PMBCL group, the 2-year OS was 92%. Standard curative chemotherapy regimens were successfully delivered to 64% of women in the AN cohort; however, counselling regarding future fertility and termination of pregnancy were suboptimal, and a standardised approach to staging lacking. Neonatal outcomes were generally favourable. We present a large multicentre cohort of LIP reflecting contemporary practice and identify areas in need of ongoing research.

Primary Cardiac Lymphoma Presenting with Thrombocytopenia, Right Heart Failure, and Cardiogenic Shock.

Primary cardiac lymphoma (PCL) is a rare, potentially fatal subtype of non-Hodgkin's lymphoma. Thrombocytopenia has also infrequently been reported in association with other primary cardiac tumours and can add substantial morbidity to an already life-threatening diagnosis if present. We report a rare case of a 70-year-old man who presented with thrombocytopenia (91 × 109/L) and progressive right heart failure. Transthoracic echocardiogram revealed a large 8 × 4 cm right atrial mass with severe tricuspid obstruction, confirmed as PCL on subsequent endomyocardial biopsy and immunohistochemistry. He deteriorated into cardiogenic shock precipitated by atrial fibrillation, with worsening thrombocytopenia (18 × 109/L) in the setting of ischaemic hepatitis. The patient stabilised with initiation of high dose steroids prior to tissue diagnosis and platelet counts normalised following chemotherapy. This case demonstrates the importance of considering PCL as a diagnosis and preemptive initiation of high dose steroids to improve outcomes in PCL associated with cardiogenic shock. This case also elucidates a potential pathophysiological association between PCL and thrombocytopenia.

Capturing the lived experiences of women with lymphoma in pregnancy: a qualitative study.

Lymphoma in pregnancy is a rare and challenging diagnosis that complicates ∼1:6000 pregnancies; posing a series of unique therapeutic, social, and ethical challenges to the patient, her family, and the medical professionals involved. These difficulties are compounded by the paucity of real-world data on the management of LIP, and a lack of relevant support systems for women in this setting. We conducted a retrospective multicenter qualitative study, interviewing women aged ≥18 years of age diagnosed with Hodgkin (HL) or non-Hodgkin lymphoma (NHL) during pregnancy or within 12 months postpartum, between 1 January 2009 and 31 December 2020 from 13 Australasian sites. Semi-structured telephone interviews were conducted, recorded, and analyzed using QSR Int NVivo 12 Pro (March 2020, USA) to quantify salient themes. Of the 32 women interviewed, 20 (63%) were diagnosed during pregnancy (16, 34, and 13% in the 1st, 2nd, and 3rd trimesters, respectively), while 12 (37%) were diagnosed post-partum. Women recalled that their chief concerns at diagnosis were the welfare of their child (n = 13, 41%) and a fear of dying (n = 9, 28%). Perceived diagnostic delay attributed to pregnancy was reported by 41% of participants. Other key themes were communication, educational materials, psychosocial supports, and oncofertility issues. To our knowledge this is the first report capturing the lived experiences of survivors of lymphoma during pregnancy, affording a unique opportunity to consider the management, psychosocial supports, and delivery of care to meet the needs of these women.What is the NEW aspect of your work? To our knowledge, this is the first report capturing and analyzing the healthcare experiences of survivors of Lymphoma in Pregnancy (LIP).What is the CENTRAL finding of your work? Women valued clear and empathic communication, provision of tailored educational materials, access to psychosocial supports (particularly childcare and financial supports), and timely oncofertility management in their healthcare journey.What is (or could be) the SPECIFIC clinical relevance of your work? Women's personal accounts of positive and negative experiences of LIP care provide insights into their specific concerns and needs which can shape healthcare policy and development of a specific framework for managing and supporting patients with LIP (and other cancers).

VEXAS syndrome: lessons learnt from an early Australian case series.

VEXAS is a newly recognised adult-onset autoinflammatory syndrome resulting from a somatic mutation in the UBA1 gene. Herein, we present three cases of VEXAS syndrome in Sydney, Australia, that capture key clinical features and the refractory nature of the condition. They highlight the importance of multidisciplinary collaboration for early diagnosis and the need for new therapeutic options.

Antenatal haemoglobinopathy screening - Experiences of a large Australian Centre.

BACKGROUND: Antenatal screening is vital to identifying couples at risk of having children with a clinically significant haemoglobinopathy. In Australia, immigration is increasing carrier incidence. METHODS: A retrospective analysis was performed of full blood count, high-performance liquid chromatography and haemoglobin electrophoresis of women and their partners who underwent antenatal haemoglobinopathy screening over three years at a major NSW laboratory. Genetic testing results were included where available. RESULTS: One thousand six hundred and twenty-eight women and 729 male partners were screened at a median gestation of 14 weeks. 8.2% of women had a clinically significant result, with a median 16-day interval to partner testing. In 35% of couples screened simultaneously, the partner did not require testing. Genetic confirmatory testing was performed in 65% of high risk couples. CONCLUSION: There was a significant delay to antenatal haemoglobinopathy screening for mothers, limiting time for genetic diagnosis, prenatal diagnosis and management of affected pregnancies. Screening should be performed earlier. Simultaneous couple testing is not cost-effective.

The use of intravenous iron in pregnancy: for whom and when? A survey of Australian and New Zealand obstetricians.

BACKGROUND: Iron deficiency anaemia in pregnancy (IDAP) affects 11-18% of Australian pregnancies and is associated with adverse perinatal outcomes. National prescribing data suggests the use of intravenous iron in pregnancy is increasingly common. This study aimed to: 1) Establish the current patterns of intravenous iron use by Fellows of the Royal Australian and New Zealand College of Obstetricians (FRANZCOG) when treating iron deficiency and IDAP including immediately postpartum and; 2) Assess FRANZCOG opinions regarding potential trial of intravenous iron for first-line treatment of IDAP. METHODS: An online survey of RANZCOG Fellows practicing obstetrics was distributed in September 2018. Results were analysed descriptively and responses compared by clinician demographics using Chi-squared testing. RESULTS: Of 484 respondents (21% of FRANZCOG), 457 were currently practicing obstetrics. Most prescribed intravenous iron in pregnancy (96%) and/or postpartum (85%). Most intravenous iron was prescribed for IDAP (98%) rather than iron deficiency without anaemia (53%), and for IDAP most commonly second-line to failed oral iron supplementation and first-line in special circumstances (59%). Intravenous iron prescribing was associated with shorter time since FRANZCOG completion (p = 0.01), public hospital practice (p = 0.008) and higher hospital birth numbers (p = 0.01). Most respondents (90%) would consider a randomised controlled trial of first-line intravenous iron for IDAP, although views on appropriate thresholds differed. CONCLUSIONS: Almost all respondents prescribed intravenous iron for IDAP, and while mostly used for second-line treatment over half sometimes used it first-line. With accelerating intravenous iron use, further research is required into its optimal use in pregnancy, recognizing important clinical outcomes and cost effectiveness.

18F-Fluorodeoxyglucose PET/CT-Guided Palliative Radiotherapy Provides Durable Responses to Over a Dozen Sites of Disease in Relapsed Myeloid Sarcoma.

Myeloid sarcoma (MS) is a rare entity, and FDG PET/CT is a useful tool for staging at diagnosis and response assessment. We present a case of a 72-year-old woman diagnosed with multifocal extramedullary MS, using FDG PET/CT to guide palliative radiotherapy to 13 sites of disease over 2 separate relapses with complete and durable local responses and minimal toxicity. This case represents the largest reported burden of disease in MS successfully treated with FDG PET/CT-guided radiotherapy.

Intravenous or oral iron for treating iron deficiency anaemia during pregnancy: systematic review and meta-analysis.

OBJECTIVES: To compare the effects on perinatal maternal and neonatal outcomes of intravenous and oral iron therapy as first-line treatment of iron deficiency anaemia (IDA) in pregnant women. STUDY DESIGN: A meta-analysis, applying fixed and random effects models, of randomised controlled trials (RCTs) that compared the effects of intravenous and oral iron therapy for pregnant women with IDA. DATA SOURCES: MEDLINE, EMBASE, Scopus, Cochrane Register of Controlled Trials, Web of Science; bibliographies of identified articles. DATA SYNTHESIS: Fifteen eligible studies with a total of 1938 participants were identified. Each was at high risk of bias in at least one domain; ten were undertaken in low or middle income countries. Evidence (from nine RCTs) that intravenous iron was superior to oral iron in reducing the need for blood transfusion at delivery was low quality (Peto odds ratio, 0.19 [95% CI, 0.05-0.78]; number needed to treat, 95 [95% CI, 81-348]). Evidence that intravenous iron was superior to oral iron in increasing neonatal birthweight (eight RCTs: mean difference, 58 g; 95% CI, 4-112 g) or reducing the rate of breastfeeding cessation within 24 months of delivery (one RCT: hazard ratio, 0.70; 95% CI, 0.50-0.99) was of low or very low quality. While intravenous iron treatment was superior to oral iron for improving maternal haematological parameters at delivery, their effects on neonatal haematological parameters were similar. CONCLUSIONS: There is no strong evidence that first-line therapy with intravenous iron is superior to oral administration for treating IDA in pregnant women. The few identified differences in outcomes were small in magnitude and from studies at high risk of bias. REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO), CRD42019120652.

Impact of salvage treatment modalities in patients with positive FDG-PET/CT after R-CHOP chemotherapy for aggressive B-cell non-Hodgkin lymphoma.

INTRODUCTION: To compare outcomes of different salvage treatment modalities in patients with aggressive B-cell non-Hodgkin lymphoma (NHL) who remain FDG-PET positive after R-CHOP chemotherapy. Existing data on these patients with FDG-PET primary refractory disease are limited. METHODS: Patients with diffuse large B-cell lymphoma or grade 3 follicular lymphoma were retrospectively reviewed from the Prince of Wales Hospital databases. Eligibility criteria were: age≥18 years, treated with R-CHOP, with positive post-chemotherapy FDG-PET. Salvage treatment modalities were: radical radiotherapy (RT, dose≥30 Gy), high dose chemotherapy and autologous stem cell transplant (ASCT), or non-radical management. Survival was calculated from date of post-chemotherapy FDG-PET to last follow-up. RESULTS: Twenty-six patients from 2003-2015 met the inclusion criteria. Median age was 60 (range 19-84). Most had adverse baseline features: 21 (81%) stage III-IV, 24 (92%) bulky disease and nine (35%) skeletal involvement. Characteristics of PET-positivity post-chemotherapy were single site in 16 (62%), sites of prior bulk in 24 of 24, skeletal sites in five of nine, and able to be encompassed by RT in 21 (81%). Salvage treatment was: radical RT in 17 (65%), ASCT in four (15%) and non-radical in five (20%). Median follow-up of surviving patients was 31 months. Kaplan-Meier estimates of 3-year PFS and OS were 41% and 52%, respectively. By salvage modality, 3-year PFS was 51% for RT, 25% for ASCT and 20% for non-radical treatment, (P = 0.453); 3-year OS was respectively 65%, 25% and 40% (P = 0.173). CONCLUSION: Patients with FDG-PET positive disease after R-CHOP for aggressive B-cell NHL are salvageable with radiotherapy.

Update on inherited disorders of haemostasis and pregnancy.

Inherited bleeding disorders have the potential to cause bleeding complications during pregnancy, childbirth and the postpartum period as well as effect fetal outcomes. There is an evolving understanding of the need for specialised and individualised care for affected women during these times. The aim for each patient is to estimate the risk to mother, fetus and neonate; to implement measures to minimise these risks; and to anticipate complications and develop contingencies for these scenarios. This includes accurate diagnosis, preconceptual care, prenatal diagnostic options, antenatal care, delivery and postpartum care as well as care of an affected neonate. An understanding of the physiologic haemostatic changes associated with pregnancy as well as the scope of defects, inheritance and management of inherited bleeding disorders is paramount when caring for these women. Collaborative and prospective management in conjunction with haematology services underpins the approach advocated. This review draws on the available literature, and outlines the principles of care for women with inherited bleeding disorders before, during and after pregnancy, as well as their babies, based on both available data and collective clinical experience.

Antenatal haemoglobinopathy screening in Australia.

Haemoglobinopathy screening should be performed in women with microcytic indices, women from high risk ethnic populations and those with unexplained anaemia. Early testing of women and their partners expedites appropriate management prior to and during pregnancy. Haemoglobinopathy screening is a multistep process beginning with a full blood count, ferritin assay, screening tests for haemoglobinopathies (ie, haemoglobin electrophoresis, high performance liquid chromatography, capillary electrophoresis) and assessment of clinical risk. Iron deficiency may obscure the diagnosis of ß-thalassaemia trait. If possible, haemoglobinopathy testing should be performed when the woman is iron-replete. Genetic testing can be offered on the basis of the combined risk of the couple; but turnaround times are lengthy at present, hence the emphasis on early pregnancy or pre-conception screening. Screening processes vary between states and local health districts; a uniform approach to screening and genetic testing with a national registry to record results would improve management of this growing problem.

Caring for pregnant women for whom transfusion is not an option. A national review to assist in patient care.

Postpartum haemorrhage (PPH) is the leading cause of maternal mortality and morbidity globally. Obstetric bleeding can be catastrophic and management is challenging, involving a coordinated multidisciplinary approach, which may include blood products. In settings where blood transfusion is not an option, either because of patient refusal (most commonly in Jehovah Witnesses) or because of unavailability of blood, management becomes even more challenging. Observational studies have demonstrated an association between refusal of blood products in major obstetric haemorrhage and increased morbidity and mortality. This review draws upon evidence in the literature, physiological principles and expert opinion for strategies and guidance to optimise the outcomes of pregnant women in whom blood transfusion is either refused or impossible. The importance of a multidisciplinary antenatal and perinatal management plan, including optimisation of haemoglobin and iron stores pre-delivery, blood loss minimisation, early haemorrhage control and postpartum anaemia treatment, is discussed.

Trajectory of platelets in pregnancy - do low-risk women need an intrapartum full blood count prior to epidural?

This study aimed to investigate whether pregnant women with a normal 28-week gestation platelet count and no high-risk conditions for thrombocytopenia require a pre-epidural platelet count. All 1844 included women (platelet count > 150 × 10(9) /L at 28 weeks' gestation, term singleton birth, no thrombocytopenia risk conditions) had a platelet count > 100 × 10(9) /L prebirth, suggesting low-risk pregnant women do not require pre-epidural full blood count solely to check platelet count.

Antenatal haemoglobinopathy screening: Patterns within a large obstetric service. Working towards a standard of care.

BACKGROUND: Antenatal screening can predict clinically significant haemoglobinopathies, however in Australia, practices are not standardised and are evolving as the population becomes more ethnically diverse. This study describes antenatal screening practices in a large Australian laboratory/antenatal service. METHODS: Data were collected retrospectively on consecutive antenatal haemoglobin electrophoresis over 16 months and correlated with obstetric data, obtained from the local obstetric database. RESULTS: 462 patients were included, with an average gestation of 25.8 weeks. 'Pregnancy' was the most common stated indication, with absent indication/clinical information in 8%. Gestational age was documented in 54%. In 15%, no contact details of the referrer were documented and partner screening was traceable in only 25 cases (5.4%). In 82% of cases, no abnormalities were detected. Beta thalassemia trait was the most common positive result. Only 52% of patients had recent iron studies. The mean haemoglobin was 111.6 g/L and mean cell volume was 80.5 fl at the time of testing. Ethnicity was documented on the request form in 3%. After Australasia, the most common ethnicity of patients was South East Asia and the Middle East. CONCLUSION: Referral patterns in our health service are diverse and reflect our changing population and care practices. Detailed guidelines are required and we propose a comprehensive algorithm for general use where selective screening is practiced within an Australasian population or one with similar demographics.