Attitudes towards COVID-19 vaccination in adults with haematological malignancies.

INTRODUCTION: Despite people with haematological malignancies being particularly vulnerable to severe COVID-19 infection and complications, vaccine hesitancy may be a barrier to optimal vaccination. This study explored attitudes towards COVID-19 vaccination in people with haematological malignancies. METHODS: People with haematological malignancies at nine Australian health services were surveyed between June and October, 2021. Sociodemographic and clinical characteristics were collected. Attitudes towards COVID-19 vaccination were explored using the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale, and the Disease Influenced Vaccine Acceptance Scale-Six. Open-ended comments were qualitatively analysed. RESULTS: A total of 869 people with haematological malignancies (mean age 64.2 years, 43.6% female) participated. Most participants (85.3%) reported that they had received at least one COVID-19 vaccine dose. Participants who were younger, spoke English as a non-dominant language, and had a shorter time since diagnosis were less likely to be vaccinated. Those who were female or spoke English as their non-dominant language reported greater vaccine side-effects concerns. Younger participants reported greater concerns about the vaccine impacting their treatment. CONCLUSION: People with haematological malignancies reported high vaccine uptake, however, targeted education for specific participant groups may address vaccine hesitancy concerns, given the need for COVID-19 vaccine boosters.

Variability of bone marrow biopsy reporting affects accuracy of diagnosis of myeloproliferative neoplasms: data from the ALLG MPN01 registry.

The Philadelphia-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of overlapping bone marrow disorders defined by characteristic peripheral blood counts and bone marrow morphological findings in conjunction with recurrent somatic mutations. The accurate diagnosis and subclassification of MPN relies upon careful reporting of bone marrow morphology combined with ancillary information in an integrated pathology report. This co-operative trial group study ALLG MPN01 (ANZCTR:12613000138785), led by the Australasian Leukaemia & Lymphoma Group (ALLG), aimed to describe the current approach to diagnosis of MPN in routine practice. Specifically, we assessed the frequency with which bone marrow biopsies were performed, and the adherence of reporting pathologists to recommendations contained in the revised 2016 WHO classification pertaining to MPN. We reviewed the diagnosis of 152 patients from eight institutions who were enrolled in a national MPN registry of the ALLG between 2010 and 2016. The ALLG MPN01 registry is now closed to recruitment. Key features were extracted from pathology reports provided to the registry. Bone marrow biopsies were performed in 112/152 cases (74%). The pathological information entered was concordant with the stated clinical diagnosis in 75/112 cases (67%). The main reasons for discordant results were incomplete descriptions of megakaryocyte topography and morphology, inconsistent grading of reticulin fibrosis, and failure to integrate the available morphological and ancillary clinicopathological information. In this retrospective audit, 26% of MPN patients did not undergo a diagnostic bone marrow biopsy. In those who did, the specific MPN subtype may not have been reported correctly in 33% of cases, as evidenced by inconsistent features reported or insufficient information to assess. A more standardised approach to bone marrow reporting is required to ensure accuracy of MPN diagnoses and consistent reporting to cancer registries and clinical trials.

The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry.

The bone marrow failure syndromes (BMFS) are a diverse group of acquired and inherited diseases which may manifest in cytopenias, haematological malignancy and/or syndromic multisystem disease. Patients with BMFS frequently experience poor outcomes, and improved treatment strategies are needed. Collation of clinical characteristics and patient outcomes in a national disease-specific registry represents a powerful tool to identify areas of need and support clinical and research collaboration. Novel treatment strategies such as gene therapy, particularly in rare diseases, will depend on the ability to identify eligible patients alongside the molecular genetic features of their disease that may be amenable to novel therapy. The Australian Aplastic Anaemia and other Bone Marrow Failure Syndromes Registry (AAR) aims to improve outcomes for all paediatric and adult patients with BMFS in Australia by describing the demographics, treatments (including supportive care) and outcomes, and serving as a resource for research and practice improvement.

Long-term effectiveness of eculizumab: Data from the International PNH Registry.

OBJECTIVES: Data from the International PNH Registry (NCT01374360) were used to estimate the overall survival and first occurrence of thromboembolic events/major adverse vascular events (TEs/MAVEs) for eculizumab-treated patients with paroxysmal nocturnal hemoglobinuria (PNH) compared with a contemporaneous untreated cohort. METHODS: Patients enrolled in the Registry from March 16, 2007, to February 14, 2022, were included. Treated patients received eculizumab for >35 days; untreated patients did not receive eculizumab at any time. Univariable and multivariable analyses were performed using a Cox proportional hazards regression model comparing eculizumab treatment periods to untreated periods and were adjusted for baseline covariates (e.g., high disease activity [HDA], transfusion dependency, and eculizumab treatment status). RESULTS: The analysis included 4118 patients. The univariable hazard ratio (HR) (95% CI) for mortality in eculizumab-treated time versus untreated time was 0.51 (0.41-0.64; p < 0.0001). Significant baseline covariates included age, sex, history of bone marrow failure, ≥4 erythrocyte transfusions within 12 months before baseline, and an estimated glomerular filtration rate ≤ 60 mL/min/1.73 m2 (all p < 0.0001). In the adjusted analysis, patients with baseline HDA had the greatest reduction in mortality risk (HR [95% CI], 0.51 [0.36-0.72]). Treated patients had approximately 60% reduction in TE/MAVE risk during treated versus untreated time (HR [95% CI]: TE: 0.40 [0.26-0.62], MAVE: 0.37 [0.26-0.54]; p < 0.0001). CONCLUSION: Using data from the largest Registry of patients with PNH, with ≥14 years of overall follow-up, we demonstrate that treatment with eculizumab conferred a 49% relative benefit in survival and an approximately 60% reduction in TE/MAVE risk.

Significant heterogeneity in management of calreticulin-mutated essential thrombocythemia and its progression to myelofibrosis: results of a national survey.

Despite the recent publication of calreticulin (CALR)-mutated essential thrombocythemia (ET) management guidelines by the European Leukemia Net (ELN), there remains a paucity of data regarding the optimal way to manage this condition. To determine practice around Australia, we constructed a survey asking investigation and treatment questions in a hypothetical case of a young woman with CALR-mutated ET and subsequent progression to myelofibrosis. 51 of 88 hematologists replied. The responses demonstrated significant heterogeneity in specific issues such as the use of aspirin, when to initiate cytoreduction, the preferred type of cytoreduction, and platelet targets. These observations support the ELN acknowledgment that a strong evidence base for many management recommendations is lacking in this disease, and that substantial further research is needed.

Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41.

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.

Clinical characteristics of Australian treatment-naïve patients with classical Hodgkin lymphoma from the lymphoma and related diseases registry.

Comprehensive clinical characteristics of Australian patients with classical Hodgkin Lymphoma (cHL) have not previously been systematically collected and described. We report real-world data of 498 eligible patients from the first 5 years of the Lymphoma and Related Diseases Registry (LaRDR), including baseline characteristics, histologic subtype, and treatment patterns in first-line therapy. Patient demographics and distribution of histopathological subtypes of cHL are similar to reported international cohorts. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was the most common therapy for both early and advanced-stage disease, and 48% of patients with the early-stage disease received radiotherapy. Treatment patterns are consistent with international guidelines. In comorbid patients ≥60 years of age with advanced-stage disease, there is greater variation in treatment. In patients with a recorded response, the objective response rate (ORR) was 96% in early-stage disease, and 88% in advanced-stage disease. Early progression-free survival data suggest Australian patients with cHL have good outcomes, similar to other international studies.

Paraprotein associated heparin resistance during cardiopulmonary bypass.

INTRODUCTION: Heparin resistance during cardiopulmonary bypass poses a significant intraoperative dilemma. Antithrombin deficiency related heparin resistance is well described, but less common causes are still poorly understood and inadequately managed. CASE REPORT: We present a case of heparin resistance during cardiopulmonary bypass in a gentleman with no previous haematological history or thrombotic risk factors. The patient required three times the regular dose of unfractionated heparin to achieve acceptable conditions to initiate and maintain bypass. The patient was found to have elevated serum immunoglobulin M (IgM) kappa paraprotein on post-operative investigation. DISCUSSION: Paraproteins may exhibit non-specific binding to long polymeric chains of unfractionated heparin and inhibits the interaction between heparin and antithrombin. As a result, excessive doses of heparin are required to overcome this, which increases the risk of perioperative bleeding and other complications. CONCLUSION: Elevated serum paraprotein levels should be recognised as a cause of heparin resistance during cardiopulmonary bypass.

Proteasome inhibitor-induced coronary vasospasm in multiple myeloma: a case report.

BACKGROUND: Coronary vasospasm is an increasingly recognized cause of myocardial infarction or myocardial ischaemia in patients without obstructive coronary artery disease. A thorough medication review may identify drugs or toxins that could trigger coronary vasospasm. This case provides mechanistic insight into the off-target effect of proteasome inhibition leading to coronary vasospasm in a patient referred with chest pain consistent with typical angina. CASE SUMMARY: A 72-year-old lady presented with anginal chest pain at rest with electrocardiogram evidence of myocardial ischaemia who was referred for invasive coronary angiography. This demonstrated minor coronary disease without an obstructive lesion. Vasoreactivity testing revealed diffuse coronary vasospasm of the left anterior descending artery. Carfilzomib was identified as the trigger for coronary vasospasm. Symptoms resolved without recurrence after appropriate treatment including cessation of the triggering agent. CONCLUSION: Coronary spasm is a rare but important adverse reaction to proteasome inhibitors. This case supports the clinical utility of invasive coronary vasoreactivity testing in patients with ischaemia with no obstructive coronary artery disease.

Non-anaemic iron deficiency.

Iron deficiency without anaemia is common. Patients may present with unexplained, non-specific symptoms. Iron studies will usually show a low ferritin and low transferrin saturation with a normal haemoglobin concentration. The cause of the iron deficiency should be identified and managed. There is limited evidence about the benefits of giving iron to people who do not have anaemia. If there is iron deficiency, most people can be given oral iron supplements. Iron studies are repeated after 60-90 days of oral iron supplements. Further investigations are needed if the iron deficiency has not been corrected. Some patients, including those who have not responsed to oral supplements may benefit from intravenous iron. There is no role for intramuscular injections of iron.

Correction to: Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product.

Page 608, 4 Discussion, right column, second paragraph.

Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product.

INTRODUCTION: ABP 798 is being developed as a biosimilar to rituximab reference product (RP), a CD20-directed cytolytic antibody that is approved in the US and EU for the treatment of non-Hodgkin lymphoma (NHL). METHODS: This randomized, double-blind, comparative clinical study (JASMINE) evaluated the efficacy and safety of ABP 798 compared with rituximab RP. Adult, anti-CD20 treatment naïve patients diagnosed with grade 1, 2, or 3a follicular B-cell NHL expressing CD20 were randomized 1:1 to receive a 375 mg/m2 infusion of either ABP 798 or rituximab RP once weekly for 4 weeks and at weeks 12 and 20. Tumor assessments were performed at baseline and weeks 12 and 28. Primary endpoint was the risk difference (RD) of overall response rate (ORR) of complete response, unconfirmed complete response, or partial response by week 28 based on data from central, independent, and blinded assessments of disease. RESULTS: Of the 256 randomized patients, 254 were treated with ABP 798 (n = 128; 100%) or rituximab RP (n = 126; 98.4%); 96 (78.0%) patients in the ABP 798 group and 87 (70.2%) in the rituximab RP group had a best ORR by week 28. The point estimate of RD in ORR between ABP 798 and rituximab RP from the adjusted generalized linear model for stratification factors was 7.7%. Clinical equivalence was based on sequential testing of the one-sided 95% lower confidence limits and one-sided 95% upper confidence limits of RD in ORR (- 1.4% and 16.8%, respectively) which was within the prespecified non-inferiority margin (- 15%) and non-superiority margin (35.5%), respectively. Results of sensitivity analyses were consistent with the primary efficacy analysis. ABP 798 was also comparable to rituximab RP across additional secondary endpoints, further supporting the conclusion of similarity, and including: RD of ORR at week 12; trough serum concentrations; percent of patients with complete depletion of CD19+ cell count at day 8; safety; and immunogenicity. CONCLUSIONS: These results support a conclusion of similar clinical efficacy between ABP 798 and rituximab RP in patients with follicular lymphoma. NCT NUMBER: NCT02747043; first posted April 21, 2016. EUDRACT NUMBER: 2013-005,542-11; submitted 14 October, 2014.

Two monogenic disorders masquerading as one: severe congenital neutropenia with monocytosis and non-syndromic sensorineural hearing loss.

BACKGROUND: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. METHODS: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. RESULTS: We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. CONCLUSIONS: We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.

Outpatient rituximab, ifosfamide, etoposide (R-IE) in patients older than 60 years with relapsed or refractory diffuse large B-cell lymphoma who are not candidates for stem cell transplantation.

Patients with relapsed-refractory diffuse large B-cell lymphoma (RR-DLBCL) ineligible for autologous stem cell transplantation (autoSCT) have poor survival. Thirty transplant-ineligible patients older than 60 years were administered rituximab 375 mg/m2 day 1, ifosfamide 1333 mg/m2 days 1 to 3, and etoposide 80 mg/m2 days 1 to 3 (R-IE) every 21 days for 6 cycles plus 2 doses of rituximab. Revised international prognostic index 3-4 was seen in 53% and prior rituximab exposure in 60%. The complete and overall response rates were 55% and 76%, respectively. Median progression free survival (PFS) and overall survival were 23 and 24 months, respectively. Patients relapsing within 12 months of prior treatment had a median PFS of 2.5 months compared to 23 months for those relapsing beyond 12 months. Grade 3-4 thrombocytopenia and neutropenia occurred in one and eight patients, respectively. R-IE is an effective, well tolerated regimen in RR-DLBCL patients not fit for autoSCT.

The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia.

Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age (P = .022) and dyslipidemia (P = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued (P = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.