INTRODUCTION:Thrombocytopenia has heterogeneous mechanisms, including peripheral destruction, consumption, and reduced marrow production. This study developed an unsupervised global complete blood count/research-use-only/cell population data (CBC/RUO/CPD) phenotyping model and evaluated post hoc whether thrombocytopenia severity and clinically adjudicated mechanisms were enriched within the resulting clusters. METHODS:Retrospective haematology analyser data from 254 289 unique specimens were analysed after cleaning 537 279 extracted rows. Exploratory missingness filtering retained 123 features and 173 851 complete-case specimens. The final model used a refined 41-feature CBC_EXTENDED complete-case dataset containing 241 591 specimens. Features were standardised, reduced using principal component analysis to 20 components explaining 92.94% of cumulative variance, and clustered using k-means. Thrombocytopenia thresholds and electronic health record (EHR) adjudicated primary mechanism labels were evaluated post hoc. RESULTS:The final global k-means model (k = 4) generated four broad haematological clusters comprising 14%-37% of specimens. Internal separation was modest but interpretable, with sampled silhouette 0.10, Davies-Bouldin 2.21, and Calinski-Harabasz 6536.92 in the fixed 60 000 specimen model comparison analysis. Cluster 3 showed progressive post hoc enrichment with thrombocytopenia severity, accounting for approximately 46%, 60%, and 71% of specimens with platelet counts < 150, < 100, and < 50 × 109/L, respectively. In 225 clinically annotated thrombocytopenic specimens, k-means k = 4 showed limited but non-random concordance with adjudicated mechanisms (purity 0.59; adjusted Rand index 0.14; normalised mutual information 0.18). CONCLUSION:Unsupervised global CBC/RUO/CPD clustering identified broad laboratory phenotypes with post hoc enrichment for thrombocytopenia severity and adjudicated mechanisms. These findings support underutilised analyser-derived parameters for laboratory phenotyping and hypothesis generation, not standalone diagnosis.

Complement-amplifying events/conditions associated with thrombotic microangiopathy (TMA) include pregnancy/postpartum period, severe hypertension, autoimmune diseases, drug exposures, infections and organ transplantation. Some of these 'triggers' may exist comorbidly with atypical haemolytic uraemic syndrome (aHUS; a complement-mediated form of TMA), unmask previously undiagnosed aHUS, or occur secondary to aHUS, thus creating a considerable diagnostic challenge. A major goal in patients presenting with TMA is to differentiate complement-mediated aHUS from other causes of TMA such that appropriate targeted treatment with complement 5 (C5) inhibitors can be initiated rapidly to avoid irreversible end-organ damage. To this end, nephrologists and haematologists from Australia, Hong Kong, Japan, Korea and Taiwan met virtually to discuss the management of TMA/aHUS in the presence of trigger conditions, focusing on the role of C5 inhibitors. To assist primary healthcare physicians and specialists from other disciplines in identifying and managing aHUS in the presence of triggers, the panel developed diagnostic and treatment algorithms as the main meeting output. Individual algorithms are presented for the settings of pregnancy, hypertension, autoimmune diseases, drug exposures, and kidney transplant. The algorithms combine clinical evidence with the panel's collective expertise to provide practical steps to differentiate aHUS and can be refined by local experts to reflect respective healthcare systems, approval and reimbursement procedures, resources and access to treatments for aHUS in any Asia-Pacific country.

BACKGROUND:An increasing number of patients in Australia are taking direct oral anticoagulants for a variety of indications since their introduction in the treatment landscape. There has always been some concern about the optimal management approach in the setting of major and/or life-threatening bleeding. In particular, patients who present with factor Xa inhibitor-associated intracranial haemorrhages are associated with high morbidity and mortality. AIM:To determine the efficacy of pro-haemostatic agents in the management of factor Xa inhibitor-related intracranial haemorrhages. METHODS:A retrospective audit of rivaroxaban and apixaban-associated intracranial haemorrhages was performed between January 2015 and December 2021, inclusive. RESULTS:The bleeding-related mortality was similar between the patients who received pro-haemostatic agents versus patients who did not receive pro-haemostatic agents (90% vs 93% respectively). The mean volume expansion for those who received pro-haemostatic agents was +1.0mL versus -6.8 mL for patients who did not receive pro-haemostatic agents (P = 0.51, 95% confidence interval: -11.7 to +5.9). CONCLUSION:Patients who presented with intracranial haemorrhages in the presence of clinically significant direct oral anticoagulant levels had a higher risk of mortality that does not appear to change with the use of prohaemostatic agents. The efficacy of prohaemostatic agents may not be as clinically significant based on real-world experience in contrast to previously reported studies.

Background/Purpose: Autoimmune cytopenias (AICs), including immune thrombocytopenia (ITP), warm autoimmune hemolytic anemia (wAIHA), cold agglutinin disease (CAD), and Evans Syndrome (ES), are rare, chronic disorders characterized by destruction of blood cells, mediated by autoreactive antibodies. Existing therapies are often immunosuppressive and associated with short- and long-term morbidities. A meaningful proportion of patients are unable to achieve a complete response with standard of care, and some are refractory to multiple lines of therapy. Among patients who do initially respond, durability of response can be challenging, and relapse is not uncommon. Long-lived plasma cells are critical drivers of autoantibody production but are not specifically targeted by current therapies. OM336 is an investigational, humanized, bispecific, IgG4-like T cell engager antibody that targets both B cell maturation antigen (BCMA) and CD3, leading to depletion of autoreactive plasma cells as well as memory B cells, with the goal of “resetting” the immune system to achieve sustained remission off therapy. Previously published data from an investigator-initiated study have demonstrated the efficacy of OM336 for the treatment of highly refractory AIHA, with durable benefit after discontinuation of standard of care therapies in the absence of any additional transfusions1. Based on these data, this phase 1b study has been initiated (NCT07083960). Study Design and Methods: This is an open-label, Phase 1b, multinational, multiple ascending dose study to assess the safety and tolerability of OM336 in adult participants with active AICs (e.g., ITP, wAIHA, CAD or mixed forms, including ES), that are relapsed/refractory to standard therapies. Eligible participants will be enrolled into dose escalation cohorts in a sequential fashion. After the completion of dosing in each cohort, an Internal Monitoring Committee will review the emerging safety data to determine whether participants in the next cohort may be dosed. Participants who achieve clinical response may taper or discontinue their background therapies for AIC, per investigator judgment. A total of up to 32 participants are to be enrolled: three (3) in each dose escalation cohort, for a total of 12 participants across Cohorts A1-A4, and up to five (5) in each dose expansion cohort, for a total of 20 participants across Cohorts B1-B4. Objectives: The primary endpoints are safety and tolerability as assessed by the incidence and severity of treatment-emergent adverse events. Secondary endpoints include PK profiles and anti-drug antibody titers. Exploratory endpoints include measures of efficacy (cell counts and other laboratory parameters), patient-reported outcomes, biomarkers (e.g., soluble BCMA levels, markers of inflammation), and glucocorticoid- and other immunosuppressive-sparing effects. Eligibility: Participants must be 18-75 years of age, with active, relapsed/refractory ITP, wAIHA, CAD, mixed hemolysis, or ES, despite ≥1 prior therapy, with or without other concurrent autoimmune diseases. Key exclusion criteria include prior BCMA-targeting therapy, recent B cell depletion, or uncontrolled infection. Enrolment: Up to 32 participants are to be enrolled across approximately 12 sites in the United States, the United Kingdom, and Australia. Conclusion: Patients with relapsed/refractory AICs have unmet medical need requiring additional safe and effective therapy options. This Phase 1b study evaluates a potential treatment for AICs utilizing OM336, a novel T cell engager that targets B cell maturation antigen (BCMA) and CD3. The study is open and actively enrolling patients. References: Zhang L, et al. BCMA-Targeted T-Cell Engager for Autoimmune Hemolytic Anemia after CD19 CAR T-Cell Therapy. N Engl J Med. 2025 Jun 12;392(22):2282-2284. doi: 10.1056/NEJMc2502297. PMID: 40499177.

Hemophagocytic lymphohistiocytosis (HLH) is an immune response syndrome characterized by excessive inflammation and tissue destruction. A limited number of cases involving HLH patients with concomitant multiple myeloma (MM), leading to significant mortality, have been documented, underscoring the importance of timely diagnosis. We present the case of a 78-year-old previously healthy male admitted to our hospital with a newly diagnosed MM. Subsequently, he was diagnosed with HLH and received treatment with anakinra, intravenous immunoglobulin, and dexamethasone. This case report highlights the unique aspect of being the first documented instance of myeloma-associated HLH treated with anakinra.

We would like to update readers on the treatment landscape for severe chronic immune thrombocytopenia (ITP) in the wake of recent welcome changes to the Pharmaceutical Benefits Scheme (PBS) reimbursement criteria in Australia and since the publication of our consensus treatment guidelines.1 First, splenectomy is no longer required to access thrombopoietin receptor agonists (TPO-RAs) such as romplostim and eltrombopag. This change aligns with management guidelines and clinical data showing no difference in outcome between patients with splenectomy versus those without splenectomy receiving TPO-RAs and permits ITP treatment selection best tailored towards patient preferences and clinical factors.1-4 Second, a new TPO-RA avatrombopag is now PBS listed as an alternative to romiplostim and eltrombopag. There are no head-to-head data to suggest superiority of one TPO-RA over another, but differing administration routes, dose schedules, interactions and side effect profiles may assist clinician–patient decision-making with treatment selection. Table 1 highlights the main differences between the available TPO-RA agents. Bone marrow reticulin Thrombosis Rebound thrombocytopenia Risk of progression of myeloid malignancies Chelates polyvalent cations (such as calcium and iron) OATP1B1 and BCRP substrates caution (e.g. ciclosporin) Reduce statin dose Hepatotoxicity Cataracts Thrombosis Rebound thrombocytopenia Bone marrow reticulin Risk of progression of myeloid malignancies CYP2C9 and CYP3A4 inhibitors may increase avatrombopag levels (e.g. fluconazole) CYP2C9 and CYP3A4 inducers may reduce avatrombopag levels (e.g. rifampicin) Bone marrow reticulin Thrombosis Rebound thrombocytopenia Risk of progression of myeloid malignancies Third, switching between TPO-RAs for any reason including tolerance or failure is now permissible at any time. Previously, switching was not allowed after 24 weeks of therapy, even after the development of an unanticipated adverse event or eventual loss of response. Although one may anticipate an equivalent TPO-RA class effect with these agents, retrospective data demonstrate switching between these drugs for inadequate responses can be successful with improved platelet counts and reductions in concomitant medications.5, 6 Thus, with the relaxation of switching rules and the PBS listing of avatrombopag, we now have an additional line of therapy rather than just another oral alternative to romiplostim or eltrombopag. Fourth, a clinical response as determined by the treating physician is sufficient to warrant ongoing PBS reimbursement in lieu of absolute platelet targets that were insensitive to clinically apparent improvements in bleeding and quality of life (QoL). Previously, the threshold for some patients to meet platelet response criteria devised for clinical trial environments was extremely difficult to achieve for PBS reimbursement purposes, even though there was clear benefit for patients in terms of reduced bleeding, improved platelet counts and lower concomitant ITP therapies. Along with penalising patients who needed intermittent rescue therapies, these measures had seemed to restrict TPO-RA access for the patients with the most severe disease. This has now been rectified as the threshold for ongoing use is clinically determined by the treating physician most cognisant of their patients' medical priorities. Finally, rituximab (intravenous B-cell depleting anti-CD20 monoclonal antibody) is now unrestricted on the PBS. Previously, off-label rituximab use was either self-funded or compassionately supported with a bias towards lower dosing schedules that were more cost-effective.7 Any new enthusiasm for PBS-reimbursed rituximab is probably balanced by recent coronavirus disease 2019 (COVID-19) pandemic concerns and tempered by previous analyses demonstrating only a modest long-term success rate, particularly when administered in monotherapy.8, 9 There are still many uncertainties ahead for optimal ITP management such as targeting the natural history of ITP before it becomes chronic, exploring the role of TPO-RAs in earlier stages of ITP, predicting and targeting patients at the highest risk of bleeding and rationally drafting the optimal sequence or combination of novel and existing therapies for severely refractory patients. Data from the iWISh survey suggest that patients prefer to halt the progression or worsening of their ITP above QoL and bleeding, in contradistinction to their physicians.10 The ultimate goal for most patients is to optimise initial therapy of newly diagnosed ITP to prevent progression to the chronic phase. The recent FLIGHT (Newly Diagnosed Immune Thrombocytopenia Testing the Standard Steroid Treatment Against Combined Steroid & Mycophenolate) study, which explored the addition of mycophenolate mofetil to corticosteroids in first-line therapy, demonstrated an improved response and a halving of the progression rate to chronic ITP. This was at the expense of worsened patient-reported QoL measures at the end of the study11; however, it seems reasonable to expect that the longer-term impact on cumulative disease and treatment burden by preventing the development of chronic ITP will eventually lead to better QoL. Treatment strategies addressing the pervasive but insidious symptom of fatigue in ITP are also lacking. Patients with newly diagnosed ITP remain vulnerable to the uncertainties of their diagnosis, anxious about their prognosis, and still have limited treatment options available to them. Despite these therapeutic challenges, we welcome these updates to the PBS listings for the TPO-RAs. We look forward to the promise of these and other novel agents in the modern treatment landscape ahead. Amongst newer therapies, fostamatinib (spleen associated tyrosine kinase inhibitor) was listed by the Food and Drug Administration for chronic ITP in 2018 but remains unavailable in Australia. Clinical trials in ITP have recently been completed for rilzabrutinib (Bruton’s tyrosine kinase [BTK] inhibitor) and efgartigimod (neonatal Fc receptor [FcRn] inhibitor).12, 13 As new clinical trials are opening across Australia now with B-cell activating factor [BAFF] and a proliferation-inducing ligand [APRIL] inhibitors, the prospect of better targeting the immune lesion in ITP beckons.

Carfilzomib-induced thrombotic microangiopathy (TMA): an under-recognised

INTRODUCTION:Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal microangiopathy, with an untreated mortality rate of around 90%. TTP is caused by severe deficiency in ADAMTS13, which results in accumulation of ultra large von Willebrand factor multimers, triggering a consumptive thrombocytopenia, microangiopathic hemolytic anemia and end-organ dysfunction and damage. Demonstration of severe ADAMTS13 deficiency is diagnostic for TTP, but long turnaround times for quantitative activity testing often necessitates empirical plasma exchange and/or caplacizumab treatment.METHODS:Multisite (n = 4) assessment of the Technoscreen ADAMTS13 activity assay (semi-quantitative flow through screening assay) for diagnosis/exclusion of TTP compared to current standard practice of quantitative assays (ELISA or chemiluminescence AcuStar).RESULTS:A total of 128 patient samples were analyzed, with quantitative ADAMTS13 values ranging from 0% to 150%. The Technoscreen assay demonstrated high sensitivity and negative predictive value (NPV) for ADAMTS13 deficiency, but low specificity and positive predictive value (PPV), especially with one lot of reagent. Good inter-observer reliability was demonstrated. Excluding one possibly compromised batch and other test failures, results of 80 samples yielded sensitivity of 100% (95% CI = 84-100), specificity of 90% (80-95), PPV 77% (58-89) and NPV 100% (93-100).CONCLUSION:The Technoscreen assay appears to be a reliable screening test for ADAMTS13 activity to exclude TTP in routine clinical practice. However, the assay falsely identified ADAMTS13 deficiency in many cases, partially batch related, which mandates confirmation with a quantitative assay, as well as initial assessment of kits as 'fit for purpose' prior to use for patient testing.

BackgroundWe present this challenging case report of Atypical Haemolytic Uremic Syndrome (aHUS) presenting with multi-organ involvement in a patient and heterozygous CFHR1/CFHR3 gene variant, which was refractory to initial eculizumab therapy.Case presentationA forty-three year old female presented with aHUS and had heterozygous disease-associated deletions in the complement genes CFHR1/CFHR3. She had progressive kidney failure and severe extra-renal manifestations including cardiomyopathy and haemorrhagic cystitis; as well as pulmonary, gastrointestinal and neurological involvement. The initial kidney biopsy revealed thrombotic microangiopathy (TMA) changes involving all glomeruli. Clinical improvement was initially seen during eculizumab initiation with suppressed CH50 level, but a new rhinovirus/enterovirus upper respiratory tract infection triggered further severe multi-organ disease activity. The extra-renal manifestations stabilised, then ultimately improved after a period of eculizumab dose intensification. However, the impact on dose intensification on this improvement is unclear. Despite the extra-renal clinical improvement, she ultimately progressed to end-stage kidney disease (ESKD), commencing peritoneal dialysis for three years before undergoing a successful uncomplicated cadaveric kidney transplant without prophylactic eculizumab. Two years after transplant, she has excellent transplant graft function without any further disease recurrence.ConclusionsThis case highlights the concept of extra-renal manifestations in aHUS initially resistant to eculizumab, which potentially responded to dose intensification. Whilst organ injuries are potentially reversible with timely targeted treatment, it appears that the kidneys are most vulnerable to injury.

BackgroundImmune thrombocytopenia (ITP) has been reported following COVID-19 vaccination. After index case fatalities, there was concern among patients both with and without a prior history of ITP in Australia.ObjectivesTo describe treatment outcomes of ITP after COVID-19 vaccination and compare relapsed vs historical pre-COVID-19 ITP cohorts.MethodsWe collected ITP cases in Australia within 6 weeks of receiving any COVID-19 vaccination as part of primary vaccination (up to October 17, 2021). Second, we reviewed platelet charts in a historical ITP cohort to determine whether platelet variability was distinct from relapsed ITP after vaccination.ResultsWe report on 50 patients (37 de novo, 13 relapsed ITP) vaccinated from March 22, 2021, to October 17, 2021. Although there was 1 fatality, bleeding was otherwise mostly minor: (70% WHO bleeding grade <2). De novo ITP was more likely after AstraZeneca ChAdOx1 nCoV-19 (89%) than Pfizer BNT162b2 (11%). Most patients responded quickly (median, 4 days; complete response, 40 of 45 [89%]). In the historical cohort, only 6 of 47 patients exhibited platelet variability (>50% decrease and platelets <100 × 109/L), but median platelet nadir was significantly higher than vaccination relapse (27 vs 6 × 109/L, P =.005).ConclusionITP was more frequently reported after AstraZeneca ChAdOx1 nCoV-19 than Pfizer BNT162b2 vaccination. Standard ITP treatments remain highly effective for de novo and relapsed ITP (96%). Although thrombocytopenia can be severe after vaccination, bleeding is usually mild. Despite some sampling bias, our data do not support a change in treatment strategies for patients with ITP after vaccination.

INTRODUCTION:The absence of high quality evidence for basic clinical dilemmas in immune thrombocytopenic purpura (ITP) underlines the need for contemporary guidelines relevant to the local treatment context. ITP is diagnosed by exclusions, with a hallmark laboratory finding of isolated thrombocytopenia.MAIN RECOMMENDATIONS:Bleeding, family and medication histories and a review of historical investigations are required to gauge the bleeding risk and possible hereditary syndromes. Beyond the platelet count, the decision to treat is affected by individual bleeding risk, disease stage, side effects of treatment, concomitant medications, and patient preference. Treatment is aimed at achieving a platelet count > 20 × 109 /L, and avoidance of severe bleeding. Steroids are the standard first line treatment, with either 6-week courses of tapering prednisone or repeated courses of high dose dexamethasone providing equivalent efficacy. Intravenous immunoglobulin can be used periprocedurally or as first line therapy in combination with steroids.CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT:There is no consensus on choice of second line treatments. Options with the most robust evidence include splenectomy, rituximab and thrombopoietin receptor agonists. Other therapies include azathioprine, mycophenolate mofetil, dapsone and vinca alkaloids. Given that up to one-third of patients achieve a satisfactory haemostatic response, splenectomy should be delayed for at least 12 months if possible. In life-threatening bleeding, we recommend platelet transfusions to achieve haemostasis, along with intravenous immunoglobulin and high dose steroids.

Aims To describe the baseline characteristics and treatment of Australian patients diagnosed with atypical haemolytic uraemic syndrome (aHUS) reported to the Global aHUS Registry. Methods Descriptive analysis of the Australian cohort with aHUS (n = 106) was undertaken for demographics, disease characteristics and prior treatment with eculizumab; comparing with the global cohort (n = 1688) for certain pre-specified disease characteristics. Results In Australia, almost two-thirds of patients diagnosed with aHUS were female and over 80% of patients were Caucasians, with similar proportions reported in the global cohort. Less than 6% of patients in the Australia and global cohorts were reported to have a history of autoimmune disease (4% vs 2%, respectively; P = .21) or cancer (5% vs 5%, respectively; P = .93), conditions that have been associated with secondary HUS. In the Australian cohort, 26% had received a kidney transplant and 68% of patients had received eculizumab. Kidneys were the most common organ involvement, followed by gastrointestinal tract (26%) and cardiovascular system (19%), with 35% of patients reported to have had at least two organs involved within 6 months prior to baseline visit or entry into the registry. Complement factor H was the most common pathogenic complement gene variant in the Australian patients. Conclusion Data from the aHUS registry confirms and defines region-specific disease characteristics among a selected group of Australian children and adults with aHUS reported to the registry. Ongoing and more inclusive data will provide further information about temporal trends and treatment outcomes, representing a unique opportunity for clinicians and researchers to further develop knowledge surrounding this rare disease.

BACKGROUND:Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal disorder caused by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency. Prompt identification/exclusion of TTP can thus be facilitated by rapid ADAMTS13 testing. The most commonly utilized (enzyme-linked immunosorbent assay [ELISA]-based) assay takes several hours to perform and so does not generally permit rapid testing. OBJECTIVES:To evaluate the utility of a new automated test for ADAMTS13 activity, the HemosIL AcuStar ADAMTS13 Activity assay, based on chemiluminescence and able to be performed on an ACL AcuStar instrument within 33 minutes. PATIENTS/METHODS:This multicenter (n = 8) assessment included testing of more than 700 test samples, with similar numbers of prospective (n = 348) and retrospective (n = 385) samples. The main comparator was the Technozym ADAMTS13 Activity ELISA. We also assessed comparative performance for detection of ADAMTS13 inhibitors using a Bethesda assay. RESULTS:Overall, the chemiluminescent assay yielded similar results to the comparator ELISA, albeit with slight negative bias. ADAMTS13 inhibitor detection was also comparable, albeit with slight positive bias with the AcuStar assay. Assay precision was similar with both assays, and we also verified assay normal reference ranges. CONCLUSIONS:The HemosIL AcuStar ADAMTS13 Activity assay provided results rapidly, which were largely comparable with the Technozym ADAMTS13 Activity ELISA assay, albeit lower on average. Conversely, inhibitor levels tended to be identified at a higher level on average. Thus, the HemosIL AcuStar ADAMTS13 Activity assay provides a fast and accurate means to quantitate plasma levels of ADAMTS13 for TTP/ADAMTS13 identification/exclusion, and potentially also for other applications.

Background Pregnancy-related Atypical Haemolytic Uremic Syndrome (P-aHUS) is a rare condition affecting genetically predisposed women during pregnancy. It is often difficult to diagnose and has a significant impact on maternal and foetal outcomes. It is characterised by microangiopathic haemolytic anaemia and kidney injury from thrombotic microangiopathy. Case presentation A 27-year-old female of Lebanese descent presented at 36 weeks’ gestation with foetal death in-utero (FDIU) with placental abruption on a background of previously normal antenatal visits. She was coagulopathic and anaemic with anuric acute kidney injury, requiring emergency Caesarean section, intubation and dialysis. Her coagulopathy rapidly resolved, however, her anaemia and renal dysfunction persisted. A diagnosis of P-aHUS was made, and she was empirically treated with Eculizumab. Her ADAMTS13 level was normal, effectively excluding thrombotic thrombocytopenic purpura. Within 2 weeks of treatment her haematological parameters improved, and her renal function began to recover and within 2 months she became dialysis independent. Conclusion This case highlights the challenges of a timely diagnosis of P-aHUS from other pregnancy-related diseases. Although our patient is dialysis-independent, her risk of relapse remains high with subsequent pregnancies. Currently we are awaiting her genetic sequencing to complete her assessment for underlying mutations and are determining the safest approach to a future planned pregnancy.

Background DLBCL is the most common subtype of non-Hodgkin lymphoma in elderly patients (age ≥70). R-CHOP is the standard of care for upfront treatment of fit patients, but may not be tolerated in patients with advanced age and/or comorbidities. There is no established standard of care for this group of patients and dose reduction (R-miniCHOP) or avoidance/replacement of anthracyclines are common strategies, aiming to deliver tolerable immunochemotherapy and provide meaningful outcomes and potential cure. R-CEEP is a dose-reduced regimen that incorporates etoposide and an alternate anthracycline epirubicin. We describe our single-centre experience with R-CEEP for elderly (age ≥70) or unfit patients (CIRS-G >6) with newly-diagnosed or relapsed DLBCL deemed unsuitable for R-CHOP. Method All patients receiving R-CEEP for a histological diagnosis of DLBCL at Royal Prince Alfred Hospital from 2000 to 2019 were retrospectively reviewed. R-CEEP (rituximab 375mg/m2 day 1, cyclophosphamide 300mg/m2 day 1, epirubicin 50mg/m2 day 1, etoposide 100mg/m2 day 1 and prednisolone 50mg daily for days 1-5) was delivered every 14 or 21 days at physician discretion planning for 6 cycles. GCSF and antimicrobial prophylaxis were used at physician discretion. The cardiac ejection fraction was assessed as satisfactory (>50%) prior to commencement. Baseline demographics, R-IPI, co-morbidities as assessed by CIRS-G, treatment response and adverse events (AEs) were recorded. Results Data from 61 patients were reviewed; 54 received R-CEEP for de novo DLBCL and 7 for DLBCL with a background of previously-treated lymphoma (1 DLBCL; 6 low-grade NHL). The median age at diagnosis was 80 (range 34-93), with 79% aged 75 and 28% aged 85. Thirty-three patients (54%) were female; 87% had Ann Arbor stage III/IV and 52% had R-IPI 3-5. Median CIRS-G was 9 (range 2-20) with 74% of patients having CIRS-G >6. GCSF prophylaxis was used in 67%. The median follow-up was 2.7 years (range 0.1-10.0 years). Overall response was 54/61 (89%), with complete response (CR) in 42 (69%), partial response (PR) in 12 (20%) and progressive disease (PD) in 1 (2%). Response was not assessed in 6 patients due to early treatment discontinuation for palliation or AEs (4), cerebral palsy (1) and loss to follow-up (1). In patients receiving R-CEEP as upfront therapy, CR was obtained in 38/54 (70%), PR in 10/54 (19%) and 6 were not assessed as above. In the 7 patients receiving R-CEEP as salvage therapy, 4 obtained CR, 2 PR and 1 had PD. Median PFS and OS for the total cohort were 5.2 and 9.4 years respectively; for de novo DLBCL patients, 7.1 and 9.4 years and for patients receiving salvage therapy, 1.1 and 2.0 years. There was no statistically significant difference in PFS or OS when comparing patients aged <80 and ≥80, or with CIRS-G ≤6 and >6, or CIRS-G ≤9 and >9. Relapsed disease was identified in 19 patients (31%) during follow-up. Of the 75 AEs reported, grade 3/4 AEs accounted for 67%. Infective complications were the most frequent (53%; 40) and febrile neutropenia accounted for 8 AEs. Grade 3/4 haematological toxicity occurred in 19% (14). Despite this, the majority (43/61; 70%) received six cycles of R-CEEP. In the remaining 18 patients, 5 completed 6 cycles with dose-reduction and 13 patients discontinued therapy due to serious AEs (9), treatment intolerance (2) or patient preference (2). Of the 29 deaths recorded during the follow-up period, 18 were due to relapsed/progressive disease; 5 to infection (4 of these in CR, 0.5 to 9 years after the end of treatment, and 1 of urinary sepsis in a patient 3 months after early treatment discontinuation due to toxicity) and 6 to unrelated causes. Discussion We demonstrate that R-CEEP is an effective and deliverable immunochemotherapy in elderly or unfit patients with DLBCL. Furthermore, survival outcomes were not impacted by CIRS-G >9 or age ≥80, illustrating efficacy and tolerability even in patients predicted to have a particularly poor prognosis. Our cohort outcomes are not inferior to those reported in elderly fit patients treated with other dose-reduced regimens including R-miniCHOP (Peyrade et al, Lancet Oncology 2011) and R-miniCEOP (with epirubicin; Merli et al, Leukemia and Lymphoma 2012). This data supports the use of R-CEEP as an alternative immunochemotherapy option for patients with DLBCL who may not be candidates for R-CHOP. Disclosures Iland: Celgene: Other: Speaker honorarium. Ho:La Jolla: Other: investigator meeting travel costs; Novartis: Other: investigator meeting travel costs; Janssen: Other: investigator meeting travel costs; Celgene: Other: investigator meeting travel costs.

Pregnancy is a well-recognised trigger of atypical haemolytic syndrome (P-aHUS) and often occurs in the post-partum period. Similar to atypical haemolytic uremic syndrome, it carries a poor prognosis with high morbidity particularly in the form of renal failure. Early recognition and intervention is crucial in its management particularly with the recent availability of eculizumab, a humanized monoclonal antibody to complement component C5, which has demonstrated drastic improvement in prognosis. The issue, however, is arriving at a timely diagnosis given the considerable amount of overlap in the clinical and biochemical manifestation of P-aHUS, HELLP syndrome (haemolysis, elevated liver enzyme and low platelet count) and other hypertensive disorders of pregnancy. We present a case report and literature review that highlights the clinical conundrum of arriving at the diagnosis. We also highlight the importance of early management of P-aHUS with eculizumab and its impact on improving morbidity.