Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is an established complication in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT). Defibrotide is an effective and safe pharmacologic option for treating diagnosed SOS/VOD. By exploring data provided to the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) by centers in Australia and New Zealand, this study aimed to describe the incidence of SOS/VOD and patterns of defibrotide use from 2016 to 2020. Patients who underwent allogeneic hemopoietic stem cell transplantation between 2016 and 2020 were identified from the ABMTRR. Data were extracted for a total of 3346 patients, 2692 from adult centers and 654 from pediatric centers, with a median follow-up of 21.5 months and 33.3 months, respectively. Descriptive statistics were used to describe the patient population, including the incidence of SOS/VOD and defibrotide use. Comparisons were made between patients without SOS/VOD and those with SOS/VOD, divided into defibrotide and no defibrotide cohorts. Associations with overall survival (OS) and day 100 survival with such variables as sex, age, disease at transplantation, stem cell source, conditioning agents, SOS/VOD diagnosis, and use of defibrotide, were determined. The reported incidence of SOS/VOD was 4.1% in adult centers and 11.5% in pediatric centers. Defibrotide was administered to 74.8% of adult patients and 97.3% of pediatric patients with SOS/VOD. Significant variability in the use, dosage, and duration of defibrotide was seen across the adult centers. The day 100 survival rate and median OS for patients managed with defibrotide was 51.8% and 103 days, respectively, for adult patients and 90.4% and not reached, respectively, for pediatric patients. In adults, older age at transplantation, an HLA-matched nonsibling relative donor, and a diagnosis of SOS/VOD treated with defibrotide were associated with reduced OS. In pediatric patients, the patient and transplantation characteristics associated with reduced OS were a diagnosis of SOS/VOD and a ≥2 HLA-mismatched related donor. A collaborative approach across Australasia to diagnosing and managing SOS/VOD, particularly with respect to consistent defibrotide use, is recommended.

BACKGROUND:Cytomegalovirus (CMV) infection increases mortality and morbidity following allogeneic hematopoietic stem-cell transplantation (alloHSCT). Universal antiviral prophylaxis with letermovir is effective but unsubsidized in Australia. Valaciclovir demonstrates anti-CMV activity in high doses, but few current real-world studies explore its use as primary prophylaxis in high-risk patients post-alloHSCT. METHODS:We performed a retrospective analysis of alloHSCT recipients at high risk of clinically significant CMV infection (cs-CMVi), defined as a plasma CMV DNA viral load of >400 IU/ml requiring preemptive therapy, or CMV disease. High-risk recipients were CMV seropositive and underwent T-cell depleted, haploidentical or umbilical cord stem-cell transplants. Consecutive patients transplanted from July 2018 to January 2020, treated with valaciclovir 2 g TDS from day +7 to +100 (HD-VALA), were compared to a historical cohort (July 2017-June 2018) who only received preemptive CMV therapy, and standard valaciclovir (SD-VALA) for varicella/herpes prophylaxis. We compared incidence of and time to cs-CMVi. RESULTS:In the SD-VALA cohort (n = 27, median CMV follow-up duration 259 days), 23/27 (85%) developed cs-CMVi at a median of 39 days. For the HD-VALA cohort (n = 35, median CMV follow-up duration 216 days), 19/35 (54%) developed cs-CMVi, at a median of 68 days. Time to cs-CMVi was significantly longer in HD-VALA cohort (p < .0001). On multivariate analysis, HD VALA reduced the risk of cs-CMVi (HR 0.32, p = .0005). CONCLUSIONS:In alloHSCT recipients at high risk for cs-CMVi, HD-VALA resulted in lower cumulative reactivation, and delayed reactivation, reducing requirement for preemptive CMV therapy in the early post-engraftment period.

Antifungal agents can have complex dosing and the potential for drug interaction, both of which can lead to subtherapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy and haemopoietic stem cell transplant recipients. Antifungal agents can also be associated with significant toxicities when drug concentrations are too high. Suboptimal dosing can be minimised by clinical assessment, laboratory monitoring, avoidance of interacting drugs, and dose modification. Therapeutic drug monitoring (TDM) plays an increasingly important role in antifungal therapy, particularly for antifungal agents that have an established exposure-response relationship with either a narrow therapeutic window, large dose-exposure variability, cytochrome P450 gene polymorphism affecting drug metabolism, the presence of antifungal drug interactions or unexpected toxicity, and/or concerns for non-compliance or inadequate absorption of oral antifungals. These guidelines provide recommendations on antifungal drug monitoring and TDM-guided dosing adjustment for selected antifungal agents, and include suggested resources for identifying and analysing antifungal drug interactions. Recommended competencies for optimal interpretation of antifungal TDM and dose recommendations are also provided.

The authors declare that they have no conflicts of interest.

Background Cytomegalovirus (CMV) is a common, potentially devastating complication of allogeneic haematopoietic stem cell transplantation (alloHSCT). Universal antiviral prophylaxis strategies including letermovir are effective, but unsubsidised in Australia. Prophylactic ganciclovir or valganciclovir are challenging due to myelotoxicity. Valaciclovir demonstrates anti-CMV activity in high doses, but little current data explore prophylaxis in the alloHSCT setting, particularly in haploidentical transplantation. We aimed to evaluate the clinical efficacy and tolerability of high dose valaciclovir (high dose VALA) as CMV prophylaxis in high risk patients undergoing alloHSCT. Methods This study was completed at the Royal Melbourne Hospital, Melbourne Australia. We performed a retrospective analysis of alloHSCT recipients at high risk of CMV reactivation (defined as recipient and/or donor CMV seropositivity, and undergoing T-cell depletion, haploidentical or umbilical cord stem cell transplantation). Patients transplanted between July 2018 - June 2019, treated with high dose VALA (2g TDS) from day +7 to +100 and beyond were compared to a historical cohort (transplanted between July 2017 - June 2018) on standard dose valaciclovir (std dose VALA) (500mg BD until engraftment then 500mg daily). We compared the rates and time to reach a CMV threshold of 400 IU/ml, at which point pre-emptive CMV therapy was commenced. Tolerability was also evaluated. Results Patient demographics are described in Table 1. Of the standard dose VALA cohort, (median follow-up 259 days), 23/31 (74%) developed a viral load >400 IU/mL, requiring pre-emptive CMV therapy. None had CMV disease. Median time to viral load >400 IU/mL was 39 days (range 13 - 68). Of the high dose VALA cohort (median follow-up 209 days), 11/25 (44%) developed a viral load >400 IU/mL, requiring pre-emptive CMV therapy. Of these 11 cases, 7 patients had viral load >400 IU/mL while on high dose VALA prior to D+100, 3 patients had ceased high dose VALA prior to D+100 due to intolerance and in 1 patient this occurred post D+100 while on high dose VALA. One patient developed CMV (gut) disease following early cessation of high dose VALA, whilst on standard dose VALA. Median time to reactivation >400 IU/mL was 64 days (range 26-170). Time to reactivation >400 IU/ml was significantly different between the standard vs high dose VALA cohorts (mean ± SEM; 37.9 ± 2.7 vs 67.8 ± 11.3 days, **p=0.0015). Median duration of high dose VALA prophylaxis was 50 days (range 11-288). Seven (28%) patients continued high dose VALA to day +100 and beyond. Intolerance led to early cessation in 10 (40%) patients (acute kidney injury, n=6; cytopenia, n=3; both, n=1). Other patients ceased due to requirement for definitive CMV therapy (n=6) and unclear reasons (n=2). Conclusions In high risk alloHSCT recipients, high dose VALA is an effective CMV prophylactic strategy resulting in lower CMV reactivation rates, and delays CMV reactivation. This may reduce requirements for myelotoxic CMV treatment during the early post-engraftment period and need for inpatient admission. CMV infection following high dose VALA cessation remains a risk, particularly when dose reductions have occurred due to toxicity, and intolerance and ongoing monitoring is required. Treatment tolerability remains a limitation. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Valaciclovir, for CMV prophylaxis

Abstract Background Thymoglobulin (Genzyme, Mass., USA) is used in allogeneic hematopoietic cell transplantation (alloHCT) for graft-versus-host disease (GVHD) prophylaxis. Infusion-related reactions are common and challenging to manage. We explored characteristics of Thymoglobulin infusion reactions (TIRs), predictors of TIR and the relevance of TIR to outcomes after alloHCT. Method We reviewed records of all patients who received Thymoglobulin prior to alloHCT for hematologic malignancy between the years 2007 and 2013 inclusive. We defined TIR as fever (temperature ≥ 38°C); rigors; or two or more episodes of heart rate > 120, respiratory rate > 26, oxygen saturation < 92%, systolic blood pressure < 90 mmHg, occurring within 24 hours of commencement of Thymoglobulin infusion, without bacteremia. Results One hundred and thirteen patients were studied (male 62%, median age 43, range 17-61). The most common indication for alloHCT was acute leukemia (n = 69) followed by chronic lymphoproliferative disorder (n = 22) and myelodysplastic syndrome (n = 10). All patients received an initial infusion of 0.5 mg/kg over 6 hours on day -3. Day -2 and -1 doses were 2 mg/kg then 2 mg/kg (n = 77); 1.5 mg/kg then 4 mg/kg (n=16); 1.5 mg/kg then 2 mg/kg (n = 16); 1 mg/kg then 2 mg/kg (n = 1); or unknown (n = 7). All patients received premedication with acetaminophen, an antihistamine, and methylprednisolone 1 mg/kg, approximately one hour prior to each Thymoglobulin infusion. Fifty-one patients (45%) experienced TIR after the first infusion. Of these, 88% first developed features of TIR during the infusion. Features of TIR were fever in 90%, rigors in 58%, tachycardia in 34%, hypotension in 18%, tachypnea in 16% and hypoxia in 10%. Median time from start of first Thymoglobulin infusion to onset of TIR was 265 minutes (range, 15 to 705). Four patients had subsequent Thymoglobulin doses omitted due to TIR (two after first dose, two after second dose). Twelve patients had first onset of TIR after second infusion, and eleven after the third infusion. No patients required intensive care transfer. On univariate analysis (Fisher exact test), age over 30, choice of conditioning regimen, and alloHCT for chronic lymphoproliferative disorder, were significantly associated with day -3 TIR, whereas conditioning intensity, alloHCT in remission, and day -3 absolute lymphocyte count and white cell count were not associated with day -3 TIR. On multivariate analysis (logistic regression), only choice of conditioning remained significant. The influence of conditioning remained significant after adjustment for age and disease type. Incidences of day -3 TIR were 13% (2/16) for total body irradiation (TBI)/etoposide (VP16), 19% (5/26) for busulfan/cyclophosphamide (BuCy), 60% (18/30) for fludarabine-based reduced intensity regimens (without TBI; mostly fludarabine and melphalan, n = 23), and 63% (26/41) for cyclophosphamide/TBI (CyTBI). Compared to CyTBI, BuCy (odds ratio 0.1, 95% CI 0.0-0.4, P=.001) and TBI-VP16 (odds ratio 0.1, 95% CI 0.0-0.3, P = .002) were associated with markedly reduced incidence of day -3 TIR. The presence of day -3 TIR did not significantly influence survival, non-relapse mortality, relapse or acute or chronic GVHD. Conclusion TIR in alloHCT, is a predictable toxicity which is manageable and varies in incidence with particular conditioning agents. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction Cytomegalovirus (CMV) reactivation is a common complication of allogeneic stem cell transplantation (ASCT), particularly within the first 100 days after stem cell infusion (D+100). It results in significant cost, morbidity and potentially mortality in the case of severe CMV disease. Intravenous polyvalent immunoglobulin (IVIg) has been used to support immunoglobulin levels post-ASCT in an attempt to reduce opportunistic infection and graft versus host disease (GVHD). Historically we employed routine IVIg therapy (0.5g/kg weekly for the first 12 weeks) as standard post-ASCT care. In July 2012 funding was withdrawn for IVIg for this indication. Since 2001 we have been using weekly quantitative polymerase chain reaction (PCR) analysis to monitor for CMV reactivation during the first 100 days after ASCT. We investigated whether the omission of post-ASCT IVIg altered the rate or consequences of CMV reactivation in the immediate post-ASCT setting. Methods We analysed sequential ASCT recipients from 2010 to 2014 and identified 100 patients who met the predetermined eligibility criteria. These subjects were then divided into two uniformly treated populations: ASCT recipients who either received (Group A, n=50) or did not receive (Group B, n=50) IVIg as part of their post-ASCT care. Inclusion criteria: matched adult unrelated or sibling donor source, age ≥18 years and CMV positive recipient by serology within 3 months prior to ASCT or CMV positive donor by serology. Exclusion criteria: CMV negative donor and recipient (D-/R-), umbilical cord donor source, death before day 100 or incomplete data available for analysis. CMV reactivation was defined as any detectable level by quantitative CMV PCR in the peripheral blood. The lower limit of detection for the assay was 20 copies/mL. A plasma CMV viral load of ≥400 copies/mL resulted in treatment with intravenous ganciclovir (5mg/kg twice daily) which was continued for a minimum of 2 weeks and was thereafter guided by weekly CMV viral load response. Patients with a CMV viral load of <400 copies/mL were observed with no specific treatment. CMV reactivation was recorded as minor (not requiring ganciclovir treatment) if CMV viral load remained <400 copies/mL and as major (requiring treatment) if CMV viral load reached ≥400 copies/mL within a single episode of infection. Time to first CMV reactivation and cumulative days of major CMV reactivation were also recorded. Results A total of 169 consecutive subjects were screened for study entry. Abstract 2482. Table 1:Cohort compositionsTotal screenedD-/R-Death *: 1 subject had active CMV infection at time of death #: 2 subjects had active CMV infection at time of death Demographics were similar between Group A and Group B in terms of age (median 51.0 vs 48.5 years), sex (male: 33 vs 29) and transplant indication (acute leukaemia/MDS 28 vs 28; lymphoma 11 vs 11) and D+/R- transplants (9 vs 11). Comparing Group A and Group B, the number of subjects who had a CMV reactivation was 37 vs 39 and for minor reactivations the number was 28 vs 25. The median time to CMV infection was likewise similar: D+38 vs D+35. The number of patients with a major reactivation, however, was significantly different between Group A and Group B (13 vs 25 – RR 0.52, 95% CI [0.30-0.90], p 0.018), as was the cumulative number of days of major reactivation (181 vs 604 – RR 0.30, 95% CI [0.25-0.35], p <0.0001). The median number of days of major reactivation per patient was 13 vs 21 respectively. Conclusion Routine IVIg use in the immediate post-ASCT period did not reduce the rate or latency of CMV reactivation but was associated with a lower magnitude of CMV reactivation and a reduced requirement for anti-CMV therapy. These findings suggest that the use of IVIg post-ASCT may assist in reducing CMV viral burden. Disclosures No relevant conflicts of interest to declare.