Healthcare Resource Utilization and Cost Associated with Allogeneic Hematopoietic Stem Cell Transplantation: A Scoping Review.

This scoping review summarizes the evidence regarding healthcare resource utilization (HRU) and costs associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study was conducted in accordance with the Joanne Briggs Institute methodology for scoping reviews. The PubMed, Embase, and Health Business Elite Electronic databases were searched, in addition to grey literature. The databases were searched from inception up to November 2022. Studies that reported HRU and/or costs associated with adult (≥18 years) allo-HSCT were eligible for inclusion. Two reviewers independently screened 20% of the sample at each of the 2 stages of screening (abstract and full text). Details of the HRU and costs extracted from the study data were summarized, based on the elements and timeframes reported. HRU measures and costs were combined across studies reporting results defined in a comparable manner. Monetary values were standardized to 2022 US Dollars (USD). We identified 43 studies that reported HRU, costs, or both for allo-HSCT. Of these studies, 93.0% reported on costs, 81.4% reported on HRU, and 74.4% reported on both. HRU measures and cost calculations, including the timeframe for which they were reported, were heterogeneous across the studies. Length of hospital stay was the most frequently reported HRU measure (76.7% of studies) and ranged from a median initial hospitalization of 10 days (reduced-intensity conditioning [RIC]) to 73 days (myeloablative conditioning). The total cost of an allo-HSCT ranged from $63,096 (RIC) to $782,190 (double umbilical cord blood transplantation) at 100 days and from $69,218 (RIC) to $637,193 at 1 year (not stratified). There is heterogeneity in the reporting of HRU and costs associated with allo-HSCT in the literature, making it difficult for clinicians, policymakers, and governments to draw definitive conclusions regarding the resources required for the delivery of these services. Nevertheless, to ensure that access to healthcare meets the necessary high cost and resource demands of allo-HSCT, it is imperative for clinicians, policymakers, and government officials to be aware of both the short- and long-term health resource requirements for this patient population. Further research is needed to understand the key determinants of HRU and costs associated with allo-HSCT to better inform the design and delivery of health care for HSCT recipients and ensure the quality, safety, and efficiency of care.

Peripheral Blood Haploidentical Allogeneic Stem Cell Transplantation in Older Adults with Acute Myeloid Leukemia and Myelodysplastic Syndromes Demonstrates Long Term Survival, Results from Australia and New Zealand Transplant and Cellular Therapies.

There is a limited body of evidence for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients. Previous studies have used a high proportion of bone marrow-derived grafts and a variety of conditioning regimens. In Australia and New Zealand, haplo-HCST is predominantly performed using peripheral blood (PB) with universal use of post-transplantation cyclophosphamide (PTCy). To characterize the outcomes of older recipients undergoing haplo-HSCT for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB haplo-HSCT for AML/MDS between January 2010 and July 2020. A total of 44 patients were included in the analysis. The median follow-up time was 377 days. The median age was 68 (range 65-74) with a median Karnofsky performance status of 90. Thirty patients (68.2%) had AML, whereas 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was nonmyeloablative fludarabine, cyclophosphamide, and total body irradiation (75%); the remainder of the patients received either melphalan- or busulfan-based regimens, and the majority were reduced intensity, with only 2 patients undergoing myeloablative conditioning. All patients received post-transplantation cyclophosphamide and mycophenolate mofetil, with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporine (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients at a median of 18 days, whereas platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of cytomegalovirus (CMV) reactivation and CMV disease were 52.5% and 5.1% at 1 year. The incidence of grade 2-4 acute Graft Versus Host Disease (GVHD) was 18.2%. The incidence of chronic GVHD at 2 years was 40.7%, with extensive chronic GVHD occurring in 17.7% of patients. The incidences of relapse and non-relapse mortality (NRM) at 2 years were 8.8% and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year overall survival was 74%. Relapse free survival and GVHD free, relapse free survival at 2 years was 70% and 48%. Haplo-HSCT using a peripheral blood graft and PTCy GVHD prophylaxis demonstrates long-term disease control with acceptable rates of NRM for older patients with AML/MDS.

Australia and New Zealand consensus position statement: use of COVID-19 therapeutics in patients with haematological malignancies.

Despite widespread vaccination rates, we are living with high transmission rates of SARS-CoV-2. Although overall hospitalisation rates are falling, the risk of serious infection remains high for patients who are immunocompromised because of haematological malignancies. In light of the ongoing pandemic and the development of multiple agents for treatment, representatives from the Haematology Society of Australia and New Zealand and infectious diseases specialists have collaborated on this consensus position statement regarding COVID-19 management in patients with haematological disorders. It is our recommendation that both patients with haematological malignancies and treating specialists be educated regarding the preventive and treatment options available and that patients continue to receive adequate vaccinations, keeping in mind the suboptimal vaccine responses that occur in haematology patients, in particular, those with B-cell malignancies and on B-cell-targeting or depleting therapy. Patients with haematological malignancies should receive treatment for COVID-19 in accordance with the severity of their symptoms, but even mild infections should prompt early treatment with antiviral agents. The issue of de-isolation following COVID-19 infection and optimal time to treatment for haematological malignancies is discussed but remains an area with evolving data. This position statement is to be used in conjunction with advice from infectious disease, respiratory and intensive care specialists, and current guidelines from the National COVID-19 Clinical Evidence Taskforce and the New Zealand Ministry of Health and Cancer Agency Te Aho o Te Kahu COVID-19 Guidelines.

Reproducible Bioinformatics Analysis Workflows for Detecting IGH Gene Fusions in B-Cell Acute Lymphoblastic Leukaemia Patients.

B-cell acute lymphoblastic leukaemia (B-ALL) is characterised by diverse genomic alterations, the most frequent being gene fusions detected via transcriptomic analysis (mRNA-seq). Due to its hypervariable nature, gene fusions involving the Immunoglobulin Heavy Chain (IGH) locus can be difficult to detect with standard gene fusion calling algorithms and significant computational resources and analysis times are required. We aimed to optimize a gene fusion calling workflow to achieve best-case sensitivity for IGH gene fusion detection. Using Nextflow, we developed a simplified workflow containing the algorithms FusionCatcher, Arriba, and STAR-Fusion. We analysed samples from 35 patients harbouring IGH fusions (IGH::CRLF2 n = 17, IGH::DUX4 n = 15, IGH::EPOR n = 3) and assessed the detection rates for each caller, before optimizing the parameters to enhance sensitivity for IGH fusions. Initial results showed that FusionCatcher and Arriba outperformed STAR-Fusion (85-89% vs. 29% of IGH fusions reported). We found that extensive filtering in STAR-Fusion hindered IGH reporting. By adjusting specific filtering steps (e.g., read support, fusion fragments per million total reads), we achieved a 94% reporting rate for IGH fusions with STAR-Fusion. This analysis highlights the importance of filtering optimization for IGH gene fusion events, offering alternative workflows for difficult-to-detect high-risk B-ALL subtypes.

Diagnosis and management of endothelial disorders following haematopoietic stem cell transplantation.

Haematopoietic stem cell transplantation is a mainstay of therapy for numerous malignant and nonmalignant diseases. Endothelial activation and dysfunction occur after stem cell transplantation, driven by various patient- and transplant-specific factors. This can manifest as one of the relatively uncommon endothelial injury syndromes, such as sinusoidal obstruction syndrome, transplant-associated thrombotic microangiopathy, idiopathic pneumonia syndrome, capillary leak syndrome, engraftment syndrome or posterior reversible encephalopathy syndrome. This review focuses on the pathogenesis, classification and diagnosis of these disorders, as well as provides guidance on risk mitigation and treatment.

Early cessation of calcineurin inhibitors is feasible post-haploidentical blood stem cell transplant: the ANZHIT 1 study.

Haploidentical hematopoietic stem cell transplant (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) is appropriate for those who lack matched donors. Most studies using PTCy have been retrospective making conclusions difficult. ANZHIT-1 was a phase 2 study conducted at 6 Australian allogeneic HSCT centers. The primary end points were disease-free and overall survival at 2 years after HSCT. The reduced-intensity conditioning (RIC) included fludarabine, cyclophosphamide, and 200 cGy total body irradiation, and the myeloablative conditioning (MAC) was IV fludarabine and busulfan. PTCy, MMF and a calcineurin inhibitor (CNI) were used for graft-versus-host disease (GVHD) prophylaxis. CNIs were weaned and ceased by day +120 in eligible patients on day 60. Patients (n = 78) with hematological malignancies were included in the study, with a median follow-up of 732 days (range, 28-1728). HSCT was RIC in 46 patients and MAC in 32 patients. Disease-free survival probability at 2 years was 67.5% (95% [CI], 53.2-85.6) for MAC recipients and 68.3% (95% CI, 56.3-83.01) for RIC recipients. Transplant-related mortality (TRM) on day 100 and year 1 was 4.9% (95% CI, 1.6-15.3) and 17.9% (95% CI, 8.8-36.5), respectively, in the MAC group compared with 3.1% (95% CI, 0.8.1-12) and 11.6% (95% CI, 6-22.4), respectively, in the RIC group. The median time for elective cessation of CNI was day 142.5 days, with no excess chronic GVHD (cGVHD) or mortality. Of the evaluable patients, 71.6% discontinued immunosuppression 12 months after transplant. This prospective haplo-HSCT trial using PTCY demonstrated encouraging survival rates, indicating that early CNI withdrawal is feasible and safe.

Long-term outcomes of corticosteroid graft versus host disease prophylaxis in peripheral blood allogeneic haemopoietic stem cell transplant: a comparative cohort analysis.

BACKGROUND: Corticosteroids (CSs) have previously been incorporated into graft versus host disease (GVHD) prophylaxis regimens for bone marrow (BM) and haemopoietic stem cell transplant (HSCT). AIMS: To assess the impact of prophylactic CS in HSCT using peripheral blood (PB) stem cells. METHODS: Patients were identified from three HSCT centres receiving a first PB-HSCT between January 2011 and December 2015 from a fully human leukocyte antigen (HLA)-matched sibling or unrelated donor for acute myeloid leukaemia or acute lymphoblastic leukaemia. To enable meaningful comparison, patients were divided into two cohorts. RESULTS: Cohort 1 included only myeloablative-matched sibling HSCT, where the only variation in GVHD prophylaxis was the addition of CS. In these 48 patients, there were no differences in GVHD, relapse, non-relapse mortality, overall survival or GVHD-relapse-free-survival (GRFS) at 4 years after transplant. Cohort 2 included the remaining HSCT recipients, where one group received CS-prophylaxis and the non-CS group received an antimetabolite, ciclosporin and anti-T-lymphocyte globulin. In these 147 patients, those receiving CS-prophylaxis experienced higher rates of chronic GVHD (71% vs 18.1%, P < 0.001) and lower rates of relapse (14.9% vs 33.9%, P = 0.02). Those receiving CS-prophylaxis had a lower 4-year GRFS (15.7% vs 40.3%, P = 0.002). CONCLUSIONS: There does not appear to be a role for adding CS to standard GVHD prophylaxis regimens in PB-HSCT.

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.

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).

Gene expression differentials driven by mass rearing and artificial selection in black soldier fly colonies.

The micro-evolutionary forces that shape genetic diversity during domestication have been assessed in many plant and animal systems. However, the impact of these processes on gene expression, and consequent functional adaptation to artificial environments, remains under-investigated. In this study, whole-transcriptome dynamics associated with the early stages of domestication of the black soldier fly (BSF), Hermetia illucens, were assessed. Differential gene expression (DGE) was evaluated in relation to (i) generational time within the cultured environment (F2 vs. F3), and (ii) two selection strategies [no artificial selective pressure (NS); and selection for greater larval mass (SEL)]. RNA-seq was conducted on 5th instar BSF larvae (n = 36), representing equal proportions of the NS (F2 = 9; F3 = 9) and SEL (F2 = 9; F3 = 9) groups. A multidimensional scaling plot revealed greater gene expression variability within the NS and F2 subgroups, while the SEL group clustered separately with lower levels of variation. Comparisons between generations revealed 898 differentially expressed genes (DEGs; FDR-corrected p < 0.05), while between selection strategies, 213 DEGs were observed (FDR-corrected p < 0.05). Enrichment analyses revealed that metabolic, developmental, and defence response processes were over-expressed in the comparison between F2 and F3 larvae, while metabolic processes were the main differentiating factor between NS and SEL lines. This illustrates the functional adaptations that occur in BSF colonies across generations due to mass rearing; as well as highlighting genic dynamics associated with artificial selection for production traits that might inform future selective breeding strategies.

Australia and New Zealand Transplant and Cellular Therapies (ANZTCT) position statement: COVID-19 management in patients with haemopoietic stem cell transplant and chimeric antigen receptor T cell.

Patients with post-haemopoietic stem cell transplant or chimeric antigen receptor T -cell (CAR-T) therapy face a significant risk of morbidity and mortality from coronavirus disease 2019 because of their immunosuppressed state. As case numbers in Australia and New Zealand continue to rise, guidance on management in this high-risk population is needed. Whilst we have learned much from international colleagues who faced high infection rates early in the pandemic, guidance relevant to local health system structures, medication availability and emerging therapies is essential to equip physicians to manage our patients optimally.

Second primary malignancies in chronic lymphocytic leukaemia: Skin, solid organ, haematological and Richter's syndrome.

Chronic lymphocytic leukaemia (CLL) is invariably accompanied by some degree of immune failure, and CLL patients have a high rate of second primary malignancy (SPM) compared to the general population. We comprehensively documented the incidence of all forms of SPM including skin cancer (SC), solid organ malignancy (SOM), second haematological malignancy (SHM) and separately Richter's syndrome (RS) across all therapy eras. Among the 517 CLL/small lymphocytic lymphoma (SLL) patients, the overall incidence of SPMs with competing risks was SC 31.07%, SOM 25.99%, SHM 5.19% and RS 7.55%. Of the 216 treated patients, 106 (49.1%) had at least one form of SPM, and 63 of 106 (29.2% of treated patients) developed an SPM 1.5 years (median) after treatment for their CLL. Melanoma accounted for 30.3% of SC. Squamous cell carcinoma (SCC), including eight metastatic SCCs, was 1.8 times more than basal cell carcinoma (BCC), a reversal of the typical BCC:SCC ratio. The most common SOMs were prostate (6.4%) and breast (4.5%). SHM included seven acute myeloid leukaemia (AML) and five myelodysplasia (MDS) of which eight (four AML, four MDS) were therapy-related. Any SPM occurred in 32.1% of 53 Monoclonal B-lymphocytosis (MBL) patients. Age-adjusted standardised rates of SPM (per 100,000) for CLL, MBL and the general Australian population were 2648, 1855 and 486.9, respectively. SPMs are a major health burden with 44.9% of CLL patients with having at least one SPM, and apart from SC, associated with significantly reduced overall survival. Dramatic improvements in CLL treatment and survival have occurred with immunochemotherapy and targeted therapies, but mitigating SPM burden will be important to sustain further progress.

Voriconazole in Hematopoietic Stem Cell Transplantation and Cellular Therapies: Real-World Usage and Therapeutic Level Attainment at a Major Transplantation Center.

Voriconazole (VCZ) was one of the first mold-active triazoles available; however, its current use among high-risk hematology populations is unknown as the uptake of posaconazole (PCZ) and isavuconazole (ISZ) increases. We evaluated the usage and therapeutic level attainment of VCZ in hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapy patients at our cancer center. Electronic medical records for all adult HCT or CAR-T patients with an order for VCZ, PCZ, or ISV between January 1, 2018, and June 30, 2020, were extracted. Clinical characteristics, VCZ indication, trough VCZ levels, and frequency of VCZ initiation from 6 months before to 6 months after HCT/CAR-T infusion in consecutive HCT/CAR-T recipients within the study period (infusion between July 1, 2018, and January 1, 2020) were assessed. The association between relevant clinical characteristics and the attainment of subtherapeutic or supratherapeutic levels was also evaluated. Of 468 patients prescribed mold-active triazoles, 256 (54.7%) were prescribed VCZ, 324 (69.2%) PCZ, and 60 (12.8%) ISZ; 152/468 (32.5%) treatment regimens were sequentially modified to alternate mold-active triazoles. Among consecutive HCT and CAR-T recipients at our center, evaluated 6 months pre- or post- HCT/ CAR-T, VCZ was commonly initiated before or after allogeneic HCT (102/381, 26.8%), with most use in the first 30 days after stem cell infusion (40/381, 10.5%); VCZ use was less common in autologous HCT (13/276, 4.7%) and CAR-T (10/153, 6.5%). Of 223 VCZ orders that met inclusion for analysis, indications included empiric treatment in 108/223 (48.4%), directed therapy in 25/223 (11.2%), primary prophylaxis in 69/223 (30.9%) and secondary prophylaxis in 21/223 (9.4%). Of 223 eligible VCZ patients, 144 (64.6%) had at least 1 VCZ level measured during the study period; 75/144 (52.1%) had a therapeutic VCZ level (1.0-5.5 mg/L) at the first measurement (median 2.8mg/L [range 0.1-13.5]) at a median of 6 days of therapy, with 26.4% subtherapeutic and 21.5% supratherapeutic; 46/88 (52.3%) were therapeutic at the second measurement (2.1mg/L [0.1-9.9]) at a median of 17 days of therapy; and 33/48 (68.8%) at the third (2.3mg/L [0.1-7.7]) at a median of 29 days. In multivariable analysis of factors associated with sub- or supratherapeutic levels (body mass index ≥30, concurrent omeprazole use, concurrent letermovir use, indication for VCZ, history/timeframe of HCT), the only significant association was lower odds of a supratherapeutic VCZ level among those undergoing HCT within the previous 30 days compared to those without a history of HCT. VCZ continues to remain an important option in the treatment and prevention of invasive fungal infections in an era when alternative oral mold-active triazoles are available. In spite of long-standing experience with VCZ prescribing, therapeutic level attainment remains a challenge.

The improvement in overall survival from unrelated donor transplantation in Australia and New Zealand is driven by a reduction in non-relapse mortality: A study from the ABMTRR.

Unrelated donors (UDs) are the commonest source for allogeneic transplantation (alloSCT), with higher non-relapse mortality (NRM) than siblings. We analyzed data from the Australasian Bone Marrow Transplant Recipient Registry from adults receiving a first UD alloSCT during 2001-2015, to determine whether and how NRM has changed. Predictors of outcome were determined using cox regression, accounting for time-interactions and competing risks. A total of 2308 patients met inclusion criteria. Changes over time included increasing age, utilization of peripheral blood cells, reduced intensity conditioning, and T-cell depletion. Three-year OS increased significantly from 44% in 2001-2005 to 58% in 2011-2015 (p < 0.001). This was attributed to a reduction in NRM from 35% to 24% (p < 0.001) with no change in relapse. Factors associated with increased NRM included age, male sex, CMV seropositivity, HLA mismatch, transplant more than 6 months from diagnosis, and T-cell depletion when administered during 2001-2005. Survival following UD SCT has improved by almost 15% over the past decade, driven by improvements in NRM. This has occurred despite increasing recipient age and appears to be due to better donor selection, reduced delays to transplantation, and improved prevention and management of GVHD.

Sensitive Measurement of Minimal Residual Disease in Blood by HAT-PCR.

PCR is widely used to measure minimal residual disease (MRD) in lymphoid neoplasms, but its sensitivity is limited. High Adenine/Thymine PCR and High Annealing Temperature PCR (HAT-PCR) is a modified PCR designed to minimize nonspecificity and hence increase sensitivity. It was evaluated in the laboratory and the clinic, using samples from 58 patients. Of these patients, 57 were adolescents or young adults who were participating in the Australasian Leukemia and Lymphoma Group ALL06 trial in which MRD was measured in blood principally by HAT-PCR and in marrow by conventional PCR. HAT-PCR produced significantly less nonspecificity than conventional PCR, and its limit of detection was <10-6 in 90% of patients. In 196 samples, an excellent correlation was found between blood and marrow MRD. Variable partitioning of leukemic cells between blood and marrow was observed. Measurement of MRD in blood by HAT-PCR was noninferior to measurement of MRD in marrow by conventional PCR, in terms of both detecting disease and predicting clinical outcome. At a median follow-up of 3 years and for MRD levels in blood at the end of consolidation treatment, an MRD level of >10-4 cells/L significantly predicted relapse and mortality, whereas undetectable MRD significantly predicted relapse-free survival and overall survival. HAT-PCR is a simple, quick, cheap and sensitive method for measurement of MRD, and its adoption for MRD in blood may be clinically useful.