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.

Australia and New Zealand Transplant and Cellular Therapies COVID-19 vaccination consensus position statement.

Australia and New Zealand have achieved excellent community control of COVID-19 infection. In light of the imminent COVID-19 vaccination roll out in both countries, representatives of all adult and paediatric allogeneic bone marrow transplant and cellular therapy (TCT) centres as well as representatives from autologous transplant only centres in Australia and New Zealand collaborated with infectious diseases specialists with expertise in TCT on this consensus position statement regarding COVID-19 vaccination in TCT patients in Australia and New Zealand. It is our recommendation that TCT patients, should have expedited access to high-efficacy COVID-19 vaccines given that these patients are at high risk of morbidity and mortality from COVID-19 infection. We also recommend prioritising vaccination of TCT healthcare workers and household members of TCT patients. Vaccination should not replace other public health measures in TCT patients given the effectiveness of COVID-19 vaccination in TCT patients is unknown. Furthermore, given the limited available data, prospective collection of safety and efficacy data of COVID-19 vaccination in this patient group is a priority.

Australasian Trends in Allogeneic Stem Cell Transplantation for Myelofibrosis in the Molecular Era: A Retrospective Analysis from the Australasian Bone Marrow Transplant Recipient Registry.

To review the updated trends of national practice and outcomes in transplantation to treat myelofibrosis (MF), we retrospectively evaluated 142 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) for primary (n = 94) or secondary (n = 48) MF at an Australian/New Zealand transplantation center between 2006 and 2017. The median duration of follow-up was 51.8 months (range, 3.1 to 148 months). The median age at allo-HSCT was 56 years (range, 26 to 69 years). Fifty-two percent of the patients had HLA-identical sibling donors, and 45% had matched unrelated donors (UD). Conditioning regimens were predominantly reduced intensity (83%). Before transplantation, 16% of the patients had undergone splenectomy or splenic irradiation, and 38% (n = 54) received JAK inhibitor therapy. JAK2 mutation testing was performed in 66.9% of the patients, whereas other mutations (CALR, MPL, ASXL1, SRSF2, U2AF1Q57, EZH2, and IDH1/2) were rarely tested (1.4% to 8.4%). Only 4.2% of patients had next-generation sequencing mutation analysis. The median time to neutrophil engraftment was 19 days (range, 10 to 43 days), and the median time to platelet engraftment was 27 days (range, 13 to 230 days). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 21.4% at 100 days, and that of extensive chronic GVHD (cGVHD) at 5 years was 18.1%. Overall survival (OS) was 67% at 1 year and 57% at 5 years. GVHD-free, relapse-free survival was 54% at 1 year and 42% at 5 years. The cumulative incidence of nonrelapse mortality (NRM) was 16% at 100 days and 25% at 1 year. In multivariate analysis, age ≥65 years and use of an UD were identified as significant unfavorable risk factors for OS and NRM. Use of an UD increased the incidence of aGVHD, whereas administration of antithymocyte globulin/alemtuzumab lowered the risk of both aGVHD and cGVHD. Pretransplantation splenectomy/splenic irradiation had a positive influence on time to engraftment. There have been no improvements in the outcomes of allo-HSCT for MF in Australasia over the last decade, with a low uptake of molecular genomic technology due to limited access to funding.

Association between P2X7 Polymorphisms and Post-Transplant Outcomes in Allogeneic Haematopoietic Stem Cell Transplantation.

Allogeneic stem cell transplantation (alloSCT) is a highly effective treatment method for haematologic malignancies. However, infection of acute organ dysfunction and graft versus host disease (GVHD) impact negatively on patient outcomes. Pre-transplant conditioning regimes are associated with high levels of immunogenic cell death and the release of extracellular ATP, which binds to the P2X7 receptor. It has been proposed that signaling through the P2X7 receptor may lead to activation of downstream effectors that influence alloSCT outcome. In this study, we examined the effect of gain-of-function (GOF) or loss-of-function (LOF) P2X7 Single Nucleotide Polymorphisms (SNP) in 453 paired alloSCT donors and recipients and correlated their presence or absence to the major post-transplant outcomes of acute GVHD, relapse free survival and overall survival. The allelic frequency of P2X7 SNP in recipients and donors was not different from those SNP for which there is published population data. The LOF SNP Glu496Ala was overrepresented in recipients who did not develop severe acute GVHD and was associated with improved overall survival in rare homozygous recipients, whereas the LOF SNP Ile568Asn was more common in patients with grade 1-4 GVHD but lost statistical association in patients with grade 2-4 aGVHD, and was associated with reduced overall survival in heterozygotes due to an excess of infection-related deaths. The GOF variant haplotype (homozygous Gln460Arg-Ala348Thr) had no impact on post-alloSCT outcomes. Overall, our data indicate that allelic variations in recipients or donors occurs at the same frequency as the general population and may have a minor, but clinically nominal, impact on post-alloSCT outcomes.

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.

Incidence of Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease and Treatment with Defibrotide in Allogeneic Transplantation: A Multicenter Australasian Registry Study.

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.

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.

Good Engraftment but Quality and Donor Concerns for Cryopreserved Hemopoietic Progenitor Cell Products Collected During the COVID-19 Pandemic.

Changes to donor availability, collection center capacity, and travel restrictions during the early phase of the COVID-19 pandemic led to routine cryopreservation of most unrelated donor products for hematopoietic transplantation prior to the recipient commencing the conditioning regimen. We investigated the effect of this change on unrelated donor product quality and clinical outcomes. Product information was requested from transplantation centers in Australia and New Zealand and clinical outcome data from the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR). In total, 191 products were collected between April 1, 2021, and September 30, 2021, and most (74%) were from international collection centers. Median post-thaw CD34 recovery was 78% (range 25% to 176%) and median post-thaw CD34 viability was 87% (range 34% to 112%). Median time to neutrophil recovery was 17 days (interquartile range 10 to 24 days), and graft failure occurred in 6 patients (4%). These clinical outcomes were similar to those of "fresh" unrelated donor transplants reported to the ABMTRR in 2019. However, recipient transplantation centers reported problems with 29% of products in the form of damage during transit, low cell dose, inadequate labeling, missing representative samples, or missing documentation. These problems were critical in 7 cases (4%). At last follow-up, 22 products (12%) had not been infused. Routine cryopreservation of unrelated donor hemopoietic progenitor cell products has enabled safe continuation of allogeneic transplant services during the COVID-19 pandemic. However, practices for product tracing, documentation, and transportation can be optimized, and measures to reduce the incidence of unused unrelated donor product are required.

Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE).

INTRODUCTION: Autologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL. METHODS AND ANALYSIS: Eligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×104 CAR T-cells/kg with a maximum dose of 1×106 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings. TRIAL REGISTRATION NUMBER: NCT04049513.

The role of a specialist bridging service. A New Zealand prospective study of 600 patients.

BACKGROUND: A proposition for the Wellington hospital thrombosis service to manage periprocedure anticoagulation bridging was made after a number of cancellations and key incidents were caused by lack of a consistent management approach. We provided individual bridging assessments, with implementation, communication, and education. The only funded anticoagulants in New Zealand at that time were dabigatran, warfarin, and enoxaparin. METHODS: On initiation of the bridging service, we prospectively collected data on 600 consecutive patients referred to the periprocedure bridging service between May 2015 and February 2017. We recorded the 30-day major bleeding events, thrombotic events, and related mortality. We followed the patients up for 30 days postprocedure. As part of this process, we ensured optimal transition back to their initial anticoagulant. CONCLUSION: We found low rates of major bleeding 1.9% and thrombosis 0.8% at day 30 comparable to randomized controlled trials. Of the 222 patients taking dabigatran experienced no major bleeding events. We believe using a specialist coagulation service is optimal to ensure surgery can proceed safely.

Natural killer receptor ligand expression on acute myeloid leukemia impacts survival and relapse after chemotherapy.

Natural killer (NKs) cells provide rapid responses to viral-infected and malignant cells, including acute myeloid leukemia (AML) blasts. The balance among inhibitory and activating signals, delivered by multiple interactions between ligands on target cells and NK receptors, determines the posture of the NK cell response to either one of target cell elimination or tolerance. The aim of this work was to study the influence of the differential expression of activating and inhibitory NK receptor ligands (NKRLs) by leukemic blasts on clinical outcome in newly diagnosed AML patients. Leukemic cells and clinical data from 66 patients undergoing induction chemotherapy were obtained from the Australasian Leukemia Lymphoma Group tissue bank. Expression of 6 activating (MICA, MICAB, CD155, CD112, ULBP1, and ULBP2/5/6) and 3 inhibitory (HLA class I, PD-L1, and PD-L2) NKRLs was analyzed by flow cytometry. AML blasts displayed heterogeneous expression of NKRLs. MICA, CD112, and ULBP1 were most frequently expressed. ULBP1 expression was significantly associated with improved 2-year overall survival (51.4% vs 11.4%), relapse-free survival (42.5% vs 10.0%), and reduced relapse (44.1% vs 78.6%). We calculated a net score of activating minus inhibitory ligands and demonstrated that the expression of an overall activating NK ligand phenotype was associated with superior 2-year overall survival (59.6% vs 24.4%) and reduced relapse (31.5% vs 68.2%). Our study provides clinical evidence for the role of NK cell-mediated immunoediting against AML, mediated by the expression of NKRLs on blasts, and supports investigation into strategies to enhance NK cell function to improve outcomes in patients with AML.

Double umbilical cord blood transplant is effective therapy for relapsed or refractory Hodgkin lymphoma.

A sub-group of patients with Hodgkin Lymphoma (HL) who relapse after autologous stem cell transplant can achieve long-term disease-free-survival after allogeneic stem cell transplant (alloSCT). There is limited information regarding the tolerability and efficacy of double umbilical cord blood transplant (dUCBT) for relapsed/refractory HL. We analyzed 27 consecutive, heavily pre-treated patients receiving dUCBT for relapsed/refractory HL at two centers from 2003-2014. The majority of patients relapsed <6 months after autologous stem cell transplant. A total of 15 patients received myeloablative (most commonly melphalan, fludarabine, thiotepa and anti-thymocyte globulin [ATG]) and 12 non-myeloablative conditioning regimens (fludarabine, cyclophosphamide, 200cGy total body irradiation +/- ATG). All patients engrafted; median time to neutrophil and platelet engraftment was 17 and 37 days, respectively. Overall response rate was 68%; 58% achieved complete remission. Median progression-free survival (PFS) was 12.2 months; median overall survival was 27 months. Cumulative incidences of relapse and of non-relapse mortality at 5 years were 30% and 37.9%, respectively; 5-year PFS was 31.3% (95%CI 10.1-52.5). There was a trend toward inferior PFS in patients with lymph node size ≥2 cm at the time of alloSCT (p = 0.07) and toward inferior survival in patients with chemorefractory disease pre-alloSCT (p = 0.12). dUCBT is feasible in patients with heavily pre-treated HL and can achieve long-term disease-free survival in approximately 30% of patients.