Allogeneic haemopoietic cell transplant services in Australia and New Zealand in the first year of the COVID-19 pandemic: a report from Australia and New Zealand transplant and cellular therapies.

BACKGROUND: The COVID-19 pandemic has caused major disruption to health systems, with allogeneic haemopoietic cell transplant (alloHCT) services a particularly vulnerable area. Ongoing provision of alloHCT has required dynamic responses at national and local levels. In Australia and New Zealand (ANZ), a high reliance on unrelated donors from overseas registries has posed an additional challenge. AIMS: To describe the impact of COVID-19 on alloHCT services in ANZ in the first year of the pandemic. METHODS: Data from the national alloHCT patient and unrelated donor registries were extracted for a 2-year time frame. Comparisons were made between a pre-pandemic period of 1 March 2019 to 29 February 2020 and the corresponding dates during the pandemic, 1 March 2020 to 28 February 2021. RESULTS: There was a 13% decrease in the number of allogeneic transplants, a reversal of steady increases in previous years, with the largest decrease in unrelated donor transplants. Local donors supplied a greater proportion of unrelated stem cell products. With a switch to universal cryopreservation, the time from request of a product to infusion increased by a median of 25.5 days for overseas products and 14 days for local products. There was a significant increase in the number of products collected but not used. CONCLUSIONS: A strong public health response and coordinated transplant community activities allowed for safe provision of alloHCT in ANZ; however, our data suggest that the timely delivery of allogeneic transplants was affected by the COVID-19 pandemic. Continued dedicated efforts are required to minimise further impacts.

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.

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID-19 pandemic.

The COVID-19 pandemic poses a unique challenge to the care of patients with haematological malignancies. Viral pneumonia is known to cause disproportionately severe disease in patients with cancer, and patients with lymphoma, myeloma and chronic lymphocytic leukaemia are likely to be at particular risk of severe disease related to COVID-19. This statement has been developed by consensus among authors from Australia and New Zealand. We aim to provide supportive guidance to clinicians making individual patient decisions during the COVID-19 pandemic, in particular during periods that access to healthcare resources may be limited. General recommendations include those to minimise patient exposure to COVID-19, including the use of telehealth, avoidance of non-essential visits and minimisation of time spent by patients in infusion suites and other clinical areas. This statement also provides recommendations where appropriate in assessing indications for therapy, reducing therapy-associated immunosuppression and reducing healthcare utilisation in patients with specific haematological malignancies during the COVID-19 pandemic. Specific decisions regarding therapy of haematological malignancies will need to be individualised, based on disease risk, risks of immunosuppression, rates of community transmission of COVID-19 and available local healthcare resources.

CD56bright natural killer regulatory cells in filgrastim primed donor blood or marrow products regulate chronic graft-versus-host disease: the Canadian Blood and Marrow Transplant Group randomized 0601 study results.

Randomized trials have conclusively shown higher rates of chronic graft-versus-host disease with filgrastim-stimulated apheresis peripheral blood as a donor source than unstimulated bone marrow. The Canadian Blood and Marrow Transplant Group conducted a phase 3 study of adults who received either filgrastim-stimulated apheresis peripheral blood or filgrastim-stimulated bone marrow from human leukocyte antigen-identical sibling donors. Because all donors received the identical filgrastim dosing schedule, this study allowed for a controlled evaluation of the impact of stem cell source on development of chronic graft-versus-host disease. One hundred and twenty-one evaluable filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow patient donor products were immunologically characterized by flow cytometry and tested for their association with acute and chronic graft-versus-host disease within 2 years of transplantation. The immune populations evaluated included, regulatory T cells, central memory and effector T cells, interferon γ positive producing T cells, invariate natural killer T cells, regulatory natural killer cells, dendritic cell populations, macrophages, and activated B cells and memory B cells. When both filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow were grouped together, a higher chronic graft-versus-host disease frequency was associated with lower proportions of CD56bright natural killer regulatory cells and interferon γ-producing T helper cells in the donor product. Lower CD56bright natural killer regulatory cells displayed differential impacts on the development of extensive chronic graft-versus-host disease between filgrastim-stimulated apheresis peripheral blood and filgrastim-stimulated bone marrow. In summary, while controlling for the potential impact of filgrastim on marrow, our studies demonstrated that CD56bright natural killer regulatory cells had a much stronger impact on filgrastim-stimulated apheresis peripheral blood than on filgrastim-stimulated bone marrow. This supports the conclusion that a lower proportion of CD56bright natural killer regulatory cells results in the high rate of chronic graft-versus-host disease seen in filgrastim-stimulated apheresis peripheral blood. clinicaltrials.gov Identifier: 00438958.

Filgrastim-Stimulated Bone Marrow Compared with Filgrastim-Mobilized Peripheral Blood in Myeloablative Sibling Allografting for Patients with Hematologic Malignancies: A Randomized Canadian Blood and Marrow Transplant Group Study.

In adult hematopoietic cell transplantation (HCT), filgrastim-mobilized peripheral blood (G-PB) has largely replaced unstimulated marrow for allografting. Although the use of G-PB results in faster hematopoietic recovery, it is also associated with more chronic graft-versus-host disease (cGVHD). A potential alternative allograft is filgrastim-stimulated marrow (G-BM), which we hypothesized may be associated with prompt hematopoietic recovery but with less cGVHD. We conducted a phase 3, open-label, multicenter randomized trial of 230 adults with hematologic malignancies receiving allografts from siblings after myeloablative conditioning to compare G-PB with G-BM. The primary endpoint was time to treatment failure, defined as a composite of extensive cGVHD, relapse/disease progression, and death. With a median follow-up of 36 months (range, 9.6 to 48), comparing G-BM with G-PB, there was no difference between the 2 arms with respect to the primary outcome of this study (hazard ratio [HR], .91; 95% confidence interval [CI], .68 to 1.22; P = .52). However, the cumulative incidence of overall cGVHD was lower with G-BM (HR, .66; 95% CI, .46 to .95; P = .007) and there was no difference in the risk of relapse or progression (P = .35). The median times to neutrophil recovery (P = .0004) and platelet recovery (P = .012) were 3 days shorter for recipients allocated to G-PB compared with those allocated to G-BM, but there were no differences in secondary engraftment-related outcomes, such as time to first hospital discharge (P = .17). In addition, there were no graft failures in either arm. This trial demonstrates that, compared with G-PB, the use of G-BM allografts leads to a significantly lower rate of overall cGVHD without a loss of the graft-versus-tumor effect and comparable overall survival. Our findings suggest that further study of this type of allograft is warranted.

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.

The association of socioeconomic deprivation with access and survival after hematopoietic stem cell transplantation in New Zealand.

BACKGROUND: Socioeconomic deprivation (SED) is a risk factor for reduced survival of hematopoietic stem cell transplant (HSCT) recipients. This study aimed to evaluate access and long-term survival of HSCT recipients. METHODS: This was a hospital HSCT Registry-based retrospective cohort study. Patients who underwent HSCT from January 2010 to June 2020 were identified. HSCT recipients younger than 16 years of age, patients who reported their residential address as a post office box or the Department of Corrections, and those who left the country after HSCT were excluded from the study. HSCT recipients with the 2018 New Zealand deprivation index (NZDep2018) deciles 8, 9, and 10 were assigned to the higher SED group and those with NZDep2018 deciles from 1 to 7 were allocated to the lower SED group. The total number of New Zealanders in the higher and lower SED strata was obtained from the 2018 Census. RESULTS: Eight hundred fifty-one HSCT recipients met the eligibility criteria. HSCT recipients from the higher and lower SED strata of the New Zealand population had similar access to HSCT (odds ratio = .9; 95% confidence interval (CI): .77-1.04; p = .155). Mortality in the higher and lower SED groups of HSCT recipients was 9.6/100 person-years (95% CI: 7.7-12/100 person-years) and 8.1/100 person-years (95% CI: 6.9-9.4/100 person-years), respectively. The mortality ratio was 1.2 (95% CI: .9-1.6), p = .098. Both groups had similar survival. CONCLUSION: New Zealand residents from the higher and lower SED strata have similar access to HSCT. SED is not associated with reduced survival in adult HSCT recipients.

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.

Staphylococcus haemolyticus meningitis and bacteremia in an allogenic stem cell transplant patient.

Staphylococcus haemolyticus is a rare cause of bacterial meningitis and most commonly occurs as a nosocomial infection in patients' post-neurosurgery. We report a patient post-allogenic stem cell transplant, with no prior history of neurosurgical procedures, who developed S. haemolyticus meningitis and bacteremia following central catheter-related bloodstream infection. The patient failed therapy with vancomycin and daptomycin but was successfully treated with a prolonged course of linezolid. We review the pharmacological management of coagulase negative Staphylococcus (CoNS) meningitis, with a focus on the pharmacokinetic properties of vancomycin, daptomycin and linezolid within the cerebrospinal fluid (CSF).

Treatment outcomes of patients with acute promyelocytic leukaemia between 2000 and 2017, a retrospective, single centre experience.

All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are effective induction therapy for acute promyelocytic leukaemia (APL). However, early thrombo-haemorrhagic complications and mortality remain high. We aimed to investigate how the timing of ATRA initiation and the inclusion of ATO influence patient outcomes. Clinical records were retrospectively reviewed for all patients treated for APL in a single, tertiary centre during 2000-2017. Among 70 patients with APL, 36 (51.4%) presented with thrombo-haemorrhagic complications, and four (5.8%) died within 30 days. The median time to ATRA initiation was 11.2 (range 0-104) h from the time of admission. Patients requiring more transfusions started on ATRA sooner (P = 0.04). Patients with adverse early events did not start ATRA later (P = 0.99). Nevertheless, patients that required additional tests for diagnosis (PML immunofluorescence or molecular) started on ATRA later (28.5 versus 5.3 h; P < 0.0001), and had more thrombo-haemorrhagic complications (P = 0.04). Long-term survival was actually better in patients who started ATRA later (P = 0.03), which is likely explained by higher proportion of low risk patients in this group. Patients treated with ATO (n = 23) maintained higher fibrinogen levels and required less transfusions during induction (P < 0.05), with no disease-related deaths in this group over a median follow-up time of 37.8 months (interquartile range 44.9 months). In summary, fast ATRA initiation reduces early but not late adverse events in APL patients, and the inclusion of ATO helps further improve both early and late outcomes in APL.

Early treatment of acute promyelocytic leukaemia is accurately guided by the PML protein localisation pattern: real-life experience from a tertiary New Zealand centre.

Current guidelines recommend that a rapid test be used to assist diagnosis of acute promyelocytic leukaemia (APL), but the choice of an assay is discretionary. PML immunofluorescence (PML IF) identifies the microparticulate pattern of the PML protein localisation, highly specific for APL. The aim of this study was to evaluate clinical utility of PML IF in a real-life setting based on a retrospective records review for all patients who had PML IF performed in our centre between 2000 and 2017. Final analysis included 151 patients, 70 of whom had APL. PML IF was reported on average 3 days faster than cytogenetics. Compared with genetic results, PML IF showed sensitivity of 96% and specificity of 100%. PML IF accurately predicted APL in four APL cases with cryptic karyotype/FISH and excluded APL in 98% cases tested based on the suspicious immunophenotype alone, 21/28 of whom had mutated NPM1. Results of PML IF influenced decision to start ATRA in 25 (36%) APL patients and led to its termination in six non-APL patients. In conclusion, PML IF is a fast and reliable test that facilitates accurate treatment decisions when APL is suspected. This performance of PML IF remains hard to match in a real-life setting.

Allogeneic hematopoietic cell transplant for multiple myeloma using reduced intensity conditioning therapy, 1998-2006: factors associated with improved survival outcome.

This study reports on the outcome of 95 allogeneic hematopoietic cell transplants (HCTs) using reduced intensity conditioning (RIC) performed for patients with multiple myeloma (MM) in Australia and New Zealand between 1998 and 2006. The median age at HCT was 52 years. Of the 32 patients for whom the allograft was performed as a first transplant, 15 (47%) had their allograft less than 1 year from diagnosis, while for the 63 patients who had an allograft following an autograft, nine (14%) were allografted within 1 year post-diagnosis (p < 0.001). The cumulative incidence of transplant-related mortality (TRM) was 19% at 1 year post-transplant. At 5 years post-transplant the overall survival (OS) was 40% and progression-free survival (PFS) was 23%, with no apparent survival plateau. Three factors were independently favorable predictors of OS in a Cox regression model: immunoglobulin G (IgG) myeloma (hazard ratio [HR] = 0.42, 95% confidence interval [CI] 0.24-0.75, p = 0.004), a human leukocyte antigen (HLA)-identical sibling donor (HR = 0.37, 95% CI 0.18-0.74, p = 0.005), and less than 1 year between MM diagnosis and RIC HCT (HR = 0.27, 95% CI 0.12-0.59, p = 0.001). Patterns of outcome indicate that RIC HCT may offer the potential for cure for only a small group of patients with MM.

Novel sequence insertion in a Mâori patient with transfusion-dependent beta-thalassaemia.

Although beta-thalassaemia is common throughout the world, it has not been previously described in Polynesia. We report a novel sequence insertion where homozygosity for the defect results in transfusion-dependent anaemia. The repeated 45 base pair (bp) insertion causes duplication of the start codon and consequent transcription from the original initiation code would be predicted to lead to the production of an irrelevant seven-residue peptide, while residual translation from the novel initiation site would result in diminished yields of beta-globin and consequent clinical beta(+)-thalassaemia.

Allogeneic haematopoietic stem-cell transplantation for relapsed and refractory aggressive histology non-Hodgkin lymphoma.

Forty-four patients with relapsed or refractory aggressive histology non-Hodgkin lymphoma (NHL) (diffuse large B cell, n = 23; peripheral T cell, n = 5; transformed B cell, n = 16) proceeded to allogeneic stem cell transplant (allo-SCT) between 1987 and 2003. Median age at transplant was 40 years (range 19-56 years). At the time of transplant, 35 were chemosensitive and nine were chemorefractory. Thirty-three patients had matched sibling donors and 11 had unrelated donors. Forty-two patients (95%) received radiation-based conditioning regimens. Event-free survival (EFS) and overall survival (OS) at 5 years was 43% [95% confidence interval (CI): 27-58%] and 48% (95% CI: 32-63%) respectively. Treatment-related mortality was 25% at 1 year. Grade III-IV acute graft-versus-host disease (GVHD) was the only significant variable affecting OS and EFS, and had a negative impact. Chronic GVHD did not influence survival. Lymphoma relapse <12 months after initial therapy predicted for increased risk of relapse post-transplant (P = 0.02). Patients with chemorefractory lymphoma were not at increased risk of relapse (P = 0.20) with four of nine patients remaining alive without disease 12-103 months post-transplant. In conclusion, allo-SCT for relapsed or refractory aggressive histology NHL results in long-term EFS and OS of 40-50%. Patients with chemorefractory disease can have a durable remission post-transplant.