Effect of donor age on adult unrelated donor haemopoietic cell transplant outcome: the Australian experience.

BACKGROUND: Results have been varied regarding the effect of donor age on the outcome of unrelated donor haemopoietic cell transplantation (HCT). AIMS: To determine the influence of donor age on adult unrelated donor HCT outcome in Australia. METHODS: Patients were included in the study if they were aged 16 years or above and underwent first allogeneic unrelated donor HCT in Australia for the indications of acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), chronic myelogenous leukaemia (CML) or myelodysplastic syndromes (MDS) between the years of 2001 and 2014 inclusive. The main outcome measure was overall survival (OS), which was tested against independent variables using univariate Kaplan-Meier methods and multivariate Cox regression. RESULTS: A total of 1158 unrelated donor HCT were represented in the data. Cumulative incidences of engraftment, transplant related mortality (TRM), acute graft-versus-host disease (GvHD), chronic GvHD and relapse were not significantly affected by donor age. OS probability at 5 years post-transplant was 48.3%. In multivariate analysis of OS, year of transplant 2001-2007, recipient age 40 years or greater, poor risk disease, human leukocyte antigen (HLA) match less than 6/6 and poor performance status at transplant (Karnofsky scale) were independently significant adverse OS risk factors. Donor age was not a significant risk factor for OS in univariate or multivariate analysis. CONCLUSIONS: The conclusion from this study was that donor age (up to 59 years) did not influence post-transplant outcome among adult unrelated donor HCT performed in Australia for haematologic malignancies.

Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) has been explored as a therapeutic intervention in multiple sclerosis (MS) over the last two decades; however, prospective clinical trials of the most common myeloablative conditioning regimen, BEAM, are limited. Furthermore, patient selection, optimal chemotherapeutic regimen and immunological changes associated with disease response require ongoing exploration. We present the outcomes, safety and immune reconstitution (IR) of patients with active, treatment refractory MS. METHODS: This study was a single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS). Patients underwent AHSCT using BEAM (carmustine, etoposide, cytarabine, melphalan)+antithymocyte globulin chemotherapeutic regimen. OUTCOMES: The primary outcome was event-free survival (EFS); defined as no clinical or radiological relapses and no disability progression. Multiparameter flow cytometry was performed for evaluation of post-transplant IR in both MS and lymphoma patients receiving the same chemotherapy regimen. RESULTS: Thirty-five patients (20 RRMS, 15 SPMS) completed AHSCT, with a median follow-up of 36 months (range 12-66). The median Expanded Disability Status Scores (EDSS) was 6 (2-7) and patients had failed a median of 4 (2-7) disease modifying therapies. 66% failed treatment with natalizumab. EFS at 3 years was 60%, (70% RRMS). Sustained improvement in EDSS was seen in 15 (44%) of patients. There was no treatment-related mortality. A sustained rise in CD39+ T regulatory cells, immunosuppressive CD56hi natural killer cells and ablation of proinflammatory mucosal-associated invariant T cells was seen for 12 months following AHSCT in patients with MS. These changes did not occur in patients with lymphoma receiving the same chemotherapy for AHSCT. CONCLUSIONS: The EFS in our MS cohort is significantly greater than other high-efficacy immunosuppressive therapies and similar to other AHSCT studies despite a more heavily pretreated cohort. TRIAL REGISTRATION NUMBER: ACTRN12613000339752.

Activity and Capacity Profile of Transplant Physicians and Centers in Australia and New Zealand.

We conducted a study to analyze and report on indicators of hematopoietic cell transplant (HCT) physician time use and HCT center output measures. HCT centers in Australia and New Zealand (A&NZ) were invited to provide demographic and time use details for physicians participating in HCT patient care (HCT physicians). Resource details for adult and pediatric centers were included. From a total of 46 centers that were invited to participate, completed data were received from 37 centers (80%) representing 185 HCT physicians, with a median age of 48 (range, 33 to 72), of whom 31% were women. Just over half of HCT physicians cited prior work experience in large overseas HCT centers (97, 52%) and over one-third (79, 43%) possessed postgraduate qualifications other than specialist training. Total annual mean HCTs per HCT physician full-time equivalent (FTE) were 14.2 for centers performing both allogeneic and autologous HCT, 6.6 for autologous only centers, and 10.6 for all centers. For all HCT physicians surveyed the mean proportion of time spent on HCT related tasks was 31.7%. In A&NZ, for centers that perform both allografts and autografts, there was a mean of 4.0 allogeneic HCT annually per HCT bed, compared with 2.6 for the United States and 7.1 allogeneic HCT annually per HCT physician FTE (United States, 6.3). Projections of the A&NZ HCT physician workforce indicated that the numbers of HCT physicians are likely to stay within the region of 170 to 190 for the next 10 years, whereas HCT activity will likely continue to climb steadily. Healthcare and government authorities should be prepared to enable and support greater HCT activity in A&NZ in the future.

Dealing with the spiralling price of medicines: issues and solutions.

Escalating cost of medicines is rapidly becoming a serious threat to patients and health systems. This trend has been documented to impact patient outcomes adversely. As clinicians and tax payers, it is our responsibility to be aware of the potential detrimental effects spiralling costs have on our patients, our community and our health system and to mitigate these effects by exposing this issue to our respective professional societies, representatives of the pharmaceutical companies that we interact with, government regulatory bodies and to patients who we are caring for. Only through understanding and constructive actions will we be able to provide the best quality of care to our patients and continue to enjoy universal healthcare in our country.

A Review of Hematopoietic Cell Transplantation in Australia and New Zealand, 2005 to 2013.

This report describes hematopoietic cell transplantation (HCT) activity and outcome in Australia and New Zealand during the years 2005 to 2013. In 2013, 1018 autologous, 221 allogeneic with related donors, and 264 allogeneic with unrelated donors HCT were performed in 40 centers in Australia, with corresponding figures of 147, 39, and 47 in 6 centers in New Zealand. Annual numbers of HCT in 2013 increased, compared to 2005, by 25% in Australia and by 52% in New Zealand. The majority of both allogeneic and autologous HCT used peripheral blood as the stem cell source for all years studied. Major indications for transplantation were acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), plasma cell disorders, and non-Hodgkin lymphoma (NHL). Overall survival probabilities at 5 years after transplantation for adult (16+) allogeneic first HCT recipients were 54.2% for ALL, 46.0% for AML, 48.4% for myelodysplastic syndromes, and 58.6% for NHL. Consistent patterns over time include a steady increase in HCT, particularly for older recipients, relatively constant numbers of allografts using cord blood, and a recent increase in the number of allografts with 2 or more HLA-mismatched related donors.

MicroRNA-155 as an inducer of apoptosis and cell differentiation in Acute Myeloid Leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) is characterised by the halt in maturation of myeloid progenitor cells, combined with uncontrolled proliferation and abnormal survival, leading to the accumulation of immature blasts. In many subtypes of AML the underlying causative genetic insults are not fully described. MicroRNAs are known to be dysregulated during oncogenesis. Overexpression of miR-155 is associated with some cancers, including haematological malignancies, and it has been postulated that miR-155 has an oncogenic role. This study investigated the effects of modulating miR-155 expression in human AML cells, and its mechanism of action. RESULTS: Analysis of miR-155 expression patterns in AML patients found that Fms-like tyrosine kinase 3 (FLT3)-wildtype AML has the same expression level as normal bone marrow, with increased expression restricted to AML with the FLT3-ITD mutation. Induction of apoptosis by cytarabine arabinoside or myelomonocytic differentiation by 1,23-dihydroxyvitaminD3 in FLT3-wildtype AML cells led to upregulated miR-155 expression. Knockdown of miR-155 by locked nucleic acid antisense oligonucleotides in the FLT3-wildtype AML cells conferred resistance to cytarabine arabinoside induced apoptosis and suppressed the ability of cells to differentiate.Ectopic expression of miR-155 in FLT3-wildtype AML cells led to a significant gain of myelomonocytic markers (CD11b, CD14 and CD15), increase in apoptosis (AnnexinV binding), decrease in cell growth and clonogenic capacity.In silico target prediction identified a number of putative miR-155 target genes, and the expression changes of key transcription regulators of myeloid differentiation and apoptosis (MEIS1, GF1, cMYC, JARID2, cJUN, FOS, CTNNB1 and TRIB2) were confirmed by PCR. Assessment of expression of apoptosis-related proteins demonstrated a marked increase in cleaved caspase-3 expression confirming activation of the apoptosis cascade. CONCLUSIONS: This study provides evidence for an anti-leukaemic role for miR-155 in human FLT3-wildtype AML, by inducing cell apoptosis and myelomonocytic differentiation, which is in contrast to its previously hypothesized role as an oncogene. This highlights the complexity of gene regulation by microRNAs that may have tumour repressor or oncogenic effects depending on disease context or tissue type.

Allogeneic hematopoietic cell transplantation for chronic myelofibrosis in Australia and New Zealand: older recipients receiving myeloablative conditioning at increased mortality risk.

This retrospective registry analysis examined predictive factors for outcome in 57 patients who underwent allogeneic or syngeneic hematopoietic cell transplantation (HCT) for chronic myelofibrosis (CM), either primary (n = 49) or following an antecedent condition (n = 8), reported to the Australasian Bone Marrow Transplant Registry (ABMTRR) between 1993 and 2005. During the 6 years 2000 to 2005, 40 HCTs were performed for CM compared with 17 in the 7 years 1993 to 1999. Twenty-four recipients (42%) were age 50 or over at transplantation; all of these patients were transplanted after 1997, and 15 were given reduced intensity conditioning (RIC) pretransplantation. The cumulative incidence of transplantation-related mortality was 18% at 100 days and 25% at 1 year posttransplantation. Up to 1 year posttransplantation 16 patients died, with the most common causes being infection (n = 6) and graft-versus-host disease (GVHD) (n = 5). A total of 27 patients survived for 3 years or longer posttransplantation. None of these patients required regular red blood cell transfusions, and of the 17 who had not had splenectomies, none had detectable splenomegaly. Twelve patients had no detectable bone marrow fibrosis, 7 had grade 1 fibrosis, and in 8 patients no information was available. The overall survival (OS) probability for all patients was 72% at 1 year and 58% at 5 years posttransplantation. Patients age 50 and over who received myeloablative conditioning fared poorly, with 1-year overall actuarial survival of 44% compared with 77% for all other patients (P = .007). In multivariate analysis, age 50 years and over at transplantation was the only significant independent unfavorable risk factor for survival post-HCT (hazard ratio 2.71, 95% confidence interval 1.16-6.34, P = .02). This study shows a clear increase in annual numbers of allogeneic HCT performed for CM in Australia and New Zealand in recent years. Five-year survival was favorable compared with international studies, but for older recipients who received myeloablative conditioning, mortality risk was elevated.

Potential benefits of a virtual, home-based combined exercise and mindfulness training program for HSC transplant survivors: a single-arm pilot study.

PURPOSE: Impaired quality of life (QOL) including reduced physical fitness is a recognized late effect of hemopoietic cell transplantation (HCT). Guided exercise and mindfulness-based stress management (MBSM) programs have shown promise, mainly in the inpatient setting. We aimed to examine the feasibility of a virtual, home-based, combined exercise and MBSM program. METHODS: Patients attending post-HCT clinic were invited to participate in this single-arm pre-post study. Eligibility criteria included age 18-75 years, > 6 months post allogeneic HCT. Consented participants attended an in-person session, followed by weekly exercise and MBSM training for 6 weeks via videoconferencing. Assessments were performed pre-training, and at 3-, 6- and 12-months and compared using a linear mixed effects model. RESULTS: 21 of 24 patients consenting to the study completed the program (median age 56 years [IQR 46-62], median time post-HCT 37 months [IQR 26-46]). Six-minute walk test scores were significantly higher at 3 (mean difference 79.6, 95%CI 28-131, ES 0.55) and 12 months (mean difference 48.4, 95%CI 13-84, ES 0.33) compared to baseline. Sit-to-stand test was significantly higher at 3 (mean difference 4.4, 95%CI 1.4-7.4, ES 0.68) and 12 months (mean difference 3.9, 95%CI 0.24-7.6, ES 0.61). Dominant hand grip was significantly stronger at 3 (mean difference 0.16, 95%CI 0.04-0.28, ES 0.45), and 12 months (mean difference 0.21, 95%CI 0.08-0.24, ES 0.62). Significantly higher FACT-BMT total (mean difference 6.9, 95%CI 1.5-12.4, ES 0.49) and FACT-G scores (mean difference 5.2, 95%CI 1.4-9.1, ES 0.48) were found at 3 months. Over 80% of participants rated the virtual combined modal program highly and no adverse events were reported. CONCLUSION: A 6-week virtual, home-based exercise and MBSM program was an acceptable, and potentially effective intervention for sustained improvement of some physical capacity and QOL outcomes in HCT survivors. Virtual-based healthcare service is highly relevant particularly during pandemics. To our knowledge, this study has the longest follow-up observation period for Internet based combined modality training program reported to date and warrants additional investigation. Trial Registration Research protocol approved by St Vincent's Hospital Ethics Committee (HREC 12/SVH/175), approved 27/09/2012, trial commenced 24/05/13 and the first participant 07/06/13. Retrospectively registered with ANZCTR (ACTRN12613001054707) 23/09/2013.

Sustained immunotolerance in multiple sclerosis after stem cell transplant.

OBJECTIVE: Autologous haematopoietic stem cell transplantation (AHSCT) has the potential to induce sustained periods of disease remission in multiple sclerosis (MS), which is an inflammatory disease of the central nervous system (CNS) characterised by demyelination and axonal degeneration. However, the mechanisms associated with durable treatment responses in MS require further elucidation. METHODS: To characterise the longer term immune reconstitution effects of AHSCT at 24 and 36 months (M) post-transplant, high-dimensional immunophenotyping of peripheral blood mononuclear cells from 22 MS patients was performed using two custom-designed 18-colour flow cytometry panels. RESULTS: The higher baseline frequencies of specific pro-inflammatory immune cells (T-helper-17 (Th17) cells, mucosal-associated invariant T-cells and CNS-homing T-conventional (T-conv) cells observed in MS patients were decreased post-AHSCT by 36M. This was accompanied by a post-AHSCT increase in frequencies and absolute counts of immunoregulatory CD56hi natural killer cells at 24M and terminally differentiated CD8+ CD28- CD57+ cells until 36M. A sustained increase in the proportion of naïve B-cells, with persistent depletion of memory B-cells and plasmablasts was observed until 36M. Reconstitution of the B-cell repertoire was accompanied by a reduction in the frequency of circulating T-follicular helper cells (cTfh) expressing programmed cell death-1 (PD1+ ) at 36M. Associations between frequency dynamics and clinical outcomes indicated only responder patients to exhibit a decrease in Th17, CNS-homing T-conv and PD1+ cTfh pro-inflammatory subsets at 36M, and an increase in CD39+ T-regulatory cells at 24M. INTERPRETATION: AHSCT induces substantial recalibration of pro-inflammatory and immunoregulatory components of the immune system of MS patients for up to 36M post-transplant.

Identification of microRNA-mRNA modules using microarray data.

BACKGROUND: MicroRNAs (miRNAs) are post-transcriptional regulators of mRNA expression and are involved in numerous cellular processes. Consequently, miRNAs are an important component of gene regulatory networks and an improved understanding of miRNAs will further our knowledge of these networks. There is a many-to-many relationship between miRNAs and mRNAs because a single miRNA targets multiple mRNAs and a single mRNA is targeted by multiple miRNAs. However, most of the current methods for the identification of regulatory miRNAs and their target mRNAs ignore this biological observation and focus on miRNA-mRNA pairs. RESULTS: We propose a two-step method for the identification of many-to-many relationships between miRNAs and mRNAs. In the first step, we obtain miRNA and mRNA clusters using a combination of miRNA-target mRNA prediction algorithms and microarray expression data. In the second step, we determine the associations between miRNA clusters and mRNA clusters based on changes in miRNA and mRNA expression profiles. We consider the miRNA-mRNA clusters with statistically significant associations to be potentially regulatory and, therefore, of biological interest. CONCLUSIONS: Our method reduces the interactions between several hundred miRNAs and several thousand mRNAs to a few miRNA-mRNA groups, thereby facilitating a more meaningful biological analysis and a more targeted experimental validation.

Expression profiling of cytogenetically normal acute myeloid leukemia identifies microRNAs that target genes involved in monocytic differentiation.

MicroRNAs are short ribonucleic acids (RNAs) that play an important role in many aspects of cellular biology such as differentiation and apoptosis, due to their role in the regulation of gene expression. Using microRNA microarrays, we characterized the microRNA gene expression of 27 patients with acute myeloid leukemia (AML) with normal cytogenetics, focusing on the microRNAs differentially expressed between the M1 and M5 French-American-British (FAB) subtypes. An accurate delineation of these two AML entities was observed based on the expression of 12 microRNAs. We hypothesized that these microRNAs may potentially be involved in the differentiation block of M1 blasts and consequently monocytic differentiation. Using publically available mRNA data and microRNA target prediction software, we identified several key myeloid factors that may be targeted by our candidate microRNAs. The expression changes of the candidate microRNAs during monocytic differentiation of AML cell lines treated with Vitamin D and phorbol 12-myristate 13-acetate were examined. All six candidate microRNAs were significantly down-regulated over the time course by quantitative reverse transcriptase polymerase chain reaction suggesting a link between these microRNAs and monocytic differentiation. To further characterize these microRNAs, we confirmed by luciferase assays that these microRNA target several key myeloid factors such as MAFB, IRF8, and KLF4 identifying a possible mechanism for the control of differentiation by these microRNAs.

Identification of microRNAs with regulatory potential using a matched microRNA-mRNA time-course data.

Over the past decade, a class of small RNA molecules called microRNAs (miRNAs) has been shown to regulate gene expression at the post-transcription stage. While early work focused on the identification of miRNAs using a combination of experimental and computational techniques, subsequent studies have focused on identification of miRNA-target mRNA pairs as each miRNA can have hundreds of mRNA targets. The experimental validation of some miRNAs as oncogenic has provided further motivation for research in this area. In this article we propose an odds-ratio (OR) statistic for identification of regulatory miRNAs. It is based on integrative analysis of matched miRNA and mRNA time-course microarray data. The OR-statistic was used for (i) identification of miRNAs with regulatory potential, (ii) identification of miRNA-target mRNA pairs and (iii) identification of time lags between changes in miRNA expression and those of its target mRNAs. We applied the OR-statistic to a cancer data set and identified a small set of miRNAs that were negatively correlated to mRNAs. A literature survey revealed that some of the miRNAs that were predicted to be regulatory, were indeed oncogenic or tumor suppressors. Finally, some of the predicted miRNA targets have been shown to be experimentally valid.

Long-Term Suppression of Circulating Proinflammatory Cytokines in Multiple Sclerosis Patients Following Autologous Haematopoietic Stem Cell Transplantation.

Autologous haematopoietic stem cell transplantation (AHSCT) is a therapeutic option for haematological malignancies, such as non-Hodgkin's lymphoma (NHL), and more recently, for autoimmune diseases, such as treatment-refractory multiple sclerosis (MS). The immunological mechanisms underlying remission in MS patients following AHSCT likely involve an anti-inflammatory shift in the milieu of circulating cytokines. We hypothesised that immunological tolerance in MS patients post-AHSCT is reflected by an increase in anti-inflammatory cytokines and a suppression of proinflammatory cytokines in the patient blood. We investigated this hypothesis using a multiplex-ELISA assay to compare the concentrations of secreted cytokine in the peripheral blood of MS patients and NHL patients undergoing AHSCT. In MS patients, we detected significant reductions in proinflammatory T helper (Th)17 cytokines interleukin (IL)-17, IL-23, IL-1ß, and IL-21, and Th1 cytokines interferon (IFN)γ and IL-12p70 in MS patients from day 8 to 24 months post-AHSCT. These changes were not observed in the NHL patients despite similar pre-conditioning treatment for AHSCT. Some proinflammatory cytokines show similar trends in both cohorts, such as IL-8 and tumour necrosis factor (TNF)-α, indicating a probable treatment-related AHSCT response. Anti-inflammatory cytokines (IL-10, IL-4, and IL-2) were only transiently reduced post-AHSCT, with only IL-10 exhibiting a significant surge at day 14 post-AHSCT. MS patients that relapsed post-AHSCT exhibited significantly elevated levels of IL-17 at 12 months post-AHSCT, unlike non-relapse patients which displayed sustained suppression of Th17 cytokines at all post-AHSCT timepoints up to 24 months. These findings suggest that suppression of Th17 cytokines is essential for the induction of long-term remission in MS patients following AHSCT.

The role of BMP-7 in chondrogenic and osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells in vitro.

This study addresses the role of bone morphogenetic protein-7 (BMP-7) in chondrogenic and osteogenic differentiation of human bone marrow multipotent mesenchymal stromal cells (BM MSCs) in vitro. BM MSCs were expanded and differentiated in the presence or absence of BMP-7 in monolayer and three-dimensional cultures. After 3 days of stimulation, BMP-7 significantly inhibited MSC growth in expansion cultures. When supplemented in commonly used induction media for 7-21 days, BMP-7 facilitated both chondrogenic and osteogenic differentiation of MSCs. This was evident by specific gene and protein expression analyses using real-time PCR, Western blot, histological, and immunohistochemical staining. BMP-7 supplementation appeared to enhance upregulation of lineage-specific markers, such as type II and type IX collagens (COL2A1, COL9A1) in chondrogenic and secreted phosphoprotein 1 (SPP1), osteocalcin (BGLAP), and osterix (SP7) in osteogenic differentiation. BMP-7 in the presence of TGF-beta3 induced superior chondrocytic proteoglycan accumulation, type II collagen, and SOX9 protein expression in alginate and pellet cultures compared to either factor alone. BMP-7 increased alkaline phosphatase activity and dose-dependently accelerated calcium mineralization of osteogenic differentiated MSCs. The potential of BMP-7 to promote adipogenesis of MSCs was restricted under osteogenic conditions, despite upregulation of adipocyte gene expression. These data suggest that BMP-7 is not a singular lineage determinant, rather it promotes both chondrogenic and osteogenic differentiation of MSCs by co-ordinating with initial lineage-specific signals to accelerate cell fate determination. BMP-7 may be a useful enhancer of in vitro differentiation of BM MSCs for cell-based tissue repair.

Tolerance regeneration by T regulatory cells in autologous haematopoietic stem cell transplantation for autoimmune diseases.

Autologous haematopoietic stem cell transplantation shows increasing promise as a therapeutic option for patients with treatment-refractory autoimmune disease, particularly systemic sclerosis and multiple sclerosis. However, this intensive chemotherapy-based procedure is not always possible due to potential treatment toxicities and comorbidities. The biological mechanisms of how this procedure induces long-term remission in autoimmune disease are increasingly understood. The focus of this review is on recent research findings on the role of CD4+ T regulatory cells (Tregs) in resetting the immune system leading to the eradication of the autoimmune disease after transplantation. Discovery of the precise mechanisms of this process will allow development of novel Treg-based therapies and thus avoid the need for intensive chemotherapy-based treatment for these autoimmune diseases in the future.

Relative survival of long-term hematopoietic cell transplant recipients approaches general population rates.

Whether the annual mortality rates of long-term hematopoietic cell transplant (HCT) survivors ever return to that of the general population is unclear. This study sought to determine the annual long-term mortality rates of allogeneic and autologous HCT recipients who had survived 5 years or more disease-free posttransplant and calculate their relative survival rates. Patients were included if they had a first allogeneic or syngeneic HCT for acute leukemia, chronic myelogenous leukemia (CML) or myelodysplastic syndromes (MDS), or autologous HCT for acute myelogenous leukemia (AML) or lymphoma in Australia or New Zealand between 1992 and 2001, recorded on the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) database, and were known to have survived, disease free, 5 years or more posttransplant. The annual mortality rates of 5-year transplant survivors were compared to standard Australian and New Zealand populations using relative survival. A total of 1461 HCT survivors (688 postallograft, 773 postautograft) were included in this study. The 10-year survival probability for 5-year allograft survivors was slightly higher than that of 5-year autologous survivors (93.4% versus 89.6%, P=.06). The relative survival of both allogeneic and autologous 5-year survivors was never <97% of that of the general population. However, it was statistically significantly lower than expected in the sixth to ninth years posttransplant, with no obvious pattern of either improvement or deterioration from 6 to 10 years posttransplant. This study indicates that annual relative survival rates of long-term survivors of allogeneic HCT performed in Australia and New Zealand for acute lymophoblastic leukemkia (ALL), AML, CML, and MDS are slightly, but significantly lower than population rates in the 6th to 10th years posttransplant. Annual relative survival rates of long-term survivors of autologous HCT performed in Australia and New Zealand for AML and lymphomas are also slightly lower than population rates up to the 10th year posttransplant. Late deaths from transplant and disease-related causes are unusual, but continue to occur for many years post-HCT.

Favorable Outcome of Lung Transplantation for Severe Pulmonary Graft Versus Host Disease: An Australian Multicenter Case Series.

BACKGROUND: Severe pulmonary chronic graft versus host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation. Few treatments influence outcome, with 5-year overall survival as low as 13%. Lung transplantation (LTx) has been reported in small numbers of patients worldwide. METHODS: We investigated the outcomes of LTx performed for this indication at 2 large Australian LTx centers. RESULTS: Eighteen patients (aged 10-64 y; median, 29.6 y) received bilateral deceased lung transplants for pulmonary chronic GVHD between 2002 and 2017. LTx was performed at a median of 8.6 years after allogeneic stem cell transplantation (range, 2-23 y) with a median interval of 16 months from the time of transplant unit review to LTx. There were 2 early infective deaths and 3 further deaths from pulmonary infection and lung allograft rejection. There were no primary disease relapses. At a median follow-up of 5 years, the 5-year overall survival post-LTx is 80% and comparable to the Australia and New Zealand registry data of 64% for LTx performed for all indications. CONCLUSIONS: From one of the largest series of deceased LTx for this indication, we conclude that it is a feasible option for selected patients with severe pulmonary GVHD. The outcomes appear superior to that of non-LTx-based therapies and similar to the survival of the general LTx population. Establishing guidance on referral triggers, patient eligibility, organ selection, prophylaxis of allograft rejection, and supportive care would assist hematopoietic and lung transplant units in optimizing resource allocation and patient outcomes.

Autologous hematopoietic stem cell transplant for autoimmune diseases: evolution,evidence of efficacy, and real-world economics.

Despite an increase in the development of biological therapies for autoimmune disease (AID), a proportion of patients remain treatment refractory, resulting in long term morbidity and increased rates of mortality. Furthermore, maintenance biologic therapies are associated with treatment-related side effects, significant financial cost,and restricted access, which is of particular relevance in the developing world. Although it carries a significant 'front loaded' cost both financially and regarding adverse events, autologous hematopoietic stem cell transplantation (AHSCT) represents a potential single therapeutic intervention, which in the appropriate patient, condition, and transplant center, may offer sustained disease remission resulting in improved overall survival, disease relapse-free survival, improved quality of life, and decreased financial burden. Emerging Phase II and III trial and registry data, to which our center has been a significant contributor over the past two decades, are providing invaluable evidence as to which AIDs are most likely to receive a sustained benefit from AHSCT and which conditioning regimens are preferable. Similar to trends for the treatment of malignant disease, AHSCT for AID may find a place in both developed and developing countries as nations become more familiar with the transplantation process. If this occurs, benchmarking by key regulatory bodies, collaboration between medical specialties, and the development of experienced 'centers of excellence' will be key to enhance safety and benefit to patients and society at large.

Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study.

BACKGROUND: Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases. METHODS: We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing. FINDINGS: Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]). INTERPRETATION: The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment. FUNDING: Janssen R&D.

Regenerating Immunotolerance in Multiple Sclerosis with Autologous Hematopoietic Stem Cell Transplant.

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system where evidence implicates an aberrant adaptive immune response in the accrual of neurological disability. The inflammatory phase of the disease responds to immunomodulation to varying degrees of efficacy; however, no therapy has been proven to arrest progression of disability. Recently, more intensive therapies, including immunoablation with autologous hematopoietic stem cell transplantation (AHSCT), have been offered as a treatment option to retard inflammatory disease, prior to patients becoming irreversibly disabled. Empirical clinical observations support the notion that the immune reconstitution (IR) that occurs following AHSCT is associated with a sustained therapeutic benefit; however, neither the pathogenesis of MS nor the mechanism by which AHSCT results in a therapeutic benefit has been clearly delineated. Although the antigenic target of the aberrant immune response in MS is not defined, accumulated data suggest that IR following AHSCT results in an immunotolerant state through deletion of pathogenic clones by a combination of direct ablation and induction of a lymphopenic state driving replicative senescence and clonal attrition. Restoration of immunoregulation is evidenced by changes in regulatory T cell populations following AHSCT and normalization of genetic signatures of immune homeostasis. Furthermore, some evidence exists that AHSCT may induce a rebooting of thymic function and regeneration of a diversified naïve T cell repertoire equipped to appropriately modulate the immune system in response to future antigenic challenge. In this review, we discuss the immunological mechanisms of IR therapies, focusing on AHSCT, as a means of recalibrating the dysfunctional immune response observed in MS.