ALBERT

Description: Article Improving the efficiency of reprogramming of somatic cells to induced pluripotent stem cells is of major interest. Here, the authors combine ascorbic acid and 2i (MAP kinase and GSK inhibitors) conditions and show increased efficiency and synchronicity in the reprogramming of fibroblasts and partially reprogrammed cells, and study epigenetic effectors and signalling pathways responsible for this effect. Nature Communications doi: 10.1038/ncomms7188 Authors: Khoa A. Tran, Steven A. Jackson, Zachariah P.G. Olufs, Nur Zafirah Zaidan, Ning Leng, Christina Kendziorski, Sushmita Roy, Rupa Sridharan

Description: Sleep is an essential and phylogenetically conserved behavioral state, but it remains unclear to what extent genes identified in invertebrates also regulate vertebrate sleep. RFamide-related neuropeptides have been shown to promote invertebrate sleep, and here we report that the vertebrate hypothalamic RFamide neuropeptide VF (NPVF) regulates sleep in the zebrafish, a diurnal vertebrate. We found that NPVF signaling and npvf-expressing neurons are both necessary and sufficient to promote sleep, that mature peptides derived from the NPVF preproprotein promote sleep in a synergistic manner, and that stimulation of npvf-expressing neurons induces neuronal activity levels consistent with normal sleep. These results identify NPVF signaling and npvf-expressing neurons as a novel vertebrate sleep-promoting system and suggest that RFamide neuropeptides participate in an ancient and central aspect of sleep control.

Description: Aim: Although allogeneic stem cell transplant (alloSCT) remains the only curative option for myelofibrosis, novel therapeutic agents, the application of new prognostic scoring systems and the emergence of molecular genetic analysis have lead to a new management landscape in myelofibrosis. In view of these recent advances, we aimed to review national practice in transplanting myelofibrosis patients and its outcomes. Methods: A retrospective study was conducted using the Australasian Bone Marrow Transplant Registry (ABMTRR) data on patients who underwent alloSCT for myelofibrosis at Australian/New Zealand transplant centres between 2006 and 2017. Participating centres completed an online questionnaire and responses were reviewed centrally by the ABMTRR. Results: 142 patients underwent alloSCT for myelofibrosis, primary (n=94) or secondary (n=48) (Table 1). 52% had HLA-identical sibling donors and 45% had matched unrelated donors (UD). Median follow-up was 51.8 months (range: 3.1-148). Cytogenetic abnormalities were identified in 29% of 120 patients who were tested pretransplant. JAK2 mutation testing was performed in 74% of patients whilst other mutations (CALR, MPL, EZH2, IDH, SRSF2, ASXL1) were rarely tested (1.4-8.4%). Only 4.2% of patients had next generation sequencing. Before transplant, 16% had splenectomy or splenic irradiation and 54 patients (38%) received JAK 1/2 inhibitors (JAKi), of whom 92.5% had Ruxolitinib. Median time to neutrophil engraftment was 20 (range: 10-43) days whereas median platelet recovery time was 28 (range: 13-230) days. 9 patients (6.3%) had primary graft failure and 11 patients (7.7%) had secondary graft failure. 60% had chimerism studies using cytogenetic or molecular techniques at 3 months post transplant; 63% of those assessed achieved complete (≥95%) donor chimerism. CMV reactivation was detected in 32% and 10% had sinusoidal obstruction syndrome. The cumulative incidence of grade II-IV acute GvHD was 21.4% and grade III-IV acute GvHD was 8.7%. The cumulative incidences of limited and extensive chronic GvHD at 5 years were 11.1% and 18.1% respectively. Overall survival (OS) was 67% at 1 year and 57% at 5 years. GvHD free progression free survival was 54% at 1 year and 42% at 5 years (Figure 1). The cumulative incidence of non-relapse mortality (NRM) was 16% at 100 days and 25% at 1 year. In multivariate analysis, use of an UD was a significant independent unfavourable risk factor for OS (HR 2.26, 95%CI 1.17- 4.33, p=0.015) and NRM (HR 3.02, 95%CI 1.36-6.71, p=0.007), while splenic irradiation/splenectomy resulted in shortened neutrophil (HR 1.88, 95%CI 1.00-3.54, p=0.05) and platelet recovery time (HR 2.13, 95%CI 1.12-4.05, p=0.02). Use of UD significantly increased the incidence of grade II-IV acute GvHD in multivariate analysis (HR 5.66, 95%CI 1.99-16.11, p=0.001) whereas use of antithymoglobulin or alemtuzumab significantly reduced it (HR 0.27, 95% CI 0.09-0.79, p=0.017). Neither use of JAKi prior to alloSCT nor presence of JAK2 mutation had a significant impact on OS or NRM. 9 patients underwent a second alloSCT for myelofibrosis and median length of time from the first transplant was 22 (range: 1-132) months. 4 patients were transplanted for disease relapse and 3 patients for graft failure. For the second transplant cohort, NRM at day 100 and 1 year were 11.1% (95% CI, 0.4%-40.6%) and 33.3% (95% CI, 6.6%-64%) respectively, while 1-year and 5-year OS were 66.6% (95% CI, 42%-100%) and 44.4% (95% CI, 21.4%-92.2%). Conclusion: Survival rates in alloSCT for myelofibrosis in this Australasian cohort were comparable to international studies. There is a rise in the numbers of patients treated with JAKi pretransplant (Figure 2). Although this does not appear to have any effect on transplant outcomes, reduced symptom burden associated with increasing use of pre-transplant JAKi may increase the numbers of patients considered eligible for alloSCT. Although splenectomy/splenic irradiation had a positive impact on engraftment, it did not improve the survival outcomes. Our results show a negative influence of UD on OS and NRM, possibly related to an increased incidence of acute GVHD in the UD group. In light of the rise in utilization of alloSCT in the management of myelofibrosis, there is a need for further prospective studies incorporating molecular testing and the new comprehensive clinical-molecular myelofibrosis transplant scoring system. Disclosures Spencer: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Specialised Therapeutics Australia: Consultancy, Honoraria. Purtill:MSD: Honoraria; Novartis: Honoraria, Other: Travel for speaking and advisory boards; Gilead: Honoraria, Other: Travel for speaking and advisory boards; Janssen: Honoraria. Browett:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Achillion: Research Funding; Beigene: Research Funding. Szer:Sanofi: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Alexion: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; Prevail Therapeutics: Honoraria, Other: Travel, Research Funding. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Greenwood:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gottlieb:Merck: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Novartis: Consultancy; University of Sydney: Employment; Haemalogix P/L: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: An Australasian Bone Marrow Transplant Registry (ABMTR) Study of the Trends and Outcomes of Allogeneic Haematopoietic Stem Cell Transplantation (HSCT) in Hodgkin Lymphoma between 2009-2019: Relapse remains the most common cause of death post transplantation Introduction: Hodgkin Lymphoma (HL) is an eminently curable disease, with 80% of cases achieving cure with first line therapies. There are a subset of patients who relapse and require salvage therapy including autologous stem cell transplant and more recently novel agents such as brentuximab vedotin (BV) and the PD-1 inhibitors. The latter are less toxic and achieve durable responses but are not considered curative for most (LaCasce et al., 2019). In Australia BV and PD-1 inhibitors were approved in December 2013 and September 2017 respectively. Allogeneic HSCT offers a graft vs lymphoma (GVL) effect that may contribute to long term survival in some patients (Peggs et al., 2005). The introduction of reduced intensity conditioning (RIC) has seen improved outcomes with an OS of 67% (59-74%) and Progression Free Survival (PFS)of 45% (35-56%) (Rashidi et al., 2016) Patients and methods: Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients receiving a first allogeneic transplant for HL between 2009 and 2019. The Kaplan Meier method was used to calculate OS and PFS with log rank test for comparison. Multivariable Cox proportional hazards models were used to identify associations with OS. We divided the patients into 5 year cohorts to compare transplant outcomes over time. Results: A total of 149 patients from 16 sites in Australia and New Zealand were included. The median age at time of transplant was 31 years (range 19-61) and the majority were male (60%). Seventy-five percent of patients had undergone previous autologous HSCT with data missing for 22%. Median follow up was 75 months (range 4.7-137.1). Forty five percent of patients were in complete remission (CR), 34% in partial remission and 15% relapsed/primary refractory (RR) at the time of HSCT with information missing in 4%. The majority of donors were matched unrelated donors (47%) and sibling donors were used for 37% of patients, haploidentical in 11% and umbilical cord blood in 5%. Reduced intensity conditioning was used in 86% of patients and in vivo T cell depletion with ATG or alemtuzumab was used in 27%. Acute GVHD occurred in 53/149 (30%) of which 31% was grade III-IV. In patients who survived beyond 100 days, the incidence of chronic GVHD was 38%, of which 53% was preceded by some form of aGVHD. Non-relapse mortality (NRM) at 100 days was 8% with 5/12 of these patients dying from aGVHD. Two-year OS and PFS were 75% and 49% respectively. A period effect was not detected with no significant difference in OS (p=0.8) nor PFS (0.2) based on transplant year (figure 1a & 1b). Multivariate analysis of factors associated with OS identified age at transplant of 〉40 (HR 3.24, 95% CI 1.71-6.15, p

Description: Background: Upfront autologous stem cell transplantation (ASCT) in multiple myeloma (MM) following induction therapy has been demonstrated to improve progression free survival (PFS) and overall survival (OS). Consideration of transplant eligibility involves assessment of age (typically

Description: Background HLA-matched sibling and unrelated donors are not always available for patients that are in need of an allogeneic haematopoietic stem cell transplant. Partially HLA-mismatched related (haploidentical) donors can be identified for the vast majority of patients but these transplants were historically complicated by excessive graft versus host disease (GVHD), nonrelapse mortality (NRM), and poor overall survival (OS). Haploidentical haematopoietic stem cell transplantation (Haplo HSCT) has become increasingly common over the last ten years, predominately due to the successful use of post-transplant cyclophosphamide (PTCy) in mitigating graft versus host disease (GVHD). Most studies using PTCy have been retrospective with various conditioning regimens and stem cell sources making interpretation of results difficult. ANZHIT-1 is a prospective Australian multi-centre phase II study of Haplo HSCT with defined conditioning and GVHD prophylaxis regimens. Methods: This is an ethics approved Phase II study (ACTRN: 12617000151336) conducted between 2015-2020 at six Australian allogeneic HSCT centres. All patients received peripheral blood Haplo HSCT from haploidentical family members. The reduced intensity regimen (RIC) was fludarabine, cyclophosphamide and 200cGy TBI and the myeloablative regimen (MAC) was fludarabine with IV busulfan 3.2mg/kg x 4. PTCy 50mg/kg D+3, D+4 was used with MMF (to D35) and a calcineurin inhibitor (CNI) as GVHD prophylaxis. CNIs were weaned and ceased by D+120 in patients who did not have evidence of GVHD. Choice of conditioning regimen was based on age and hematopoietic cell transplantation comorbidity index (HCT-CI) scores. Patients who had an HCTCI 〉3 or age 〉50yrs received RIC. Data collection was through the Australian Bone Marrow Transplant Recipient Registry. Survival was analysed using the Kaplan-Meier method. Results: Seventy eight patients were included in the study with a median follow up of 402.5 days (28-1259). There was a male predominance (66%). The median age was 53 years (range 18-69) and the median HCT-CI score was 1 (range 0-5). Thirty nine patients had acute myeloid leukaemia, 12 acute lymphoblastic Leukaemia, 14 Non Hodgkin lymphoma or Hodgkin lymphoma, 4 myelodysplastic syndrome and 9 other diagnoses. The majority received RIC (59%). Median neutrophil and platelet engraftment times were 18 days (range: 12-92) and 28 days (range: 13-262) respectively. Acute GVHD grade III-IV occurred in 14.1% of patients whilst chronic GVHD occurred in 20.5%. Moderate to severe cGVHD according to NIH consensus criteria occurred in 10.3% of patients. Overall survival probability at one year was 74.1% (95% CI: 52.9-86.8) for MAC recipients and 77.8% (95% CI: 61.6-87.8) for RIC recipients (Figure 1). Non relapse mortality (NRM) at D100 and 1 year were 2.2% and 8.7% respectively in the RIC group compared to 6.3% and 18.8% respectively in the MAC group. Causes of NRM included infection (n=5), GVHD (n=3) and VOD, respiratory failure and multi-organ failure in one patient each. Haemorrhagic cystitis and poor graft function were relatively common post-transplant morbidities but rarely contributed to NRM. Despite the use of peripheral blood stem cells and early weaning of CNIs, only 3/11 NRM deaths were due to GVHD. Relapse was the most common cause of death in the RIC group with 17.4% of patients relapsing at a median of 114 days (range 36-564) compared to only 6.3% at a median of 90.5 days (range 64-154) in the MAC group. Conclusion: This prospective Haplo HSCT trial utilising PTCY demonstrates encouraging overall survival rates. The RIC regimen had a promising toxicity profile but early relapse remains a concern despite early weaning of CNIs. In contrast, the MAC regimen is associated with a low relapse rate but NRM at one year remains significant. Further refinement of the conditioning and GVHD prophylaxis regimens will be incorporated in the follow-on study, ANZHIT-2, which will begin accrual in late 2020. Disclosures Bajel: Pfizer: Honoraria; Amgen: Honoraria, Speakers Bureau; Novartis: Honoraria; Astellas: Honoraria; Abbvie: Honoraria. Greenwood:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hamad:Novartis: Honoraria; Abbvie: Honoraria.