Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG.

Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P = .61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P = .08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P = .028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.

Clinical grade multiparametric cell sorting and gene-marking of regulatory T cells.

BACKGROUND AIMS: Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity. METHODS: We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs. RESULTS: We showed that Tregs could be enriched to 87- 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136-732×106 gene-marked cells, sufficient for a cell dose of at least 2 × 106 cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro, but a small percentage could secrete proinflammatory cytokines, including interferon-γ and interleukin-17A. CONCLUSIONS: This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response.

A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis.

We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day -1. All patients received T-cell-replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.

A randomised trial of topical polaprezinc to prevent oral mucositis in patients undergoing haematopoietic stem cell transplantation (ToPaZ study).

PURPOSE: Oral mucositis (OM) is a common complication in haematopoietic stem cell transplantation (HSCT). Polaprezinc, an anti-ulcer drug, has been shown to be effective to prevent OM in several studies when administered topically and systemically. This study aimed to evaluate the effectiveness of topical polaprezinc in patients undergoing HSCT. METHODS: This was an open-label randomised clinical trial comparing polaprezinc and sodium bicarbonate mouthwashes for the prevention of severe OM in HSCT patients. Adult patients who received conditioning regimens at moderate to high risk of developing OM were included. The primary endpoint was the incidence of severe (WHO grades 3-4) OM. The secondary endpoints included duration of grades 3-4 OM, incidence and duration of grades 2-4 OM, patient-reported pain and functional limitations. RESULTS: In total, 108 patients (55 test arm and 53 control arm) were randomised. There was no difference in the incidence of grades 3 to 4 OM (35% test arm versus 36% control arm). The secondary endpoints were not significantly different. In both arms, patients reported more throat pain compared to mouth pain. CONCLUSIONS: Topical polaprezinc had no effect in the prevention of OM in HSCT patients. Further research is required to evaluate the effects of systemic polaprezinc. The OM assessment tool needs to be reviewed as throat mucositis was a main issue in this study. TRIAL REGISTRATION: ACTRN12320001188921 (Date Registered: 10th November 2020).

A real-world accuracy of oral mucositis grading in patients undergoing hematopoietic stem cell transplantation.

PURPOSE: Oral mucositis is a common complication in patients undergoing hematopoietic stem cell transplantation. Accurate oral mucositis grading is essential for both clinical practice and oral mucositis research. This study aimed to evaluate the accuracy of daily oral mucositis grading by nurses in a tertiary hospital in Australia. METHODS: A retrospective study was undertaken to review the daily patient oral assessment record, including diet, pain, erythema, ulceration and the oral mucositis grade based on World Health Organization (WHO) oral mucositis grading scale. The accuracy of the grade was determined by the observations recorded, and reasons for inaccuracy were documented. Any repetition of the same error in the same patient was noted. RESULTS: In total, 6841 oral assessments in 373 patients, conducted between 2017 and 2020, were reviewed. A total of 70% (N = 4781) were graded correctly. Of these, 64% (N = 3043) were grade 0. When the grade 0 scores were excluded, the accuracy of grading was reduced to 46% (N = 1738). Common reasons for incorrect grading included: unable to grade due to diet not specified, no ulceration and no pain was scored grade 1, no ulceration was scored as grade 2-4, oral intake was not taken into account, and pain without ulcer was scored 0. A total of 77% of the errors were repeated in the same patient on consecutive days. CONCLUSIONS: Our results suggest there is frequent inaccurate evaluation of oral mucositis and a need for nurse training to accurately assess oral mucositis.

The incidence of severe oral mucositis in patients undergoing different conditioning regimens in haematopoietic stem cell transplantation.

PURPOSE: Oral mucositis is a common complication during haematopoietic stem cell transplantation (HSCT). This study aimed to assess the incidence of severe mucositis in patients undergoing different HSCT regimens. METHODS: This single-centre retrospective study reviewed daily oral assessment for 467 consecutive patients who underwent different transplant regimens for matched unrelated or related allogeneic HSCT with post-transplant methotrexate, haploidentical or mismatched HSCT with post-transplant cyclophosphamide (PTCy), or autologous HSCT. Oral care and cryotherapy with melphalan were used. Patient demographic data, oral mucositis WHO grade, use of total parenteral nutrition (TPN) and patient-controlled analgesia (PCA) were collected. RESULTS: Grade 3-4 oral mucositis was common in myeloablative total body irradiation (TBI)-based regimens cyclophosphamide/ TBI (CyTBI) (71%) and fludarabine/ TBI (FluTBI) with PTCy (46%), as well as reduced-intensity fludarabine/melphalan (FluMel) (43%) and carmustine/etoposide/cytarabine/melphalan (BEAM) autologous HSCT (41%). In contrast, grade 3-4 oral mucositis was less common in reduced-intensity haploidentical regimen melphalan/fludarabine/TBI with PTCy (19%), all non-myeloablative regimens (0-9%) and high-dose melphalan autologous HSCT (26%). TPN and PCA use were correlated to oral mucositis severity. CONCLUSIONS: Severe oral mucositis was associated with myeloablative TBI, methotrexate and melphalan in combination with methotrexate and in BEAM. Use of PTCy was preferable over methotrexate to prevent oral mucositis.

Implementation and evaluation of a nurse-allied health clinic for patients after haematopoietic stem cell transplantation.

PURPOSE: Patients who undergo haematopoietic stem cell transplantation (HSCT) often have multiple health issues following hospital discharge. In many centres, outpatient follow-up is solely conducted by specialist physicians. We aimed to implement and describe the outcomes of a nurse-allied health multidisciplinary clinic. METHODS: The clinic consisted of six disciplines-nursing, pharmacy, dietetics, physiotherapy, occupational therapy and social work. All allogeneic and high risk autologous HSCT patients were reviewed at 2 weeks after discharge and on day 100 post HSCT, with additional reviews as needed. Occasions of service, interventions, readmission data and physician satisfaction survey were collected prior to and after implementation. Additionally, patient feedback and quality of life survey (FACT-BMT) were collected during the first 6 months. RESULTS: From July to December 2019, 57 patients were reviewed in the clinic (475 reviews, average 8.3 reviews per patient). Common interventions included the following: exercise programs by physiotherapist (n = 111), diet prescription (n = 103), counselling by social worker (n = 53), medication lists provision (n = 51), fatigue management (n = 43) and nurse education (n = 22). The clinic did not reduce patients' readmission rate; however, positive feedback from patients and physicians were reported. FACT-BMT results demonstrated that there are unmet needs, particularly fatigue management, sexual education and support, body images, back to work support and quality of life improvement. From discharge to day 100, there was no significant improvement in quality of life. CONCLUSIONS: This clinic provides an innovative approach to patient-centred care in HSCT. It has been well received by patients who were supported by multidisciplinary interventions.

Management of Patients With Erythropoietic Protoporphyria-Related Progressive Liver Disease.

Erythropoietic protoporphyria (EPP) is an inherited metabolic disorder of heme synthesis resulting from overproduction of protoporphyrin IX (PPIX), which can lead to progressive liver disease characterized by recurrent EPP crises and end-stage liver disease. We used the Australian Transplant Registry to identify 5 patients referred for liver transplantation between 2008 and 2017. A total of 4 patients had EPP secondary to ferrochelatase deficiency, and 1 patient had X-linked EPP. No patient had follow-up with a specialist prior to the diagnosis of progressive liver disease. There were 3 patients who underwent orthotopic liver transplantation, whereas 2 died while on the transplant waiting list. Parenteral PPIX-lowering therapy was used in 4 patients and was effective in 3 patients, although 2 of these had rebound porphyria and worsening liver function following a decrease in the intensity of therapy. Early disease recurrence in the allograft following transplantation occurred in 2 patients requiring red cell exchange (RCE) to successfully attain and maintain low PPIX levels, but RCE was associated with hemosiderosis in 1 patient. Allogeneic stem cell transplantation (AlloSCT) was performed in 2 patients. One failed engraftment twice, whereas the second rejected the first graft but achieved full donor chimerism with a second graft and increased immunosuppression. In conclusion, our observations suggest that progressive liver disease needs parenteral PPIX-lowering treatment with the intensity adjusted to achieve a target Erc-PPIX level. Because EPP liver disease is universally recurrent, AlloSCT should be considered in all patients with adequate immunosuppression to facilitate engraftment. RCE appears to be effective for recurrent EPP liver disease but is associated with an increased risk of iron overload.

Diagnostic Utility of Endoscopy and Biopsy in Suspected Acute Gastrointestinal Graft-versus-Host Disease after Hematopoietic Progenitor Cell Transplantation.

Acute gastrointestinal graft-versus-host disease (GI-GVHD) after hematopoietic progenitor cell transplantation (HPCT) is a common and life-threatening complication. Endoscopic biopsy of the GI tract (GIT) is required for diagnosis. However, clear evidence to optimize this diagnostic approach is lacking, leading to variation in diagnostic sensitivity between institutions. We aimed to assess the clinical, endoscopic, and histologic findings of endoscopies performed for suspected acute GI-GVHD at our institution to better define the optimal use of this strategy. We performed a retrospective cohort study of adults who had undergone endoscopy for suspected acute GI-GVHD within 180 days after allogeneic HPCT for hematologic malignancy between 2011 and 2016. Details included symptoms at time of referral for endoscopy, type of procedure performed, macroscopic findings on endoscopy, and histologic findings after gut biopsy. Correlation was made with clinical GVHD severity scores. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated and compared for each procedure. Predictors of histologic GVHD and overall survival were also compared. Of the 123 patients included, acute GI-GVHD occurred in 59 (48%). Lower endoscopy demonstrated greater sensitivity than upper endoscopy (50% versus 39%). Single upper endoscopy for upper symptoms alone had the lowest yield of GI-GVHD (14%). Combination upper and lower endoscopy demonstrated strong histologic concordance between upper and lower procedures. The addition of upper endoscopy to lower endoscopy only identified an extra 2 (4%) cases of GVHD. Advanced age and the presence of lower GIT symptoms were the only pre-endoscopy predictors of histologic GVHD on multivariate analysis. Patients with isolated upper histologic GVHD showed similar survival to patients with negative biopsies. Endoscopy and biopsy only identified 74% of those ultimately requiring treatment for acute GI-GVHD. Acute GI-GVHD remains a clinical diagnosis supported by available histologic evidence. Isolated upper GI-GVHD is rare, and in the absence of lower GIT symptoms, routine upper endoscopy does not significantly improve diagnostic yield for histologic GVHD. Overall, endoscopy and biopsy underdiagnoses 26% of clinical GI-GVHD, highlighting a need for research into novel diagnostic strategies.

Early Blood Stream Infections after BMT are Associated with Cytokine Dysregulation and Poor Overall Survival.

The key complications of allogeneic bone marrow transplantation (BMT) remain graft-versus-host disease (GVHD) and opportunistic infection. We have analyzed the blood stream infections (BSIs) occurring between day -7 and day 100 in a cohort of 184 adult patients undergoing allogeneic BMT in our center. A total of 167 of the 184 patients (91%) had blood cultures collected, and 69 (38%) patients had a confirmed BSI. Enterobacteriaceae, Pseudomonas aeruginosa, Enterococcus spp., and viridans Streptococcus spp. were the most commonly isolated organisms. Gender, conditioning (myeloablative versus reduced intensity), and donor type (sibling versus unrelated) did not differ significantly between those with and without confirmed BSI. Elevated temperature (>38°C) at the time of culture collection was associated with an almost 2-fold increased likelihood of returning a positive blood culture. The absence of a BSI was associated with a significant improvement in overall survival at 2 years, due to a significant reduction in nonrelapse mortality predominantly unrelated to the primary BSI. The presence of a BSI before engraftment was associated with the dysregulation of IL-6 and IL-8. Our findings suggest that BSI early after BMT defines a group of high-risk patients with enhanced cytokine dysregulation and poor transplant outcome.

Lung parenchyma-derived IL-6 promotes IL-17A-dependent acute lung injury after allogeneic stem cell transplantation.

Idiopathic pneumonia syndrome (IPS) is a relatively common, frequently fatal clinical entity, characterized by noninfectious acute lung inflammation following allogeneic stem cell transplantation (SCT), the mechanisms of which are unclear. In this study, we demonstrate that immune suppression with cyclosporin after SCT limits T-helper cell (Th) 1 differentiation and interferon-γ secretion by donor T cells, which is critical for inhibiting interleukin (IL)-6 generation from lung parenchyma during an alloimmune response. Thereafter, local IL-6 secretion induces donor alloantigen-specific Th17 cells to preferentially expand within the lung, and blockade of IL-17A or transplantation of grafts lacking the IL-17 receptor prevents disease. Studies using IL-6(-/-) recipients or IL-6 blockade demonstrate that IL-6 is the critical driver of donor Th17 differentiation within the lung. Importantly, IL-6 is also dysregulated in patients undergoing clinical SCT and is present at very high levels in the plasma of patients with IPS compared with SCT recipients without complications. Furthermore, at the time of diagnosis, plasma IL-6 levels were higher in a subset of IPS patients who were nonresponsive to steroids and anti-tumor necrosis factor therapy. In sum, pulmonary-derived IL-6 promotes IPS via the induction of Th17 differentiation, and strategies that target these cytokines represent logical therapeutic approaches for IPS.

A randomized trial of olanzapine versus palonosetron versus infused ondansetron for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients undergoing hematopoietic stem cell transplantation.

PURPOSE: The primary aim of this study was to compare the effectiveness of olanzapine, palonosetron and ondansetron infusion (standard of care) for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients undergoing hematopoietic stem cell transplantation (HSCT). METHOD: It was a randomized open-label prospective study. Sixty-two patients were randomized to receive either ondansetron 32-mg infusion over 24 h, or olanzapine wafer 10 mg once daily in addition to ondansetron 8 mg IV three times a day or a single dose of palonosetron 0.25 mg IV instead of ondansetron. All groups were allowed rescue antiemetics. The primary endpoint was a composite outcome of no emesis, no use of rescue medication, and nausea score reduction of ≥50 %. The secondary endpoint was nausea score reduction of ≥50 %. Both endpoints were measured at 24 and 48 h after initiation of the study treatment. Statistical analysis was conducted using a double-sided Fisher's exact test. RESULT: The primary endpoint was achieved in 6, 45, and 18 %, and 6, 64, and 18 % of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48 h, respectively. The secondary outcome was observed in 17, 60, and 62 %, and 35, 71, and 43 % of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48 h, respectively. Serious adverse drug reactions were not reported in any arms. Time to engraftment was not significantly different between the arms. CONCLUSIONS: Olanzapine was an effective treatment of breakthrough CINV. A single dose of palonosetron significantly reduced nausea up to 24 h.

Pretransplant platelet transfusion refractoriness is not associated with platelet nonengraftment in T-replete hematopoietic progenitor cell transplantation for hematologic malignancies.

BACKGROUND: Cellular engraftment after allogeneic hematopoietic progenitor cell transplantation (HPCT) can be affected by pre-HPCT antibodies against donor human leukocyte antigen (HLA; donor-specific antibodies [DSAs]), which are commonly acquired by either pregnancy or transfusion. Issues regarding high assay sensitivity and variable interpretation limit routine screening for DSAs. Platelet (PLT) transfusion refractoriness (PTR) is relatively common in patients with hematologic malignancies, and anti-HLA alloantibodies can be identified in up to 20% of cases. For patients with PTR undergoing subsequent allogeneic HPCT, however, the effect if any on subsequent PLT nonengraftment is unknown. STUDY DESIGN AND METHODS: We conducted a retrospective study of 480 adults who underwent T-replete HPCT for hematologic malignancy and compared the posttransplantation clinical outcomes between patients who were PTR before HPCT and those who were not. RESULTS: Multivariate analysis demonstrated that PTR was not directly associated with PLT nonengraftment or graft failure, but did predict for early intensive care unit admission, which was the only variable associated with these outcomes (p < 0.0001). CONCLUSION: Our findings suggest that PTR before HPCT identifies patients at higher risk of early clinical rather than immunologic complications.

Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial.

BACKGROUND: Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD. METHODS: We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18-65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin [5 mg/kg per day on days -1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140-300 ng/mL) for 100 days plus methotrexate [15 mg/m(2) on day 1, then 10 mg/m(2) on days 3, 6, and 11]). The primary endpoint was incidence of grade 2-4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853. FINDINGS: Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2-4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5-24), and the incidence of grade 3-4 acute GVHD was 4% (1-13). Grade 2-4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2-4 acute GVHD were noted in patients receiving both myeloablative total body irradiation-based conditioning (12% [95% CI 2-34) and fludarabine and melphalan reduced-intensity conditioning (12% [4-27]). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION: Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted. FUNDING: National Health and Medical Research Council and Queensland Health.

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.

Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.

IL-6-mediated endothelial injury impairs antiviral humoral immunity after bone marrow transplantation.

Endothelial function and integrity are compromised after allogeneic bone marrow transplantation (BMT), but how this affects immune responses broadly remains unknown. Using a preclinical model of CMV reactivation after BMT, we found compromised antiviral humoral responses induced by IL-6 signaling. IL-6 signaling in T cells maintained Th1 cells, resulting in sustained IFN-γ secretion, which promoted endothelial cell (EC) injury, loss of the neonatal Fc receptor (FcRn) responsible for IgG recycling, and rapid IgG loss. T cell-specific deletion of IL-6R led to persistence of recipient-derived, CMV-specific IgG and inhibited CMV reactivation. Deletion of IFN-γ in donor T cells also eliminated EC injury and FcRn loss. In a phase III clinical trial, blockade of IL-6R with tocilizumab promoted CMV-specific IgG persistence and significantly attenuated early HCMV reactivation. In sum, IL-6 invoked IFN-γ-dependent EC injury and consequent IgG loss, leading to CMV reactivation. Hence, cytokine inhibition represents a logical strategy to prevent endothelial injury, thereby preserving humoral immunity after immunotherapy.

A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia.

This prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre-, mid- and post- each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 µg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19-130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment-related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.

PET assessment of acute gastrointestinal graft versus host disease.

Acute gastrointestinal graft versus host disease (GI-GVHD) is a common complication following allogeneic haematopoietic cell transplantation (HCT), and is characterised by severe morbidity, frequent treatment-refractoriness, and high mortality. Early, accurate identification of GI-GVHD could allow for therapeutic interventions to ameliorate its severity, improve response rates and survival; however, standard endoscopic biopsy is inadequately informative in terms of diagnostic sensitivity or outcome prediction. In an era where rapid technological and laboratory advances have dramatically expanded our understanding of GI-GVHD biology and potential therapeutic targets, there is substantial scope for novel investigations that can precisely guide GI-GVHD management. In particular, the combination of tissue-based biomarker assessment (plasma cytokines, faecal microbiome) and molecular imaging by positron emission tomography (PET) offers the potential for non-invasive, real-time in vivo assessment of donor:recipient immune activity within the GI tract for GI-GVHD prediction or diagnosis. In this article, we review the evidence regarding GI-GVHD diagnosis, and examine the potential roles and translational opportunities posed by these novel diagnostic tools, with a focus on the evolving role of PET.