ANZTCT consensus position statement on ruxolitinib in steroid-refractory acute and chronic graft-versus-host disease.

This position paper provides an overview of the assessment and management of both acute and chronic graft-versus-host disease (GvHD). There is a focus on the use of ruxolitinib, a selective inhibitor of Janus kinase (JAK)1 and JAK2, for the treatment of corticosteroid-refractory and corticosteroid-dependent GvHD.

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.

Long-term outcomes of corticosteroid graft versus host disease prophylaxis in peripheral blood allogeneic haemopoietic stem cell transplant: a comparative cohort analysis.

BACKGROUND: Corticosteroids (CSs) have previously been incorporated into graft versus host disease (GVHD) prophylaxis regimens for bone marrow (BM) and haemopoietic stem cell transplant (HSCT). AIMS: To assess the impact of prophylactic CS in HSCT using peripheral blood (PB) stem cells. METHODS: Patients were identified from three HSCT centres receiving a first PB-HSCT between January 2011 and December 2015 from a fully human leukocyte antigen (HLA)-matched sibling or unrelated donor for acute myeloid leukaemia or acute lymphoblastic leukaemia. To enable meaningful comparison, patients were divided into two cohorts. RESULTS: Cohort 1 included only myeloablative-matched sibling HSCT, where the only variation in GVHD prophylaxis was the addition of CS. In these 48 patients, there were no differences in GVHD, relapse, non-relapse mortality, overall survival or GVHD-relapse-free-survival (GRFS) at 4 years after transplant. Cohort 2 included the remaining HSCT recipients, where one group received CS-prophylaxis and the non-CS group received an antimetabolite, ciclosporin and anti-T-lymphocyte globulin. In these 147 patients, those receiving CS-prophylaxis experienced higher rates of chronic GVHD (71% vs 18.1%, P < 0.001) and lower rates of relapse (14.9% vs 33.9%, P = 0.02). Those receiving CS-prophylaxis had a lower 4-year GRFS (15.7% vs 40.3%, P = 0.002). CONCLUSIONS: There does not appear to be a role for adding CS to standard GVHD prophylaxis regimens in PB-HSCT.

The clinical features, management and outcomes of lymphoma in pregnancy: A multicentre study by the Australasian Lymphoma Alliance.

Lymphoma in pregnancy (LIP) presents unique clinical, social and ethical challenges; however, the evidence regarding this clinical scenario is limited. We conducted a multicentre retrospective observational study reporting on the features, management, and outcomes of LIP in patients diagnosed between January 2009 and December 2020 at 16 sites in Australia and New Zealand for the first time. We included diagnoses occurring either during pregnancy or within the first 12 months following delivery. A total of 73 patients were included, 41 diagnosed antenatally (AN cohort) and 32 postnatally (PN cohort). The most common diagnoses were Hodgkin lymphoma (HL; 40 patients), diffuse large B-cell lymphoma (DLBCL; 11) and primary mediastinal B-cell lymphoma (PMBCL; six). At a median follow up of 2.37 years, the 2- and 5-year overall survival (OS) for patients with HL were 91% and 82%. For the combined DLBCL and PMBCL group, the 2-year OS was 92%. Standard curative chemotherapy regimens were successfully delivered to 64% of women in the AN cohort; however, counselling regarding future fertility and termination of pregnancy were suboptimal, and a standardised approach to staging lacking. Neonatal outcomes were generally favourable. We present a large multicentre cohort of LIP reflecting contemporary practice and identify areas in need of ongoing research.

Capturing the lived experiences of women with lymphoma in pregnancy: a qualitative study.

Lymphoma in pregnancy is a rare and challenging diagnosis that complicates ∼1:6000 pregnancies; posing a series of unique therapeutic, social, and ethical challenges to the patient, her family, and the medical professionals involved. These difficulties are compounded by the paucity of real-world data on the management of LIP, and a lack of relevant support systems for women in this setting. We conducted a retrospective multicenter qualitative study, interviewing women aged ≥18 years of age diagnosed with Hodgkin (HL) or non-Hodgkin lymphoma (NHL) during pregnancy or within 12 months postpartum, between 1 January 2009 and 31 December 2020 from 13 Australasian sites. Semi-structured telephone interviews were conducted, recorded, and analyzed using QSR Int NVivo 12 Pro (March 2020, USA) to quantify salient themes. Of the 32 women interviewed, 20 (63%) were diagnosed during pregnancy (16, 34, and 13% in the 1st, 2nd, and 3rd trimesters, respectively), while 12 (37%) were diagnosed post-partum. Women recalled that their chief concerns at diagnosis were the welfare of their child (n = 13, 41%) and a fear of dying (n = 9, 28%). Perceived diagnostic delay attributed to pregnancy was reported by 41% of participants. Other key themes were communication, educational materials, psychosocial supports, and oncofertility issues. To our knowledge this is the first report capturing the lived experiences of survivors of lymphoma during pregnancy, affording a unique opportunity to consider the management, psychosocial supports, and delivery of care to meet the needs of these women.What is the NEW aspect of your work? To our knowledge, this is the first report capturing and analyzing the healthcare experiences of survivors of Lymphoma in Pregnancy (LIP).What is the CENTRAL finding of your work? Women valued clear and empathic communication, provision of tailored educational materials, access to psychosocial supports (particularly childcare and financial supports), and timely oncofertility management in their healthcare journey.What is (or could be) the SPECIFIC clinical relevance of your work? Women's personal accounts of positive and negative experiences of LIP care provide insights into their specific concerns and needs which can shape healthcare policy and development of a specific framework for managing and supporting patients with LIP (and other cancers).

Unrelated Donor Transplant Recipients Given Thymoglobuline Have Superior GRFS When Compared to Matched Related Donor Recipients Undergoing Transplantation without ATG.

Recipients of allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated donors (URDs) and mismatched related donors (MMRDs) typically have a higher incidence of acute and chronic graft-versus-host disease (GVHD) compared with matched related donors (MRDs). Anti-T-cell globulins (ATGs) are often used to reduce GVHD in these recipients. We report the outcomes of 211 adult peripheral blood stem cell transplant recipients with myeloid malignancies who received a standardized transplant protocol, in which ATG (Thymoglobuline 4.5 mg/kg) was administered to recipients of URD and MMRD (n = 147) but not MRD (n = 64) transplant. For all patients, incidence of acute GVHD grades 2 to 4 was 21.4%, and chronic GVHD was 35.0%. Two-year overall survival was 63.2% (95% confidence interval, 55.8% to 71.5%), relapse-free survival was 55.3% (47.4% to 64.6%), and GVHD-free, relapse-free survival (GRFS) was 30.7% (23.2% to 40.8%). There were no differences between recipients of MRDs and other donors in relapse, nonrelapse mortality, and overall and relapse-free survival. However, compared with MRD, recipients from URDs and MMRDs had reduced moderate to severe chronic GVHD (10.4% versus 30.1%, P= .002), less chronic GVHD requiring systemic therapy (19.4% versus 38.9%, P = .006), and superior 2-year GRFS (35.5% versus 20.0%, P = .003). In this retrospective review of nonrandomized transplant groups, outcomes of HSCT performed using an URD with ATG during conditioning were superior to transplant from an MRD without ATG. The addition of Thymoglobuline to conditioning in HSCT from MRD should be further examined in prospective trials.

Pre- and post-bone marrow harvest anaemia is associated with lower CD34+ stem cell collection, high harvest volume and female gender.

BACKGROUND: Donor safety is paramount when performing bone marrow stem cell harvest. The incidence of full blood count (FBC) abnormalities among donors and variables associated with anaemia after marrow harvest are not well established. AIMS: To describe the frequency of FBC abnormalities prior to bone marrow stem cell harvest and to identify variables associated with post harvest anaemia. METHODS: Outcomes of 80 consecutive adult marrow harvests performed at our centre were analysed retrospectively. RESULTS: FBC abnormalities were present in 28% of donors prior to marrow harvest with normocytic anaemia the most common abnormality in 13%. Reduced donor haemoglobin (Hb) was independently correlated with lower CD34+ cell count per kg of recipient body weight. Anaemia (Hb < 100 g/L) was seen in 20% of donors after harvest with median decrease in Hb of 19 g/L. Variables independently associated with anaemia after harvest included donor to recipient weight ratio (P = 0.011), high collection volume (P = 0.044) and female gender (P = 0.023). Total nucleated cell and CD34 concentration in the final collected product were associated with the inverse of harvested marrow volume (P < 0.001). CONCLUSIONS: Pre-harvest anaemia should be corrected where possible particularly in female donors. Marrow collection volume should be minimised to reduce post-harvest anaemia, optimise CD34+ cell number and improve nucleated and stem cell concentrations in the harvest product.

Rescue haploidentical peripheral blood stem cell transplantation for engraftment failure: a single-centre case series.

Graft failure affects approximately 5% of allogeneic stem cell transplants, with a poor prognosis. Salvage second allogeneic stem cell transplantation (alloSCT2) is limited by high rates of transplant-related mortality from infection and graft-versus-host disease. We report on five adult patients receiving rescue alloSCT2 using haploidentical peripheral blood stem cells. All patients achieved neutrophil engraftment, two subsequently died from sepsis and disease relapse, respectively. Three patients remain alive up to 2 years post-transplant. We suggest consideration of haploidentical alloSCT2 for patients with graft failure.

Anncaliia algerae Microsporidial Myositis, New South Wales, Australia.

We describe the successful management of Anncaliia algerae microsporidial myositis in a man with graft versus host disease after hemopoietic stem cell transplantation. We also summarize clinical presentation and management approaches and discuss the importance of research into the acquisition of this infection and strategies for prevention.

Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse.

BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-α in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405). CONCLUSION: Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.

Low-cost generation of Good Manufacturing Practice-grade CD19-specific chimeric antigen receptor-expressing T cells using piggyBac gene transfer and patient-derived materials.

BACKGROUND AIMS: Protocols for the production of CD19-specific chimeric antigen receptor (CAR19) T cells are often complex and expensive because of the use of retroviral and lentiviral vectors or the need for CAR19 T-cell enrichment. We aimed to simplify the generation of CAR19 T cells from the peripheral blood of normal donors and patients using the piggyBac transposon system of gene modification. METHODS: We varied electroporation voltage, cytokines and stimulation conditions for the generation and expansion of CAR19 T cells over a 3-week culture period. RESULTS: Using optimized electroporation voltage, interleukin-15 alone and co-culturing CAR T cells with peripheral blood mononuclear cells, we were able to expand CAR19 T-cell cultures by up to 765-fold over 3 weeks in normal donors and 180-fold in patients with B-cell malignancies. Final median CAR19 expression of 72% was seen in normal donors, and 81% was seen in patients with acute lymphoblastic leukaemia, chronic lymphocytic leukemia or non-Hodgkin lymphoma. CAR19 T cells produced interferon gamma on stimulation with CD19(+) cell lines and efficiently lysed both CD19(+) cell lines and primary leukemia cells. In addition, combining CAR expression with an inducible caspase safety switch allowed elimination of CAR19 T cells by the application of a small molecule dimerizer. DISCUSSION: We have produced a simple, inexpensive and easily adoptable protocol for the generation of CAR19 T cells suitable for use in clinical trials using the piggyBac transposon system. This provides a robust platform for further enhancing the T-cell product and testing new CAR technologies.

Influence of Stem Cell Source on Outcomes of Allogeneic Reduced-Intensity Conditioning Therapy Transplants Using Haploidentical Related Donors.

We compared outcomes for 2 retrospective cohorts of patients undergoing reduced-intensity conditioning (RIC) therapy transplants using haploidentical related donors and post-transplant prophylaxis against graft-versus-host disease (GVHD) with high-dose cyclophosphamide, tacrolimus, and mycophenolate. The first cohort of 13 was transplanted with bone marrow (BM) as the stem cell source, whereas the second cohort of 23 used peripheral blood stem cells (PBSCs) mobilized with granulocyte colony-stimulating factor. The BM cohort received a single 60-mg/kg dose of cyclophosphamide on day +3, whereas the PBSC cohort received 2 doses on days +3 and +4. Patients in the first cohort were slightly older and had a higher proportion of acute myeloid leukemia, but there were no differences in the distribution of Disease Risk Index scores between the 2 groups. Patients in the PBSC group received double the number of CD34(+) cells in the stem cell graft. Times to neutrophil and platelet recovery were not different between the 2 groups. Three patients, all in the PBSC group, failed to engraft but recovered with autologous hemopoiesis and survived. The 6-month cumulative incidences of acute GVHD were 55.1% for BM and 48.5% for PBSCs (P = .651), whereas 24-month cumulative rates for chronic GHVD were 28.6% for BM and 32.3% for PBSCs (P = .685). Only 2 patients, both in the BM group, died of nonrelapse causes, both of second cancers. The 2-year cumulative incidences of relapse were 43.9% for BM and 23.5% for PBSCs (P = .286). Overall survival at 2 years was significantly better for PBSC patients (P = .028), at 83.4% versus 52.7% for BM. Relapse-free and event-free survival did not differ significantly between BM and PBSC groups. In this retrospective analysis, we conclude that the use of PBSCs for haploidentical RIC transplants is a feasible strategy, with equivalent rates of acute and chronic GVHD and risk of relapse and low nonrelapse mortality compared with BM.

Single-Agent High-Dose Cyclophosphamide for Graft-versus-Host Disease Prophylaxis in Human Leukocyte Antigen-Matched Reduced-Intensity Peripheral Blood Stem Cell Transplantation Results in an Unacceptably High Rate of Severe Acute Graft-versus-Host Disease.

High-dose cyclophosphamide given early after allogeneic hemopoietic cell transplantation has been shown to be effective prophylaxis against graft-versus-host disease (GVHD) in the setting of HLA-matched myeloablative bone marrow grafts, allowing avoidance of long-term immunosuppression with calcineurin inhibitors in some patients. Whether this approach is feasible using granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell grafts is unknown. We conducted an exploratory phase 2 trial of cyclophosphamide given at 50 mg/kg i.v. on days 3 and 4 after transplantation as sole GVHD prophylaxis in recipients of G-CSF-mobilized peripheral blood stem cell grafts from HLA-matched related or unrelated donors after reduced-intensity conditioning therapy with fludarabine, carmustine, and melphalan. Five patients, ages 52 to 67 years, with high-risk hematologic malignancies were enrolled. Four of the 5 developed severe acute GVHD of grades 3 to 4, requiring treatment with methylprednisolone and cyclosporine; 3 were steroid refractory and were given salvage therapy. One of these 4 patients died of hepatic GVHD, one died of sepsis, and 2 survived. We conclude that post-transplantation cyclophosphamide is inadequate as sole GVHD prophylaxis in the context of peripheral blood reduced-intensity conditioning transplantations from HLA-matched donors. This trial is registered at ACTRN12613001154796.

Clinical-grade varicella zoster virus-specific T cells produced for adoptive immunotherapy in hemopoietic stem cell transplant recipients.

BACKGROUND AIMS: Varicella zoster virus (VZV) causes life-long latent infection in healthy individuals, which reactivates in 10-68% of stem cell transplant patients. Reconstituting immunity through adoptive transfer of T cells specific for VZV may aid in the prophylaxis and treatment of VZV infections. The potential for generating T cells specific for VZV using a clinically approved VZV vaccine strain was investigated. METHODS: The Varivax® vaccine was used to stimulate peripheral blood mononuclear cells from healthy donors. Only reagents approved for clinical manufacture were used. Monocyte-derived dendritic cells pulsed with Varivax (R) were used to stimulate autologous mononuclear cells at a responder to stimulator ratio of 10:1. On day 7, a second stimulation was performed; 20 U/mL interleukin (IL)-2 were added from day 7 and 50 U/mL IL-2 from day 14 onwards. Cell phenotype and functionality were assessed after 21 days of culture. RESULTS: A mean increase of 11-fold in cell number was observed (n= 18). Cultures were mainly T cells (mean CD3 (+) 89.7%, CD4 (+) 54.2%, CD8 (+) 28.7%) with effector and central memory phenotypes. Cells produced one or more T helper (Th)1 cytokine (interferon-γ, tumor necrosis factor-α and IL-2), and CD4 (+) (but not CD8 (+) ) cells expressed the cytoxicity marker CD107 when restimulated with VZV antigens. CONCLUSIONS: We have demonstrated a clinically applicable method that yields high numbers of highly reactive T cells specific for VZV. We propose that reconstructing host immunity through adoptive transfer of VZV-specific T cells will reduce the frequency of clinical VZV infection in the period of severe immune suppression that follows allogeneic stem cell transplantation.