John Moore

Haploidentical hematopoietic stem cell transplant (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) is appropriate for those who lack matched donors. Most studies using PTCy have been retrospective making conclusions difficult. ANZHIT-1 was a phase 2 study conducted at 6 Australian allogeneic HSCT centers. The primary end points were disease-free and overall survival at 2 years after HSCT. The reduced-intensity conditioning (RIC) included fludarabine, cyclophosphamide, and 200 cGy total body irradiation, and the myeloablative conditioning (MAC) was IV fludarabine and busulfan. PTCy, MMF and a calcineurin inhibitor (CNI) were used for graft-versus-host disease (GVHD) prophylaxis. CNIs were weaned and ceased by day +120 in eligible patients on day 60. Patients (n = 78) with hematological malignancies were included in the study, with a median follow-up of 732 days (range, 28-1728). HSCT was RIC in 46 patients and MAC in 32 patients. Disease-free survival probability at 2 years was 67.5% (95% [CI], 53.2-85.6) for MAC recipients and 68.3% (95% CI, 56.3-83.01) for RIC recipients. Transplant-related mortality (TRM) on day 100 and year 1 was 4.9% (95% CI, 1.6-15.3) and 17.9% (95% CI, 8.8-36.5), respectively, in the MAC group compared with 3.1% (95% CI, 0.8.1-12) and 11.6% (95% CI, 6-22.4), respectively, in the RIC group. The median time for elective cessation of CNI was day 142.5 days, with no excess chronic GVHD (cGVHD) or mortality. Of the evaluable patients, 71.6% discontinued immunosuppression 12 months after transplant. This prospective haplo-HSCT trial using PTCY demonstrated encouraging survival rates, indicating that early CNI withdrawal is feasible and safe.

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 CD56^hi 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.

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-1β, 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.

Cardiac amyloidosis has a very poor prognosis, but it is the nature of the involved precursor protein that ultimately dictates treatment and survival. We report the clinical characteristics and survival of 47 cardiac amyloid patients across 2 Australian centres including 39 patients evaluated for definitive amyloid subtype utilising laser microdissection and tandem mass spectrometry (LMD‐MS). A quarter of patients (n=12) were classified as wild type transthyretin amyloidosis (ATTRwt), 33 patients as light or heavy chain amyloidosis (AL or AH), and 2 as hereditary mutant transthyretin amyloidosis (ATTRv). Greater left ventricular hypertrophy (IV septum 22 vs. 15 mm, p=0.005) and history of cardiac arrhythmia (75% vs. 31%, p=0.016) were significantly associated with ATTRwt patients compared with AL/AH patients. AL patients demonstrated significantly shorter median survival compared to ATTRwt patients (3.5 vs. 37 months, (P=0.007)). New York heart association (NYHA) class III‐IV symptoms or plasma cells ≥ 10% at diagnosis, were the only independent predictors of worse survival in AL patients on multivariate analysis. In the era of novel therapies for both AL amyloid and ATTR, identification of the correct amyloid subtype is essential in making therapeutic decisions and providing accurate prognostic information to patients.