Refractory Severe Aplastic Anemia

Umbilical cord blood transplantation (UCBT) has been rarely reported as a first-line treatment for idiopathic severe aplastic anemia (SAA) patients lacking HLA-matched sibling donors (MSD).

Our study aimed to compare the clinical outcomes of pediatric SAA patients who received UCBT and immunosuppressive therapy (IST) upfront.

A retrospective analysis was performed on 43 consecutive patients who received frontline IST (n = 17) or UCBT (n = 26) between July 2017 and April 2022.

The 3-year overall survival (OS) was comparable between the UCBT and IST groups (96.2% vs. 100%, P = 0.419), while the 3-year event-free survival (EFS) was significantly better in the former than in the latter (88.5% vs. 58.8%, P = 0.048). In the UCBT group, 24 patients achieved successful engraftment, 2 patients developed severe acute graft-versus-host disease (aGVHD), no extensive chronic GVHD (cGVHD), and a high GVHD-free, failure-free survival (GFFS) of 84.6% at 3 years. After one year of treatment, 12 patients in the IST group responded, while 5 patients did not achieve remission and 2 patients had disease relapse. At both 3 and 6 months after treatment, the proportion of transfusion-independent patients was higher in the UCBT group than in the IST group. Faster immune recovery and earlier transfusion independence further reduced the risk of infection and bleeding, thereby improving health-related quality of life in the UCBT-treated group.

Our results suggested that UCBT as upfront therapy may be an effective and safe option for pediatric SAA patients, with favorable outcomes in experienced centers.

Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA.

Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a 'go/no-go' decision is made by evaluating the posterior probability of the events of interests.

The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication.

ACTRN12619001042134, ACTRN12619001043123.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder which occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly due to thromboses. Over the last 20 years treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the UK, all patients are under review at one of two reference centers. We report on all 509 UK patients with PNH treated with eculizumab and ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than age and sex matched controls (p=0.001). Only 4 patients died due to thromboses. The survival of patients with PNH (n=389) when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia (AA)) were excluded was not significantly different to age and sex matched controls (p=0.12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient years). Extravascular hemolysis was evident in patients treated, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies which reduce mortality and morbidity in PNH but further work is needed to reduce mortality in those with concomitant BMF.