BACKGROUND: An inflammatory bone marrow microenvironment contributes to acquired bone marrow failure syndromes. CK0801, an allogeneic T regulatory (Treg) cell therapy product, can potentially interrupt this continuous loop of inflammation and restore hematopoiesis.
METHODS: In this phase 1 dose-escalation study of CK0801 Treg cells, we enrolled patients with bone marrow failure syndromes with suboptimal response to their prior therapy to determine the safety and efficacy of this treatment for bone marrow failure syndromes.
RESULTS: We enrolled nine patients with a median age of 57 years (range, 19 to 74) with an underlying diagnosis of aplastic anemia (n=4), myelofibrosis (n=4), or hypoplastic myelodysplasia (n=1). Patients had a median of three prior therapies for a bone marrow failure syndrome. Starting dose levels of CK0801 were 1 × 106 (n=3), 3 × 106 (n=3), and 10 × 106 (n=3) cells per kg of ideal body weight. No lymphodepletion was administered. CK0801 was administered in the outpatient setting with no infusion reactions, no grade 3 or 4 severe adverse reactions, and no dose-limiting toxicity. At 12 months, CK0801 induced objective responses in three of four patients with myelofibrosis (two had symptom response, one had anemia response, and one had stable disease) and three of four patients with aplastic anemia (three had partial response). Three of four transfusion-dependent patients at baseline achieved transfusion independence. Although the duration of observation was limited at 0.9 to 12 months, there were no observed increases in infections, no transformations to leukemia, and no deaths.
CONCLUSIONS: In previously treated patients, CK0801 demonstrated no dose-limiting toxicity and showed evidence of efficacy, providing proof of concept for targeting inflammation as a therapy for bone marrow failure. (Funded by Cellenkos Inc.; Clinicaltrials.gov number, NCT03773393.).

OBJECTIVE: This study reports long-term outcomes from the open-label extension (OLE) period of the Phase I/II COMPOSER trial (NCT03157635) that evaluated crovalimab in patients with paroxysmal nocturnal haemoglobinuria, who were treatment-naive or switched from eculizumab at enrolment.
METHODS: COMPOSER consists of four sequential parts followed by the OLE. The primary OLE objective was to assess long-term crovalimab safety, with a secondary objective to assess crovalimab pharmacokinetics and pharmacodynamics. Exploratory efficacy endpoints included change in lactate dehydrogenase (LDH), transfusion avoidance, haemoglobin stabilisation and breakthrough haemolysis (BTH).
RESULTS: A total 43 of 44 patients entered the OLE after completing the primary treatment period. Overall, 14 of 44 (32%) experienced treatment-related adverse events. Steady state exposure levels of crovalimab and terminal complement inhibition were maintained over the OLE. During the OLE, mean normalised LDH was generally maintained at ≤1.5× upper limit of normal, transfusion avoidance was achieved in 83%-92% of patients and haemoglobin stabilisation was reached in 79%-88% of patients across each 24-week interval. Five BTH events occurred with none leading to withdrawal.
CONCLUSIONS: Over a 3-year median treatment duration, crovalimab was well tolerated and sustained C5 inhibition was achieved. Intravascular haemolysis control, haemoglobin stabilisation and transfusion avoidance were maintained, signifying long-term crovalimab efficacy.

Most of the studies on functional outcomes in pediatric survivors of cancers and bone marrow failure disorders have been conducted in North American, European, and Oceanian populations, with few studies having been performed in China. The objective of this study was to evaluate psychosocial outcomes in a cohort of Chinese pediatric survivors diagnosed with cancer or conditions requiring hematopoietic stem cell transplantation (HSCT), and to identify clinical and behavioral factors associated with adverse psychosocial outcomes.
This was a cross-sectional survey study. We recruited pediatric survivors of cancer or inherited disorder requiring HSCT at ≤18 years old and were ≥6 months post-treatment. Parents completed the St. Jude Children\'s Research Hospital After Completion of Therapy questionnaire to report their child\'s emotional functioning, social functioning, attention/concentration and behavior. Multivariable general linear modeling was used to identify clinical, treatment and behavioral factors associated with psychosocial outcomes, adjusting for sex, age and cancer diagnoses.
Ninety-five pediatric survivors were recruited (62.1% male; mean [standard deviation] age 9.7 [3.4] years; 4.1 [2.6] years post-diagnosis). They were diagnosed with bone marrow failure disorders (23.2%), hematological malignancies (45.3%) or solid tumors (23.2%). Compared with survivors with no current health problems, those with more than one current health problem performed worse in emotional functioning (Estimate = 2.42, SE = 0.88, P = 0.008) and social functioning (Estimate = 2.90, SE = 1.64, P = 0.03). Higher pain interference was significantly associated with worse emotional functioning (Estimate = 0.19, SE = 0.08, P = 0.03) and attention functioning (Estimate = 0.26, SE = 0.11, P = 0.03). Compared with survivors who reported less sleep problems, those who had more sleep problems demonstrated poorer emotional functioning (Estimate = 0.30, SE = 0.08, P = 0.001). Survivors who had a longer duration of screen usage per day reported more impairment on attention and behavior functioning than those who had a shorter duration of screen usage per day (both P<0.5).
Survivors who were diagnosed at a younger age or had unaddressed/untreated health problems may require additional psychological evaluation. The implementation of psychosocial assessments during routine long-term follow-up care may help to identify high-risk patients during the early phase of survivorship. Rehabilitation interventions should address modifiable behavioral factors (e.g. sleep habits, screen time and chronic pain).

Haploidentical transplantation strategies for patients with transfusion-dependent thalassaemia (TD-TM) remain to be investigated. In this study, 54 paediatric patients with TD-TM were treated with a novel approach using post-transplant cyclophosphamide (PTCy) and low-dose methotrexate (LD-MTX), following a myeloablative regimen. The incidence of neutrophil and platelet engraftment was 96.3% ± 2.6% and 94.4% ± 3.1% respectively. The cumulative incidence of grades II-III acute graft-versus-host disease (GVHD) was 13.8% ± 4.8% at 100 days. At three years, the cumulative incidence of chronic GVHD was 28.5% ± 8.5%. With a median follow-up of 520 days (132-1325 days), the overall survival (OS) and event-free survival (EFS) were 98.1% ± 1.8% and 90.7% ± 3.9% respectively. Compared with the low-dose cyclophosphamide (CTX) conditioning regimen (120 mg/kg), the high-CTX regimen (200 mg/kg) achieved a higher incidence of stable engraftment (100% vs 66.7% ± 15.7%, p = 0.003), a comparable incidence of grades II-III acute GVHD, a lower incidence of chronic GVHD (20.2% ± 8.3% vs 66.6% ± 19.2%, p = 0.011), and better overall survival (100% vs 88.9% ± 10.5%, p = 0.025) as well as EFS (95.6% ± 3.1% vs 66.7% ± 15.7%, p = 0.008). Our results using unmanipulated haploidentical grafts and PTCy with LD-MTX in TD-TM are encouraging. (chictr.org.cn ChiCTR1800017969).

Severe multilineage cytopenia in childhood caused by bone marrow failure (BMF) often represents a serious condition requiring specific management. Patients are at risk for invasive infections and bleeding complications. Previous studies report low rates of identifiable causes of pediatric BMF, rendering most patients with a descriptive diagnosis such as aplastic anemia (AA).
We conducted a multi-center prospective cohort study in which an extensive diagnostic approach for pediatric patients with suspected BMF was implemented. After exclusion of malignant and transient causes of BMF, patients entered thorough diagnostic evaluation including bone marrow analysis, whole exome sequencing (WES) including copy number variation (CNV) analysis and/or single nucleotide polymorphisms (SNP) array analysis. In addition, functional and immunological evaluation were performed. Here we report the outcomes of the first 50 patients (2017-2021) evaluated by this approach.
In 20 patients (40%) a causative diagnosis was made. In this group, 18 diagnoses were established by genetic analysis, including 14 mutations and 4 chromosomal deletions. The 2 remaining patients had short telomeres while no causative genetic defect was found. Of the remaining 30 patients (60%), 21 were diagnosed with severe aplastic anemia (SAA) based on peripheral multi-lineage cytopenia and hypoplastic bone marrow, and 9 were classified as unexplained cytopenia without bone marrow hypoplasia. In total 28 patients had undergone hematopoietic stem cell transplantation (HSCT) of which 22 patients with an unknown cause and 6 patients with an identified cause for BMF.
We conclude that a standardized in-depth diagnostic protocol as presented here, can increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. We underline the importance of full genetic analysis complemented by functional tests of all patients as genetic causes are not limited to patients with typical (syndromal) clinical characteristics beyond cytopenia. In addition, it is of importance to apply genome wide genetic analysis, since defects in novel genes are frequently discovered in this group. Identification of a causal abnormality consequently has implications for the choice of treatment and in some cases prevention of invasive therapies.

We analyzed the outcomes of 32 patients with paroxysmal nocturnal hemoglobinuria (PNH) who underwent either a haploidentical donor (HID) or a matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT). Seventeen patients received an HSCT from an HID and 15 patients received an HSCT from an MUD. The median follow-up time of the surviving patients was 36 months (range: 12-96 months). No significant differences were observed in the 3-year overall survival (OS) between the HID and MUD cohorts (74.1%±11.4% vs. 93.3%±6.4%, respectively, p=.222) or in the 3-year failure-free survival (68.8%±11.8% vs. 86.7%±8.8%, respectively, p=.307). Treatment-related mortality occurred in five patients. A univariate analysis of risk factors revealed platelet engraftment failure negatively impacted OS and FFS. We conclude that HID and MUD-HSCT are feasible and can be effective options for those PNH patients with concomitant bone marrow failure, recurrent life-threatening thrombosis, and uncontrollable hemolysis.

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a rare autoinflammatory disease usually presenting before the age of 10 years. Non-specific clinical features or late-onset presentation may delay its diagnosis until adulthood.
OBJECTIVE: To determine whether DADA2 diagnosed in adulthood is associated with specific characteristics compared to DADA2 diagnosed in childhood.
METHODS: We pooled a cohort of 12 adult DADA2 patients followed in France with cases identified through a systematic literature review. For each patient, we determined the type of clinical presentation and assessed six key organ involvements.
RESULTS: A total of 306 cases were included. Among the 283 patients with available data regarding age at diagnosis, 140 were diagnosed during adulthood and 143 during childhood. The vascular presentation of DADA2 was more frequent in the adult diagnosis group (77.9% vs. 62.9%, p < 0.01), whereas the hematological presentation (bone marrow failure) prevailed in the pediatric diagnosis group (10.0% vs. 20.3% p = 0.02). In patients with vasculopathy, severe skin manifestations developed in 35% and 10% of the adult and pediatric diagnosis groups, respectively. Conversely, fewer strokes occurred in the adult group presenting with systemic vasculopathy (54% vs. 81%). Symptomatic humoral immune deficiency (HID) was rarely a clinical presentation in itself (5% and 2.8%) but accompanied other phenotypes of DADA2, especially the hematological phenotype in the adult group (33% vs. 4%).
CONCLUSIONS: DADA2 diagnosed in adulthood presents more often with a vascular phenotype and less often with bone marrow failure than DADA2 diagnosed in childhood. Adults diagnosed with DADA2 vasculopathy display more severe skin involvement but fewer strokes.

A total of 244 patients with hereditary haemolytic anaemias (HHA) were screened for acute symptomatic human parvovirus B19 infection (HPV-B19) in a prospective study. To assess the risks associated with HPV-B19 infection, patients were classified into Group I and Group II according to presence or absence (symptoms, signs and specific serology) of acute HPV-B19 infection respectively. In all, 131 (53·7%) patients had β-thalassaemia, 75 (30·7%) hereditary spherocytosis (HS), 27 (11·1%) sickle cell anaemia (SCA) and 11 (4·5%) glucose-6-phosphate dehydrogenase (G6PD) deficiency. Of 33 (13·5%) patients who presented with symptomatic HPV-B19 infection, 19 (57·5%) had HS, nine (27·3%) had β-thalassaemia and five (15·2%) had SCA. In Group I, there were significant differences in the mean white blood cell, red blood cell and platelet counts, haemoglobin concentration, total bilirubin (TB), alanine aminotransferase, aspartate aminotransferase and serum creatinine (all P < 0·001) compared to Group II. In all, 27 (81·8%) patients had arthropathy and bone marrow failure (BMF); 13 (39·4%) had acute kidney injury (AKI), more in SCA (80%); and 12 (36·4%) patients had hepatitis, more in HS (66·8%). Five (15·2%) patients with HS had BMF, AKI, nervous system involvement and extreme hyperbilirubinaemia (TB range 26·3-84·7 mg/dl). Five (15·2%) patients had haemophagocytic syndrome. Two patients with HS combined with Type-I autoimmune hepatitis presented with transient BMF. Complete recovery or stabilisation was noted at 12 months in every patient except for one patient with SCA who died during the infection. HPV-B19 must be suspected and screened in patients with HHA with typical and atypical presentations with careful follow-up.

The variability in myelosuppression after chemotherapy for acute myeloid leukaemia (AML) can affect its prognosis; however, the underlying mechanism remains controversial. In the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study, we showed that prolonged neutropenia was associated with high overall survival (P = 0·011) and low frequency of relapse (P = 0·042) in patients without granulocyte-colony stimulating factor (G-CSF) who completed the indicated treatment protocol. Our data indicate that predisposition to prolonged neutropenia after chemotherapy is correlated with a better outcome of AML treatment. Our results promote the usage of individualised drug dosing strategies to improve the therapeutic outcome in AML patients.

OBJECTIVE: The aim of this study was to evaluate seizure outcome in children with hematological malignancies and PRES and to identify prognostic factors that could help manage the syndrome.
METHODS: We retrospectively reviewed the report data of 21 patients diagnosed with hematological malignancy or aplastic anemia and PRES between 2008 and 2018. Basic demographic data, oncology treatment, presymptomatic hypertension before PRES manifestation, neurological status, seizure type, and EEG and MRI findings at PRES onset and at the one-year follow-up visit were studied. Patients who developed remote symptomatic seizures or epilepsy were identified.
RESULTS: We included 21 children (11 females and 10 males) in the study. Sixteen patients (76.2%) were diagnosed with ALL and the rest individually with AML, CML, T-lymphoma, Burkitt lymphoma, and severe aplastic anemia. Presymptomatic hypertension (PSH) was evaluated in 19 patients and was present in 18 (94.7%). The duration was 9 h and more in 16 patients (88.8%); the severity was grade II in 12 patients (66.7%). Seizures as the initial symptom of PRES were present in 17 patients (80.9%). Four patients (19.0%) were assessed with remote symptomatic seizures. Two of them (9.5%) had ongoing seizures at the one-year follow-up visit and were diagnosed with epilepsy. The presence of gliosis on follow-up MRI indicated worse outcome with development of epilepsy (without statistical significance).
CONCLUSIONS: PRES syndrome has an overall good prognosis and the evolution to epilepsy is rare. The severity and duration of PSH or seizure severity and EEG findings at PRES onsetwere not associated with worse neurological outcomes in this study.