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This study describes the outcome of patients receiving haematopoietic stem cell transplantation (HSCT) to treat severe refractory autoimmune cytopenia. The registry of the European Group of Blood and Marrow Transplantation holds data on 36 patients receiving 38 transplants, the first transplant was autologous for 27 and allogeneic for nine patients. Patients had autoimmune haemolytic anaemia (autologous: 5; allogeneic: 2), Evans's syndrome (autologous: 2; allogeneic: 5); immune thrombocytopenia (autologous: 12), pure red cell aplasia (autologous: 4; allogeneic: 1), pure white cell aplasia (autologous: 1; allogeneic 1), or thrombotic thrombocytopenic purpura (autologous: 3). Patients had longstanding disease having failed multiple prior treatments. Among 26 evaluable patients mobilized for autologous HSCT, three died of treatment-related causes, one died of disease progression, seven were non-responders, six patients had transient responses and nine had continuous partial or complete remission. Of the seven evaluable patients receiving allogeneic HSCT, one died of treatment-related complications, one with transient response died of progressive disease and five had a continuous response. Autologous and allogeneic HSCT may induce a response in a subset of patients with autoimmune cytopenia of long duration albeit at the price of considerable toxicity. [ABSTRACT FROM AUTHOR]

Severe acute graft-versus-host disease (GvHD) remains a serious complication of allogeneic stem cell transplantation. An in vitro skin explant assay was used to predict the occurence and severity of acute GvHD in a cohort of 30 pediatric patients undergoing human leucocyte antigen (HLA)-matched sibling transplants (20 patients) and matched or one antigen mismatched unrelated donor transplants (10 patients). In the cohort of HLA-matched sibling transplants, the result appeared to reflect the degree of GvHD prophylaxis. The skin explant assay correlated with GvHD outcome in 12 of 20 children, but this did not reach statistical significance (chi-square 0.95, d.f.=1, p=0.32). These results support previous observations. In this present cohort, patients were treated either with cyclosporin A (CsA) monotherapy (n=7) or with CsA plus additional methotrexate (MTX) (n=13). We have previously demonstrated that the skin explant assay was not as predictive in patients receiving CsA plus additional MTX compared to cohorts treated with CsA alone. In the group of patients treated with CsA alone, four of five patients (80%) predicted to develop GvHD developed acute GvHD of grade II or above; of two patients predicted to develop only grade 0–I GvHD, one patient developed no GvHD and the other grade II GvHD. In the CsA plus MTX group, nine patients were predicted to develop GvHD. Five of nine (55%) developed acute GvHD of grade II or above, while three of four with grade 0 or I skin explant assay results developed only grade 0–I GvHD. In a cohort of 10 patients who received unrelated donor transplants, the skin explant assay correlated with GvHD outcome in all 10 patients (Fisher's exact test p=0.008). Hence, the skin explant assay is a pretransplant in vitro GvHD predictive test that predicts the occurence and severity of acute GvHD in pediatric unrelated donor transplants and to varying degrees, depending on the GvHD prophylaxis protocols, in HLA-matched sib... [ABSTRACT FROM AUTHOR]

The prognostic impact of PICALM::MLLT10 status in childhood leukaemia is not well described. Ten International Berlin Frankfurt Münster-affiliated study groups and the Children's Oncology Group collaborated in this multicentre retrospective study. The presence of the PICALM::MLLT10 fusion gene was confirmed by fluorescence in situ hybridization and/or RNA sequencing at participating sites. Ninety-eight children met the study criteria. T-cell acute lymphoblastic leukaemia (T-ALL) and acute myeloid leukaemia (AML) predominated 55 (56%) and 39 (40%) patients, respectively. Most patients received a chemotherapy regimen per their disease phenotype: 58% received an ALL regimen, 40% an AML regimen and 1% a hybrid regimen. Outcomes for children with PICALM::MLLT10 ALL were reasonable: 5-year event-free survival (EFS) 67% and 5-year overall survival (OS) 76%, but children with PICALM::MLLT10 AML had poor outcomes: 5-year EFS 22% and 5-year OS 26%. Haematopoietic stem cell transplant (HSCT) did not result in a significant improvement in outcomes for PICALM::MLLT10 AML: 5-year EFS 20% for those who received HSCT versus 23% for those who did not (p = 0.6) and 5-year OS 37% versus 36% (p = 0.7). In summary, this study confirms that PICALM::MLLT10 AML is associated with a dismal prognosis and patients cannot be salvaged with HSCT; exploration of novel therapeutic options is warranted., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF-1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild-type allele. Here we examined the two-hit concept in leukaemic cells of 25 patients with JMML and NF-1. Ten patients with JMML/NF-1 exhibited a NF1 loss-of-function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound-heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF-1 and no variation in the JMML-associated driver genes PTPN11, KRAS, NRAS or CBL (JMML-5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound-heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF-1 reliably indicates a NF1-driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF-1., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Our study presents a novel germline c.1715G>T (p.G572V) mutation in the gene encoding Toll-like receptor 8 (TLR8) causing an autoimmune and autoinflammatory disorder in a family with monozygotic male twins, who suffer from severe autoimmune hemolytic anemia worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis. The pathogenicity of the mutation was confirmed by in vitro assays on transfected cell lines and primary cells. The p.G572V mutation causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to increased pro-inflammatory responses, such as nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This unique TLR8 mutation with partial TLR8 protein loss and hyperinflammatory phenotype mediated by TLR7 ligands represents a novel inborn error of immunity with childhood-onset and a good response to TLR7 inhibition., (© 2022 Wiley Periodicals LLC.)

Minimal residual disease (MRD) at the end of induction therapy is important for risk stratification of acute lymphoblastic leukaemia (ALL), but bone marrow (BM) aspiration is often postponed or must be repeated to fulfil qualitative and quantitative criteria for morphological assessment of haematological remission and/or MRD analysis. The impact of BM aspiration delay on measured MRD levels and resulting risk stratification is currently unknown. We analysed paired MRD data of 289 paediatric ALL patients requiring a repeat BM aspiration. MRD levels differed in 108 patients (37%) with a decrease in the majority (85/108). This would have resulted in different risk group allocation in 64 of 289 patients (23%) when applying the ALL-Berlin-Frankfurt-Münster 2000 criteria. MRD change was associated with the duration of delay; 40% of patients with delay ≥7 days had a shift to lower MRD levels compared to only 18% after a shorter delay. Patients MRD-positive at the original but MRD-negative at the repeat BM aspiration (n = 50) had a worse 5-year event-free survival than those already negative at first aspiration (n = 115) (86 ± 5% vs. 94 ± 2%; P = 0·024). We conclude that BM aspirations should be pursued as scheduled in the protocol because delayed MRD sampling at end of induction may result in false-low MRD load and distort MRD-based risk assessment., (© 2016 John Wiley & Sons Ltd.)

RAS-pathway mutations, causing a proliferative advantage, occur in acute myeloid leukaemia (AML) and MLL-rearranged leukaemia. Recently, mutations in the Casitas B lineage lymphoma (CBL) gene were reported to be involved in RAS-pathway activation in various myeloid malignancies, but their role in paediatric AML is still unknown. We performed mutation analysis of 283 newly diagnosed and 33 relapsed paediatric AML cases. Only two mutant cases (0·7%) were identified in the newly diagnosed paediatric AML samples, of which one was MLL-rearranged. Both mutant cases showed CBL mRNA expression in the range of the non-mutated cases. Phosphorylated extracellular signal-regulated kinase (pERK) was not correlated with CBL protein expression (n = 11). In conclusion, we report a very low CBL mutation frequency in paediatric AML, which, together with the lack of difference in protein and mRNA expression, illustrates the limited role of CBL in paediatric AML., (© 2012 Blackwell Publishing Ltd.)

Acute promyelocytic leukaemia (APL) treatment often includes high cumulative doses of anthracyclines, which can cause long-term cardiotoxicity. Here, we report the favourable outcome in 81 paediatric APL patients treated according to the consecutive acute myeloid leukaemia-Berlin/Frankfurt/Muenster (AML-BFM) trials -93/-98/-2004 with an anthracycline-cytarabine regimen in combination with all-trans-retinoid acid (ATRA). Outcomes achieved by treatment with a reduced cumulative anthracycline dose (350 mg/m(2)) were comparable to those reported for studies with higher doses. Five-year overall survival of the total cohort was 89 +/- 4% and event-free survival (pEFS) was 73 +/- 6%. Overall survival was similar when comparing AML-BFM trial periods (trial 93: 88 +/- 8%, 98: 85 +/- 7% and 2004: 94 +/- 8%, P((logrank)) = 0.63). Seventy-five (93%) patients achieved complete remission. Most fatal events occurred during the first 6 weeks of treatment. Long-term cardiotoxicity was observed in one patient. Two patients suffered from secondary haematological malignancies. Salvage treatment was effective in 7/9 patients (78%) with relapsed APL, who now are long-term survivors after second line combination treatment with arsenic trioxide (4/7 patients) and stem cell transplantation (5/7 patients). Our results demonstrate that - combined with ATRA - a lower cumulative anthracycline dose can be used safely to maintain high cure rates and promote the reduction of long-term sequelae, such as cardiotoxicity in APL patients.

The prognosis of children with relapsed/refractory acute myeloid leukaemia (AML) is poor, and new therapies are needed. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to the antitumor antibiotic calicheamicin. We conducted an investigator-initiated phase II study with GO to assess its efficacy and safety, administering two dosages of 7.5 mg/m(2) with a 14 d-interval. Thirty children who were refractory to re-induction at first relapse or suffered from second relapse of AML received a total of 64 infusions of GO. The response rate [complete remission (CR) and CR with insufficient platelet recovery] was 37%. Nine patients were subsequently transplanted (median time to transplant, 4 weeks, range 3-21 weeks), and three of these patients are currently in continuous CR with a median follow-up of >3 years, and can considered to be cured. This resulted in a statistically significant survival advantage for children who responded to GO versus those who did not [27% (standard error 13%) vs. 0%, respectively, P = 0.001]. All other children died, mainly from progressive disease. The treatment was generally well tolerated by most patients. The frequency of transient transaminatis was low. All but one patient received defibrotide prophylaxis during the transplant procedure, and no cases of veno-occlusive disease were noted. This study showed a favourable safety/efficacy profile of single-agent GO in children with refractory first or second relapse of AML.

Sepsis in profound neutropenia after chemotherapy is associated with high mortality despite appropriate antibacterial or antifungal treatment. In a prospective phase I/II study we evaluated the feasability and efficacy of leucocyte transfusions (LT) in patients with malignancies or haematological disorders who were suffering from severe bacterial or fungal infection during therapy-related bone marrow aplasia. 30 patients with severe neutropenia and clinical signs of life-threatening sepsis not responding to adequate treatment, received LT from rhG-CSF-stimulated family donors or from prednisolone-primed volunteers. A total of 301 LT were administered. The median number of LT per patient was seven (range three to 65), the median duration of LT treatment was 8 d (range 2-35). The white cell count (WBC), absolute neutrophil count (ANC) and lymphocyte count of the concentrates from rhG-CSF-stimulated donors were significantly higher than those from prednisolone-primed volunteers (P = 0.0001). Despite the critical condition of the patients, LT were generally well tolerated. Only 39 (12.9%) LT were associated with adverse reactions. The transfusion of leucocytes collected by continuous flow leukapheresis from both rhG-CSF and prednisolone stimulated donors resulted in a measurable increment of the peripheral leucocyte and ANC counts in our patients. On day 100 after the first LT, 20/30 patients were alive with complete clearance of the infection.