A "SURFin' Leukemia": Acute Lymphoblastic Leukemia Masquerading as a Syndrome of Undifferentiated Recurrent Fever

Periodic fever is not uncommon in childhood and is often ascribed to autoinflammatory conditions; however, it may be present also in children with cancer. We here describe the case of a 3-year-old boy with acute lymphoblastic leukemia who initially presented with a 4-month history of recurrent, stereotyped episodes of fever and localized joint pain, separated by completely symptom-free intervals. These symptoms were initially interpreted as a possible syndrome of undifferentiated recurrent fever until more signs of leukemia became apparent. Our report confirms that acute lymphoblastic leukemia can rarely present with periodic fever, thus possibly leading to diagnostic errors unless a high index of suspicion is maintained

Familial Hemophagocytic Lymphohistiocytosis May Present during Adulthood: Clinical and Genetic Features of a Small Series

Familial Hemophagocytic lymphohistiocytosis (FHL) is a rare immune deficiency with defective cytotoxic function. The age at onset is usually young and the natural course is rapidly fatal if untreated. A later onset of the disease has been sporadically reported even in adolescents and adults. We report the results of our retrospective data collection of all cases diagnosed with FHL at an age of 18 years or older and enrolled in the Italian Registry of HLH. All cases were diagnosed with FHL based on evidence of genetic defect in one FHL-related gene. A total of 11 patients were diagnosed with FHL. They were 9 males and 2 females, from 10 unrelated families; their age ranged between 18 and 43 years (median, 23 years). Family history was unremarkable in eight families at the time of the diagnosis. Their genetic diagnoses are: FHL2 (n = 6), FHL3 (n = 2), FHL5 (n = 1), XLP1 (n = 2). Clinical, molecular and functional data are described. These data confirm that FHL may present beyond the pediatric age and up to the fifth decade. FHL2 due to perforin defect is the most frequently reported subtype. Adult specialists should consider FHL in the differential diagnosis of patients with cytopenia and liver or central nervous system disorders, especially when a lymphoproliferative disease is suspected but eventually not confirmed. FHL may turn to be fatal within a short time course even in adults. This risk, together with the continuous improvement in the transplant technique, especially in the area of transplant from matched unrelated donor, resulting in reduced treatment related mortality, might suggest a wider use of SCT in this population. Current diagnostic approach allows prompt identification of patients by flow-cytometry screening, then confirmed by the genetic study, and treatment with chemo-immunotherapy followed by stem cell transplantation

Candidate Biomarkers for the Detection of Serious Infections in Children: A Prospective Clinical Study

Serious bacterial infections (SBI) in children are associated with considerable morbidity and mortality, and their early identification remains challenging. The role of laboratory tests in this setting is still debated, and new biomarkers are needed. This prospective, observational, single-center study aims to evaluate the diagnostic role of blood biomarkers in detecting SBI in children presenting with signs of systemic inflammatory response syndrome (SIRS). A panel of biomarkers was performed, including C-reactive protein (CRP), procalcitonin (PCT), white blood cell count (WBC), absolute neutrophil count (ANC), interleukin (IL)-6, IL-8, IL-10, human terminal complement complex (C5b-9), Plasmalemma-Vesicle-associated protein 1 (PV-1), Intercellular Adhesion Molecule-1 (ICAM-1), and Phospholipase A2 (PLA2). Among 103 patients (median age 2.9 years, 60% males), 39 had a diagnosis of SBI (38%). Significant predictors of SBI were CRP (p = 0.001) and ICAM-1 (p = 0.043). WBC (p = 0.035), ANC (p = 0.012) and ANC/WBC ratio (p = 0.015) were also significantly associated with SBI in children without pre-existing neutropenia. ROC curves, however, revealed suboptimal performance for all variables. Nevertheless, a model that combined CRP and ANC/WBC ratio had more in-depth diagnostic accuracy than either of the two variables. Overall, this study confirms the limited usefulness of blood biomarkers for the early diagnosis of SBI. WBC, ANC, ANC/WBC ratio, CRP, and ICAM-1 showed the best, albeit moderate, diagnostic accuracy

Donor Cell Acute Myeloid Leukemia after Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease: A Case Report and Literature Review

The patient reported here underwent hematopoietic stem cell transplantation (HSCT) due to chronic granulomatous disease (CGD) caused by biallelic mutations of the NCF1 gene. Two years later, he developed AML, which was unexpected and was recognized via sex-mismatched chromosomes as deriving from the donor cells; the patient was male, and the donor was his sister. Donor cell leukemia (DCL) is very rare, and it had never been reported in patients with CGD after HSCT. In the subsequent ten years, the AML relapsed three times and the patient underwent chemotherapy and three further HSCTs; donors were the same sister from the first HSCT, an unrelated donor, and his mother. The patient died during the third relapse. The DCL was characterized since onset by an acquired translocation between chromosomes 9 and 11, with a molecular rearrangement between the MLL and MLLT3 genes-a quite frequent cause of AML. In all of the relapses, the malignant clone had XX sex chromosomes and this rearrangement, thus indicating that it was always the original clone derived from the transplanted sister's cells. It exhibited the ability to remain quiescent in the BM during repeated chemotherapy courses, remission periods and HSCT. The leukemic clone then acquired different additional anomalies during the ten years of follow-up, with cytogenetic results characterized both by anomalies frequent in AML and by different, non-recurrent changes. This type of cytogenetic course is uncommon in AML

Phase II Study of Allogeneic Hematopoietic Stem Cell Transplantation for Children with High-Risk Neuroblastoma Using a Reduced-Intensity Conditioning Regimen: Results from the AIEOP Trial

Despite aggressive multimodal treatment, the outcomes of pediatric patients with high-risk (HR) neuroblastoma (NB) remain poor. The rationale for allogeneic hematopoietic stem cell transplantation (allo-HCT) to treat NB was based on the possible graft-versus-tumor effect; however, toxicity limits its efficacy. We sought to prospectively assess the feasibility and efficacy of allo-HCT using a reduced-intensity conditioning regimen in pediatric patients with HR NB in a multicenter phase II trial. Primary endpoints were the rate of neutrophil and platelet engraftment, 5-year transplantation-related mortality (TRM), and disease-free survival (DFS). Secondary endpoint measures included the incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD. Fifty-one patients were enrolled in the study. The 5-year cumulative incidence (CuI) of TRM was 29.4 ± 6.4%, and that of DFS was 11.8 ± 4.5%. Patients undergoing allo-HCT within 1 year of diagnosis or with bone marrow as their stem cell source had a higher DFS probability. The CuI of neutrophil engraftment, platelet engraftment, and grade II-IV aGVHD was 97.9 ± 2.1%, 93.8 ± 3.5%, and 47.1 ± 7.0%, respectively. The development of new therapeutic strategies could further improve disease control

Impact of mercaptopurine metabolites on disease outcome in the AIEOP-BFM 2009 protocol for acute lymphoblastic leukemia

: In the maintenance phase of AIEOP-BFM acute lymphoblastic leukemia (ALL) 2009 protocol, mercaptopurine (MP) is given at the planned dose of 50 mg/m2/day; however, dose adjustments are routinely performed to target patients' white blood cells to the optimal range of 2000-3000 cells/μl. ALL pediatric patients (n=290, age: median (1st-3rd quartile): 4.8 (3.0-8.1) years; male: 56.9%) were enrolled mainly in four medium-large Italian pediatric hospitals; 14.1% of patients relapsed after a median (1st-3rd quartile) follow-up time of 4.43 (3.82-5.46) years from maintenance beginning. MP metabolites (thionucleotide (TGN) and methyl-derivatives (MMPN)) were measured in the erythrocytes of 387 blood samples of 200 patients by HPLC-UV. SNPs (rs1800462, rs1800460 and rs1142345 in TPMT gene, rs116855232 in NUDT15, rs1127354, rs7270101, rs6051702 in ITPA and rs2413739 in PACSIN2) were characterized by Taqman SNP genotyping assays. Cox proportional hazard models did not show an impact TGN levels and variability on relapse. In contrast, after multivariate analysis, relapse hazard ratio (HR) increased in ALL children of the intermediate risk arm compared to those in standard risk arm (3.44, 95% confidence interval (CI), 1.31-9.05, p= 0.012), and in carriers of the PACSIN2 rs2413739 T allele compared to those with the CC genotype (heterozygotes CT: HR, 2.32; 95% CI, 0.90-5.97; p=0.081; homozygous TT: HR, 4.14; 95% CI, 1.54-11.11; p=0.005). Future studies are needed to confirm the lack of impact of TGN levels and variability on relapse in the AIEOP-BFM ALL trials, and to clarify the mechanism of PACSIN2 rs2413739 on outcome

Intensified Induction Therapy for Newly Diagnosed, Localized Skeletal Ewing Sarcoma (ISG/AIEOP EW‐1): A Randomized, Open‐Label, Phase 3, Non‐Inferiority Trial

Background: Several studies have shown that the intensity of treatment in Ewing sarcoma has an impact on outcome. The present trial tested the non-inferiority of intensive, shorter, induction chemotherapy (25 weeks total treatment time) compared to the standard treatment (37 weeks) in non-metastatic Ewing sarcoma (ES) at onset. Procedure: This national, multicenter, parallel, randomized, controlled, open-label, non-inferiority, phase III trial was conducted in 14 specialized hospitals in Italy. Patients aged 2-40 years with newly diagnosed localized ES were randomized to receive four courses of induction therapy (one every 21 days) either with a standard arm (Arm A) or with an intensive arm (Arm B). For consolidation therapy, good responders (GRs) in Arm A received nine courses (37 weeks), while Arm B patients received five courses (25 weeks). Poor responders for both arms received four courses followed by high-dose busulfan/melphalan + autologous stem cell rescue. Follow-up was 5 years. Results: In the study period 2009–2018, 274 patients with ES at onset were screened, 248 were eligible, 15 refused randomization, and 233 were randomized (Arm A: 113; Arm B: 120). Median age was 14 years. Arm B was not inferior to Arm A: 5-year EFS was 77.5% and 71.6%, respectively (HR vs. Arm A: 0.74, 90% CI: 0.49–1.14). GRs were 54.9% in Arm A and 62.5% in Arm B. Hematological, gastrointestinal, and cardiovascular Grade ≥3 toxicities had higher frequencies in Arm B. Conclusions: Intensive induction therapy showed non-inferiority in 5-year EFS when compared with the standard induction therapy. Higher toxicity was reported in Arm B with similar outcome, counterbalanced in GRs with a shorter treatment plan. ClinicalTrials.gov Identifier: NCT02063022