Draga Barbaric

Transplant-Related Mortality Following Allogeneic Hematopoeitic Stem Cell Transplantation for Pediatric Acute Lymphoblastic Leukemia: 25-Year Retrospective Review

Over the last 25 years, donor source, conditioning, graft‐versus‐host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high‐risk patients in first and subsequent remission. There is a large burden of infectious and pre‐HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased.

Down syndrome and leukemia: insights into leukemogenesis and translational targets

Children with Down syndrome (DS) have a significantly increased risk of childhood leukemia, in particular acute megakaryoblastic leukemia (AMKL) and acute lymphoblastic leukemia (DS-ALL). A pre-leukemia, called transient myeloproliferative disorder (TMD), characterised by a GATA binding protein 1 (GATA1) mutation, affects up to 30% of newborns with DS. In most cases, the pre-leukemia regresses spontaneously, however one-quarter of these children will go on to develop AMKL or myelodysplastic syndrome (MDS) . AMKL and MDS occurring in young children with DS and a GATA1 somatic mutation are collectively termed myeloid leukemia of Down syndrome (ML-DS). This model represents an important multi-step process of leukemogenesis, and further study is required to identify therapeutic targets to potentially prevent development of leukemia. DS-ALL is a high-risk leukemia and mutations in the JAK-STAT pathway are frequently observed. JAK inhibitors may improve outcome for this type of leukemia. Genetic and epigenetic studies have revealed likely candidate drivers involved in development of ML-DS and DS-ALL. Overall this review aims to identify potential impacts of new research on how we manage children with DS, pre-leukemia and leukemia.

Excellent response to dasatinib of childhood Philadelphia positive intracranial acute lymphoblastic leukaemia tumours.

Bulky intracranial disease in childhood Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL) is rare and optimal management has not been well defined. Here we report two children with Ph+ ALL and bulky intracranial disease who had an excellent clinical, radiological and molecular response to dasatinib and multi-agent chemotherapy. A 4-year-old boy (Case 1) presented with priapism, bruising and a white cell count (WCC) of 845 · 10/l and was diagnosed with B-cell precursor ALL (CD10, CD19, CD22, HLA-DR and TdT positive). He commenced induction therapy with methylprednisolone (60 mg/m per day), and over the next day he was noted to have pupillary abnormalities and a fluctuating level of consciousness. A computerized tomography (CT) scan showed multiple intracranial lesions, presumed leukaemic infiltrates (Fig 1A). An atraumatic lumbar puncture was performed on day 1 and triple intrathecal chemotherapy administered (methotrexate, cytarabine and hydrocortisone, age-related doses). Cerebrospinal fluid (CSF) cytocentrifuge analysis showed 15 white cells with 40% blasts. Fluorescent in-situ hybridization (FISH) confirmed the diagnosis of Ph+ ALL. Dexamethasone (10 mg/m per day) was substituted for methylprednisolone and imatinib mesylate (340 mg/m per day) was commenced. The patient remained intubated and ventilated to manage respiratory compromise from presumed leukaemic pulmonary infiltrates. There was an excellent systemic response, with the peripheral blast count falling to 3 · 10/l by day 3 of treatment. Analysis of the CSF on day 4 showed no white cells and no blasts. However the patient failed to wake appropriately when sedation was lightened, and a repeat CT scan on day 6 showed an increase in both the size and number of intracranial lesions (Fig 1B). Open brain biopsy of a left frontal lesion demonstrated the presence of sheets of small, monomorphic lymphoid cells (Fig 1C) positive for CD10 and TdT. A magnetic resonance imaging (MRI) scan performed on day 8 confirmed the presence of multiple intracranial lesions in the cerebellum and cerebral hemispheres (Fig 1D). Dasatinib (100 mg/m per twice daily) was substituted for imatinib mesylate and systemic chemotherapy (vincristine 1Æ5 mg/m weekly, daunorubicin 30 mg/m weekly and l-asparaginase 5000 u/m twice weekly) was commenced. Emergent cranial radiation therapy was considered but not performed. Following these therapy changes, the patient was successfully extubated. Neurological examination post-extubation demonstrated focal deficits including a right hemiplegia and aphasia. The patient had progressive and complete neurological recovery over the following months and a progress MRI scan at day 79 showed complete resolution of the lesions (Fig 1E). Polymerase chain reaction-based minimal residual disease (MRD) testing confirmed an excellent response to therapy with both markers becoming undetectable in the bone marrow by day 79. The patient is currently in remission 18 months from diagnosis, having received definitive neuraxis radiation as part of an unrelated umbilical cord transplant with total body irradiation (TBI). He is planned to continue a further 12 months of dasatinib therapy post-transplant. Shortly after this, a 2-year-old girl (Case 2) presented with lethargy, bruising, epistaxis and a fluctuating level of consciousness. The WCC of 615 · 10/l, circulating blasts (immunophenotype CD10, CD19, CD22, HLA-DR and TdT positive) and FISH confirmed the diagnosis of Ph+ B-cell precursor ALL. CT scan revealed multiple intracranial parenchymal lesions consistent with bulky disease with haemorrhage. She commenced induction therapy with dexamethasone, dasatinib, and systemic chemotherapy as per Case 1. The first lumbar puncture with triple intrathecal therapy was delayed until her neurological condition stabilized and was performed on day 7. Atraumatic CSF cytocentrifuge analysis revealed nine white cells with no blasts, and subsequent CSF analyses remained free of leukaemia. She suffered multiple complications including seizures and right hemiplegia, gastro-intestinal bleeding and perineal excoriation, but made a progressive clinical and neurological recovery with almost complete radiological resolution of the intracranial lesions. Bone marrow examination at the end of induction confirmed an excellent response to therapy with both MRD markers becoming undetectable. During consolidation chemotherapy there was deterioration in the perineal skin secondary to Pseudomonas aeruginosa, and despite appropriate broad-spectrum multi-agent antibacterial therapy and surgical debridement she developed necrotising fasciitis, which progressed to multi-organ failure and death. Post-mortem examination revealed perineal ecthyma gangrenosa and advanced disseminated Pseudomonas infection. Pathological examination of the brain revealed numerous areas of old haemorrhage with central areas of necrotic leukaemic cells, and no viable leukaemia cells were identified. In Case 1, there was clear, early intracranial disease progression despite peripheral blood and CSF disease, which was rapidly controlled by dexamethasone, imatinib mesylate and triple intrathecal therapy. Poor CNS penetration and correspondence

Proliferative nodules of undifferentiated spindle cells arising in a large congenital melanocytic naevus.

Proliferative nodules (PN) are benign lesions that arise in large congenital melanocytic naevi (LCMN). Clinically and histologically they can be difficult to differentiate from malignancies, which are also associated with LCMN. The PN in this case consisted of undifferentiated spindle cells and exhibited unusual histological features including negative stains for melanocytic markers (S100, HMB45 and MelA), negative stain for c‐Kit, high mitotic index and unusual morphology of the lesional cells. As a result, a firm histological classification could not be made, which posed a challenge for the clinical management.

False-Positive MIBG Scans With Normal Computed Tomography Imaging in Patients With High-Risk Neuroblastoma

TO THE EDITOR: Kushner et al investigate the most sensitive modality for early detection of relapse in patients with asymptomatic high-risk neuroblastoma who had previously achieved complete remission or very good partial remission. They demonstrate that iodine123 (I) metaiodobenzylguanidine (MIBG) scanning was the only positive surveillance scan in 27% of patients and conclude that IMIBG scanning is the most reliable test for detection of clinically unsuspected tumor recurrence in this population. However, it is difficult to fully assess the reliability of I-MIBG scanning based on the data provided for several reasons. The authors do not indicate how the diagnosis of recurrence was confirmed. This is a particularly important question for the 27% of patients who had no indication of relapse on any other form of imaging or surveillance. If there was no histopathologic confirmation of relapse, it may be possible that some patients had false positive I-MIBG scintigraphy scans. This may partly explain the improved survival rate seen in this cohort. No data is provided on the number of patients with positive I-MIBG scans who were found not to have relapsed. In absence of this information, the clinical utility and reliability of I-MIBG scanning in this population remains unclear. The potential for a false-positive MIBG result has been described in a variety of clinical settings, including evaluation at diagnosis or relapse. Specific cases have been reported in an accessory spleen, urinoma, benign liver tumors, and pyelonephritis. Pfluger et al quote a specificity of 85% for MIBG alone that increases to 95% when used in conjunction with magnetic resonance imaging in their study of 50 newly diagnosed patients. It therefore seems likely that some patients under post-treatment surveillance who develop MIBG changes only with no changes on computed tomography (CT) imaging will have false-positive scans. To further address the specificity of I-MIBG changes in the absence of CT changes we retrospectively evaluated the posttreatment surveillance at our institution over the last 10 years in a similar patient population to that described by Kushner et al. Since 1999, our institution has had 13 patients with high-risk neuroblastoma who were treated with intensive induction therapy, autologous transplant, and radiation therapy and achieved complete or very good partial remission status. During post-treatment surveillance imaging, five patients had positive I-MIBG uptake with no evidence of evolving mass disease on concurrent CT. The patient details are described in Table 1. One patient with focal I-MIBG uptake in the liver (patient 2) had a biopsy performed that did not show any evidence of recurrent neuroblastoma. The remainder were followed with observation alone. All are currently alive with no evidence of disease at a median of 5 years follow-up (range, 7 to 100 months). One patient has long-term morbidity as a result of his treatment but no active NB disease. The remainder are well. Our results suggest that when following high-risk neuroblastoma patients who are in complete or very good partial remission status, the presence of a positive MIBG scan in the absence of changes in other surveillance scans needs to be interpreted with caution. While three of the patients were between 12 and 18

Enrolment in paediatric oncology early-phase clinical trials: The health-care professionals' perspective: Perspectives of early phase trials

Approximately 20–30% of children/adolescents with cancer will not respond to standard therapies. These children are usually offered experimental treatment in the form of an early‐phase clinical trial. We examined the perspectives of health‐care professionals (HCPs) regarding obtaining informed consent for early‐phase trials in paediatric oncology.

A risk score including microdeletions improves relapse prediction for standard and medium risk precursor B-cell acute lymphoblastic leukaemia in children

To prevent relapse, high risk paediatric acute lymphoblastic leukaemia (ALL) is treated very intensively. However, most patients who eventually relapse have standard or medium risk ALL with low minimal residual disease (MRD) levels. We analysed recurrent microdeletions and other clinical prognostic factors in a cohort of 475 uniformly treated non‐high risk precursor B‐cell ALL patients with the aim of better predicting relapse and refining risk stratification. Lower relapse‐free survival at 7 years (RFS) was associated with IKZF1 intragenic deletions (P < 0·0001); P2RY8‐CRLF2 gene fusion (P < 0·0004); Day 33 MRD>5 × 10−5 (P < 0·0001) and High National Cancer Institute (NCI) risk (P < 0·0001). We created a predictive model based on a risk score (RS) for deletions, MRD and NCI risk, extending from an RS of 0 (RS0) for patients with no unfavourable factors to RS2 + for patients with 2 or 3 high risk factors. RS0, RS1, and RS2 + groups had RFS of 93%, 78% and 49%, respectively, and overall survival (OS) of 99%, 91% and 71%. The RS provided greater discrimination than MRD‐based risk stratification into standard (89% RFS, 96% OS) and medium risk groups (79% RFS, 91% OS). We conclude that this RS may enable better early therapeutic stratification and thus improve cure rates for childhood ALL.