Lorna Storey

A doctor(s) dilemma: ETV6-ABL1 positive acute lymphoblastic leukaemia.

Sanz, M., Wieland, S., Barber, J.R. & Kantarjian, H.M. (2009) A phase II study of oral tamibarotene in acute promyelocytic leukemia (APL) patients (PTS) who have received prior therapy with all-trans retinoic acid and arsenic trioxide (STAR-1 trial). Blood (ASH Annual Meeting Abstracts), 114, 2050. Ohnishi, K. (2007) PML-RARa inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia. International Journal of Clinical Oncology, 12, 313–317. Sanz, M.A., Lo-Coco, F., Martı́n, G., Avvisati, G., Rayón, C., Barbui, T., Dı́az-Mediavilla, J., Fioritoni, G., González, J.D., Liso, V., Esteve, J., Ferrara, F., Bolufer, P., Bernasconi, C., Gonzalez, M., Rodeghiero, F., Colomer, D., Petti, M.C., Ribera, J.M. & Mandelli, F. (2000) Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood, 96, 1247–1253. Sanz, M.A., Grimwade, D., Tallman, M.S., Lowenberg, B., Fenaux, P., Estey, E.H., Naoe, T., Lengfelder, E., Büchner, T., Döhner, H., Burnett, A.K. & Lo-Coco, F. (2009) Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood, 113, 1875–1891. Tobita, T., Takeshita, A., Kitamura, K., Ohnishi, K., Yanagi, M., Hiraoka, A., Karasuno, T., Takeuchi, M., Miyawaki, S., Ueda, R., Naoe, T. & Ohno, R. (1997) Treatment with a new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete remission induced by all-trans retinoic acid. Blood, 90, 967–973.

Successful treatment with rituximab and mycophenolate mofetil of refractory autoimmune hemolytic anemia post‐hematopoietic stem cell transplant for dyskeratosis congenita due to TINF2 mutation

AIHA following allogeneic HSCT is appearing more frequently in the literature. It occurs as a result of donor cell‐derived antibodies targeting donor red cell antigens. Little guidance exists on the management of such patients, particularly in the pediatric setting. First‐line conventional treatment is corticosteroids and/or immunoglobulin therapy with monoclonal antibody therapy reserved for treatment failure. We report our experience of a child refractory to immunoglobulin and steroid therapy who required several infusions of rituximab and immunomodulatory therapy to obtain a clinically significant response.

Esophageal Strictures During Treatment for Acute Lymphoblastic Leukemia

Esophageal stricture is a rare complication of paediatric cancer treatment that usually occurs after esophageal exposure to radiotherapy. We describe 4 cases of esophageal stricture during chemotherapy for acute lymphoblastic leukemia. All patients presented with refractory vomiting and were diagnosed with radiologic contrast studies. None of the patients had received radiotherapy. Esophageal candidiasis was seen in 2 patients but the remaining 2 patients had earlier systemic candidiasis. High-dose dexamethasone may predispose these children to both esophageal candidiasis and peptic esophagitis. The etiology of esophageal strictures during treatment for acute leukemia is likely to be multifactorial but systemic candidiasis may play a significant role.

Does vaccine dose predict response to the monovalent pandemic H1N1 influenza a vaccine in children with acute lymphoblastic leukemia? A single-centre study

Vaccination against influenza is an important strategy in preventing severe infection among children with acute lymphoblastic leukemia (ALL). Successful vaccination depends on both vaccine and host‐related factors. We conducted a study on factors predicting the immunogenicity of the monovalent pandemic H1N1 (pH1N1) influenza A vaccine in children with ALL.

No prognostic impact of P2RY8-CRLF2 fusion in intermediate cytogenetic risk childhood B-cell acute lymphoblastic leukaemia.

A subset of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients have recently been found to harbour rearrangements of the cytokine receptor-like factor 2 gene (CRLF2) (Mullighan et al, 2009; Russell et al, 2009). A number of molecular lesions result in deregulated overexpression of CRLF2 (CRLF2-d); the two most common being interstitial deletions of the pseudoautosomal region PAR1 (Xp22/Yp11) that results in a P2RY8-CRLF2 fusion with CRLF2 expression driven by the P2RY8 promoter, or alternatively, translocation of CRLF2 to the IGH@ locus (14q32) leading to deregulated CRLF2 expression via IGH@ enhancer elements – IGH@-CRLF2 (Mullighan et al, 2009; Russell et al, 2009). CLRF2-d has been reported in 5–15% of childhood and adult BCP-ALL (Haslam et al, 2011; Mullighan et al, 2009; Russell et al, 2009) and is particularly more frequent in Down Syndrome (DS)-ALL patients, where its presence is associated with mutations of JAK2, postulated to cooperate in propagating the leukaemia in such instances (Harvey et al, 2010; Chen, et al 2012). The prognostic significance of this abnormality remains unclear in childhood BCP-ALL with studies assigning CRLF2-d as either an adverseor intermediate-risk prognostic factor (Cario et al, 2010; Palmi et al, 2012; Ensor et al, 2011; Harvey et al, 2010). The aim of our study was to determine the incidence and prognostic impact of CRLF2-d in diagnostic material from normal karyotype BCP-ALL patients treated according to the UK ALL 2003 protocol (ClinicalTrials.gov NCT00222612). Forty-two patients were selected from the total cohort of 238 children diagnosed with BCP-ALL and treated with UK ALL 2003 protocol between 2004 and 2010 in our institution. The selection process was based on the availability of a good quality stored diagnostic bone marrow sample for patients with intermediate cytogenetic risk, as defined by absence of the following: high hyperdiploid karyotype (chromosome N > 50), recognized translocations (ETV6-RUNX1, BCR-ABL1, MLL-AFF1 and IGH@-MYC) and constitutional trisomy 21 (DS). Cytogenetic and fluorescence in situ hybridization (FISH) data were available for all patients. CRLF2 over-expression was determined by real-time quantitative polymerase chain reaction (RQ-PCR) with underlying genomic rearrangements detected by either reverse transcription polymerase chain reaction (RT-PCR) (P2RY8-CRLF2 fusion transcripts) or FISH (break-apart IGH@; Abbott Laboratories, Abbott Park, IL, USA) as previously described (Haslam et al, 2011). Data were correlated with clinical risk factors, minimal residual disease (MRD) status and clinical outcome and analysed using Statistica (Statsoft, Milton Keynes, UK). The parents or guardians consented according to the Declaration of Helsinki for all participants. Overall, eight out of 42 patients (19%) were positive for the P2RY8-CRLF2 fusion, four of whom had high CRLF2 over-expression. No IGH@ translocations were detected. There was no significant difference in National Cancer Institute (NCI) risk status between CRLF2-d and non-CRLF2-d groups, although there was a tendency for lower blast cell count at presentation (10 0 vs. 39 0, P = 0 3) in the CRLF2-d group. No statistical significance was observed between day-28 MRD status and CRLF2-d. Four relapses were observed (two non-CRLF2-d (5 8%) and two CRLF2-d (25%). No statistical difference in overall and progression-free survival (PFS) was observed (PFS, 93 2% non-CRLF2-d versus 86% CRLF2-d, P = 0 11). There was also no clinical or laboratory differences between those patients with high and low CRLF2 expression. Genomic alterations of CRLF2 are emerging as additional high-risk molecular/cytogenetic features in some childhood ALL treatment trials. As reported by Attarbaschi et al (2012), we too did not observe a higher relapse-risk associated with the P2RY8-CRLF2 fusion regardless of any association with high levels of CLRF2 expression, suggesting that these patients are most likely to be of intermediate protocol-independent risk and therefore should not be considered at the present time for more intensive therapy. Given the deficiencies of our study, namely; small sample size and retrospective design, a larger study using multiple regression analysis would be needed to confirm the true prognostic impact of CRLF2-d in BCP-ALL. In addition, further assessment is required to define the underlying molecular mechanisms responsible for the absence of high CRLF2 expression in those patients with a P2RY8-CRLF2 translocation. Future risk algorithms are needed that will incorporate CRLF2-d status in prospective clinical trials in order to determine its true prognostic significance, as well

In support of upfront stem cell transplantation as first‐line therapy for paediatric patients with idiopathic severe aplastic anaemia who lack a sibling donor

Keywords: stem cell transplantation; paediatric patients; idiopathic severe aplastic anaemia

Pneumatosis intestinalis and imatinib mesylate.

Dear Editor, A 4-year-old female with Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL) was induced on the EsPhALL regimen (dexamethasone, vincristine, daunorubicin and L-asparaginase) and imatinib mesylate to a minimal residual disease (MRD)-negative remission. On day 17 of treatment, she was admitted with febrile neutropaenia, grade IV oral mucositis and culture-negative diarrhoea. By day 27, her neutrophil count and oral mucositis had recovered; however, diarrhoea and abdominal pain were ongoing and she developed progressive abdominal distension. Abdominal imaging revealed pneumatosis intestinalis (PI) (Fig. 1). She required supportive care with total parenteral nutrition and continuous morphine infusion. By day 32, her symptoms had improved and she was allowed oral diet. However, distension, diarrhoea and pain recurred, and plain film abdomen (PFA) again showed pneumatosis intestinalis. On day 37, imatinib mesylate was discontinued. Symptomatology gradually improved allowing reintroduction of enteral nourishment by day 48. Pneumatosis remained evident but improved on serial abdominal X-rays until complete resolution on day 116. On day 51, the patient commenced a more selective tyrosine kinase inhibitor, dasatinib. She has remained clinically well since. PI is an emerging complication of small molecule tyrosine kinase inhibitors (TKIs) [1–3] and is well described in associationwith bevacizumab [4], sorafenib [1, 5] and sunitinib [6, 7]. TKI-mediated vascular endothelial growth factor inhibition with ensuing microvascular thrombosis and intestinal mucosal injury is a putative mechanism. Non-specific inhibition of other TK receptors may also be important pathogenically. TKIinduced impairment of normal GI motility through c-kit receptor inhibition may causally contribute. There have been 16 cases of PI complicating imatinib mesylate therapy reported to the FDA (www.medsfact.com, www.ehealthme.com), but only two are published cases [8]. Themajority of the FDA-reported cases (14/16) have occurred in the setting of ALL treatment, most often within the first few months of treatment. The occurrence of PI in ALL more

Skin involvement in Down syndrome transient abnormal myelopoiesis

A new-born baby girl with phenotypic features of Down syndrome presented with hepatosplenomegaly and a haemoglobin concentration (Hb) of 146 g/l, platelet count 73 9 10/l and white blood cell (WBC) count 39·1 9 10/l. Blood cytomorphology and immunophenotyping showed 50% circulating blasts. Constitutional trisomy 21 was confirmed by karyotyping and a diagnosis of transient abnormal myelopoiesis (TAM) associated with Down syndrome was made. GATA1 mutation screening using WAVE and direct sequencing of polymerase chain reaction products failed to show any of the known common mutations. During hospitalization she developed a generalized papular skin rash, the histology of which showed a superficial perivascular infiltrate of predominantly mononuclear cells with round to reniform nuclei and variable quantities of pale cytoplasm. No mitotic figures were identified but there was conspicuous apoptosis. Immunohistochemical stains were strongly positive for CD117 in the perivascular cell population, which showed patchy CD68 positivity. CD34, CD3, CD7, CD56, CD61 and toluidine blue stain were negative. The morphological and immunophenotypic features were consistent with involvement of skin by TAM. During follow up, she became progressively pancytopenic with her Hb dropping to 60 g/l and her platelet count falling to 20 9 10/l, requiring supportive transfusion. By the second month of life she continued to be thrombocytopenic, but her WBC count normalized, her bone marrow showed no excess of blasts and her liver returned to normal size. Her skin rash subsided over the same time period with no specific intervention. In the third month of life she developed rapidly progressive hepatic dysfunction and subsequently died despite intensive management. Limited post mortem examination showed no evidence of TAM in the liver but identified extensive hepatocellular necrosis including bridging necrosis and venoocclusive disease – features previously reported in TAM. Skin involvement in TAM is rare, as is the absence of a detectable mutation in haematopoietic gene GATA1. The failure in this case to detect a mutation in GATA1, especially with the high blast count at presentation, suggests an uncommon mutation may have been driving the TAM and be responsible for the atypical phenotype.

Administration of Home Intravenous Chemotherapy to Children by their Parents: Parents' Evaluation of a Nationwide Program.

Objectives: Caring for a child with cancer can disrupt family life and financial stability, in addition to affecting the child’s social, emotional, and educational development. Health care providers must consider ways to minimize the negative impact of illness and hospitalization on the child and family. This study evaluates a nationwide initiative to educate and support parents to administer chemotherapy to their child in their home. Method: A questionnaire was circulated to parents participating in a home chemotherapy program from 2009 to 2014 (n = 140), seeking their perspective on the education program, and the benefits and concerns associated with administering home chemotherapy. Data analysis was conducted using a combination of descriptive statistics and content analysis. Results: Questionnaires were received from 108 parents (response rate = 77%). Overall, the program was positively evaluated with 100% of parents (n = 108) reporting that the training met their needs. More than one-third of parents (41%, n = 44) initially felt nervous about home chemotherapy but reported that the education program helped assuage their concerns. Benefits included reduced financial costs, reduced travel time to hospital, less disruption to family life, and less stress for the child and family. No medication errors were reported during the evaluation period. Conclusion: An important feature of the program is the partnership approach, which ensures that parents’ decision to enter the program is informed, appropriate for their situation, and centered on the needs of the child.

Infant ALK-Positive Anaplastic Large Cell Lymphoma with UnfavourablePrognostic Features and Neutrophilia at Presentation

Anaplastic large cell lymphoma (ALCL) is an uncommon form of non-Hodgkin lymphoma in younger patients, accounting for less than 15% of cases. It is exceedingly rare in infants, with a median age at diagnosis of 12 years. Various treatment strategies have been studied in pediatric ALCL, however the long-term event free survival is approximately 70% regardless of treatment approach. We present the case of six month old infant with anaplastic lymphoma kinase (ALK) positive ALCL with unfavourable prognostic features. We elected to treat with upfront brentuximab in addition to combination chemotherapy. This achieved a clinical and molelcular remission of the disease. The treament was well tolerated.