Gita Massey

Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: Pediatric Oncology Group Study.

Transient leukemia (TL or transient myeloproliferative disorder) occurs in approximately 10% of newborn infants with Down syndrome. The disorder is characterized by the presence of megakaryoblasts in the peripheral blood; most cases resolve spontaneously within the first 3 months of life, and the child is well thereafter. However, there are cases in which a severe, potentially lethal form of disease develops, manifesting as hepatic fibrosis or cardiopulmonary failure. Hitherto, the incidence of these severe forms of the disease has not been reported. A prospective study of TL was conducted by the Pediatric Oncology Group (POG Study 9481) in which 48 children with TL were identified. Life-threatening disease occurred in nine patients (19%); seven had hepatic fibrosis and two had cardiopulmonary failure. Five children died of the disease within the first 3 months of life, none of whom received antileukemic therapy. One patient died on day 31 after receiving minimal therapy within 1 day of death. Three children received low-dose cytosine arabinoside (Ara-C) (0.4–1.5 mg/kg every 12 hours for 5 or 7 days). In all these patients, the disease resolved. It is concluded that potentially lethal disease is relatively common in TL, and the available evidence suggests that these diseases are responsive to low-dose Ara-C therapy.

Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971

Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution. Later development of acute myeloid leukemia (AML) occurs in some. Prospective enrollment (n = 135) elucidated the natural history in Down syndrome (DS) patients diagnosed with TMD via the use of uniform monitoring and intervention guidelines. Prevalent at diagnosis were leukocytosis, peripheral blast exceeding marrow blast percentage, and hepatomegaly. Among those with life-threatening symptoms, most (n = 29/38; 76%) received intervention therapy until symptoms abated and then were monitored similarly. Organomegaly with cardiopulmonary compromise most frequently led to intervention (43%). Death occurred in 21% but only 10% were attributable to TMD (intervention vs observation patients: 13/14 vs 1/15 because of TMD). Among those solely observed, peripheral blasts and all other TMD symptoms cleared at a median of 36 and 49 days from diagnosis, respectively. On the basis of the diagnostic clinical findings of hepatomegaly with or without life-threatening symptoms, 3 groups were identified with differing survival: low risk with neither finding (38%), intermediate risk with hepatomegaly alone (40%), and high risk with both (21%; overall survival: 92% ± 8%, 77% ± 12%, and 51% ± 19%, respectively; P ≤ .001). Among all, AML subsequently occurred in 16% at a median of 441 days (range, 118-1085 days). The trial is registered at http://www.clinicaltrials.gov as NCT00003593.

Cardiomyopathy in Children With Down Syndrome Treated for Acute Myeloid Leukemia: A Report From the Children's Oncology Group Study POG 9421

PURPOSE To determine the outcomes, with particular attention to toxicity, of children with Down syndrome (DS) and acute myeloid leukemia (AML) treated on Pediatric Oncology Group (POG) protocol 9421. PATIENTS AND METHODS Children with DS and newly diagnosed AML (n = 57) were prospectively enrolled onto the standard-therapy arm of POG 9421 and were administered five cycles of chemotherapy, which included daunorubicin 135 mg/m(2) and mitoxantrone 80 mg/m(2). Outcomes and toxicity were evaluated prospectively and were compared with the non-DS-AML cohort (n = 565). A retrospective chart review was performed to identify adverse cardiac events. RESULTS In the DS-AML group, 54 patients (94.7%) entered remission. One experienced induction failure and two died. Of the 54 who entered remission, three relapsed and six died as a result of other causes. The remission induction rate was similar in the non-DS-French-American-British (FAB) M7 (91.7%) and non-DS-non-M7 (89.3%) groups. The 5-year overall survival was significantly better in the DS-AML group (78.6%) than in the non-DS-M7 (36.3%) or the non-DS-non-M7 (51.8%) groups (P < .001). No age-related difference in 5-year, event-free survival was seen between patients younger than 2 years (75.8%) and those aged 2 to 4 years (78.3%). Symptomatic cardiomyopathy developed in 10 patients (17.5%) with DS-AML during or soon after completion of treatment; three died as a result of congestive heart failure. CONCLUSION The POG 9421 treatment regimen was highly effective in both remission induction and disease-free survival for patients with DS-AML. However, there was a high incidence of cardiomyopathy, which supports current strategies for dose reduction of anthracyclines in this patient population.

A study of prospective surveillance for inhibitors among persons with haemophilia in the united states

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person‐years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113 205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products.

Continuous lidocaine infusion for the relief of refractory malignant pain in a terminally ill pediatric cancer patient

Despite aggressive pain management with opiates, debilitating pain still occurs in a subset of children with terminal cancer. A 5-year-old girl with metastatic retinoblastoma, profound opiate tolerance, and refractory pain was treated. Continuous lidocaine infusion was initiated at a dose of 35 microg/kg per minute and increased over 4 days to 50 microg/kg per minute, at which point the patient was discharged for continued end-of-life comfort care. The patient had excellent pain relief without the associated lethargy of high-dose opiates. No complicating neuroexcitatory symptoms or cardiac conduction abnormalities were experienced. Intravenous lidocaine may be an effective alternative to opioids in the treatment of refractory malignant pain in the pediatric patient with terminal cancer.

Benign Transient Hyperphosphatasemia in Children with Leukemia and Lymphoma

A temporary elevation of serum alkaline phosphatase has been described in young children who have no evidence of liver or bone disease. This phenomenon has been termed benign hyperphosphatasemia of infancy. Its occurrence is described in three children undergoing chemotherapy for acute lymphoblastic leukemia and lymphoma. All three children were in remission and in the consolidation or maintenance phase of their therapy when the hyperphosphatasemia occurred. All children were also receiving methotrexate (IM and IV), oral 6-mercaptopurine, and oral sulfamethoxazole/trimethoprim. Although these agents are associated with hepatotoxicity, other liver transaminases (ALT, AST) remained at normal concentrations, and there was an elevation only in the bone isoenzyme of alkaline phosphatase, thus making hepatic toxicity an unlikely etiology for the hyperphosphatasemia. No alteration in chemotherapy was necessary for resolution of the elevated alkaline phosphatase in these children.

Vitamin d deficiency in children with cancer.

A limited number of small studies have examined the vitamin D status of pediatric oncology patients, and the results indicate an increased prevalence of hypovitaminosis. We conducted a cross-sectional study with the primary aim of describing the vitamin D status of our pediatric cancer patients and any associations with demographic characteristics. Our secondary aim was to compare this prevalence to that of a healthy population. We collected data on children seen in our clinic and determined the overall prevalence of hypovitaminosis. We then compared this prevalence to that of healthy populations described in the literature. The prevalence of hypovitaminosis in our study population was 72%. Forty-three percent of our patients were considered deficient with 8% being severely deficient. Our analysis revealed a significant association between the outcome and age in that patients 6 years and above were more likely to have hypovitaminosis after adjustment for other characteristics (AOR=3.23; 95% CI, 1.11-9.40). When compared with a healthy pediatric population, our patients had a significantly higher prevalence of hypovitaminosis (P-value=0.003). Vitamin D deficiency is very common in children with cancer, representing a subpopulation of high-risk patients that could benefit most from early detection and supplementation.

Translocation positive acute myeloid leukemia associated with valproic acid therapy

Valproic acid is an effective anti‐epileptic medication often used for long‐term control of seizure disorders that has been implicated in hematological toxicities, including rare reports of myelodysplasia and acute leukemia. Here, we report a case of valproic acid‐related leukemia‐like syndrome with a t(8;16) chromosomal translocation. After discontinuing valproic acid, the hematological findings completely resolved. Pediatr Blood Cancer 2008;50:641–643.

Synonymous mutation in TP53 results in a cryptic splice site affecting its DNA‐binding site in an adolescent with two primary sarcomas

Pathologic variants in TP53 are known risk factors for the development of cancer. We report a 17‐year‐old male who presented with two primary sarcomas. Germline sequencing revealed a novel TP53 c.672 G>A mutation. Sequencing revealed wild‐type TP53 in the parents, and there was no history of cancer in first‐degree relatives. This de novo synonymous germline mutation results in a 5′ cryptic splice site that is bound by U1, resulting in a shift of the splice site by 5 base pairs. The frame shift results in a truncated protein at residue 246, which disrupts the DNA‐binding domain of p53.

Coated platelets and severe haemophilia A bleeding phenotype: Is there a connection?

Coated platelets are a subpopulation of platelets that possess highly prothrombotic properties. Previous observational data suggest that bleeding phenotype in severe haemophilia A is associated with coated platelet levels. Haemophilia A patients with higher coated platelet levels may have a mild bleeding phenotype; those with lower levels may have a more severe bleeding phenotype.