T-cell acute lymphoblastic leukemia in patients 1-45 years treated with the pediatric NOPHO ALL2008 protocol.

The NOPHO ALL2008 is a population-based study using an unmodified pediatric protocol in patients 1-45 years of age with acute lymphoblastic leukemia. Patients with T-ALL were given a traditional pediatric scheme if fast responding (minimal residual disease (MRD) < 0.1% day 29), or intensive block-based chemotherapy if slow responding (MRD > 0.1% day 29). Both treatment arms included pediatric doses of high-dose methotrexate and asparaginase. If MRD ≥ 5% on day 29 or ≥0.1% after consolidation, patients were assigned to allogeneic hematopoietic stem cell transplantation. The 5-year overall survival of the 278 T-ALL patients was 0.75 (95% CI 0.69-0.81), being 0.82 (0.74-0.88) for patients 1.0-9.9 years, 0.76 (0.66-0.86) for those 10.0-17.9 years, and 0.65 (0.55-0.75) for the older patients. The risk of death in first remission was significantly higher in adults (12%) compared with the 1-9 years group (4%). The MRD responses in the three age groups were similar, and only a nonsignificant increase in relapse risk was found in adults. In conclusion, an unmodified pediatric protocol in patients 1-45 years is effective in all age groups. The traditional pediatric treatment schedule was safe for all patients, but the intensive block therapy led to a high toxic death rate in adults.

Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia.

Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P=0.53). Event-free survival rates (pEFS5y) were 89±1% (A), 80±3% (B) and 74±4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.

Facial Dystonia with Facial Grimacing and Vertical Gaze Palsy with "Round the Houses" Sign in a 29-Year-Old Woman.

A 29-year-old woman developed progressive dysarthria and coordination problems from the age of 15. Examination showed dysarthria, facial dystonia, bibrachial dystonia, hyperreflexia, ataxia, and emotional incontinence. Downward supranuclear gaze palsy was prominent with a "Round the Houses" sign. Magnetic resonance imaging of the brain and medulla, electroneurography, and cerebrospinal fluid were normal. A computed tomography scan showed hepatosplenomegaly. This combination of progressive neurological symptoms together with hepatosplenomegaly was suggestive of inborn error of metabolism. A bone marrow biopsy showed an increased number of macrophages with foamy content, highly suggestive of lysosomal disease. Plasmatic chitotriosidase activity and CCL18 were increased. Genetic testing showed heterozygosis for the variation c.1070C→T (p.Ser357Leu) and c.1843→T (Arg615Cys), confirming the diagnosis of Niemann-Pick type C (NPC). The "Round the Houses" sign has only been described in patients with progressive supranuclear palsy (PSP). This sign is described as an inability to produce pure vertical saccades along the midline and instead moving the eyes in a lateral arc to accomplish the movement. The observation of this sign in a patient with NPC indicates that this bedside finding is not specific for PSP, but a sign of medial longitudinal fasciculus dysfunction. The presence of facial dystonia with facial grimacing together with supranuclear gaze palsy is highly characteristic and useful for the diagnosis of NPC. NPC is an important underdiagnosed condition, given the availability of treatment and a mean diagnostic delay of 6 years.

High prevalence of hereditary thrombotic thrombocytopenic purpura in central Norway: from clinical observation to evidence.

UNLABELLED: Essentials The population prevalence of hereditary thrombotic thrombocytopenic purpura (TTP) is unknown. We studied the prevalence of hereditary TTP and population frequencies of two ADAMTS-13 mutations. A high frequency of hereditary TTP related to ADAMTS-13 mutation c.4143_4144dupA was found. Vicinity of ABO blood group and ADAMTS-13 loci may facilitate screening of ADAMTS-13 mutations. SUMMARY: Background Hereditary thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS-13 mutations is a rare, but serious condition. The prevalence is unknown, but it seems to be high in Norway. Objectives To identify all patients with hereditary TTP in central Norway and to investigate the prevalence of hereditary TTP and the population frequencies of two common ADAMTS-13 mutations. Patients/Methods Patients were identified in a cross-sectional study within the Central Norway Health Region by means of three different search strategies. Frequencies of ADAMTS-13 mutations, c.4143_4144dupA and c.3178 C>T (p.R1060W), were investigated in a population-based cohort (500 alleles) and in healthy blood donors (2104 alleles) by taking advantage of the close neighborhood of the ADAMTS-13 and ABO blood group gene loci. The observed prevalence of hereditary TTP was compared with the rates of ADAMTS-13 mutation carriers in different geographical regions. Results We identified 11 families with hereditary TTP in central Norway during the 10-year study period. The prevalence of hereditary TTP in central Norway was 16.7 × 10(-6) persons. The most prevalent mutation was c.4143_4144dupA, accounting for two-thirds of disease causing alleles among patients and having an allelic frequency of 0.33% in the central, 0.10% in the western, and 0.04% in the southeastern Norwegian population. The allelic frequency of c.3178 C>T (p.R1060W) in the population was even higher (0.3-1%), but this mutation was infrequent among patients, with no homozygous cases. Conclusions We found a high prevalence of hereditary TTP in central Norway and an apparently different penetrance of ADAMTS-13 mutations.

Hereditary thrombotic thrombocytopenic purpura and the hereditary TTP registry.

Hereditary thrombotic thrombocytopenic purpura, Upshaw-Schulman syndrome, ADAMTS13 Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome, is a rare recessively inherited disease. Underlying is a severe constitutional deficiency of the von Willebrand factor-cleaving protease, ADAMTS13, due to compound heterozygous or homozygous mutations in the ADAMTS13 gene. The clinical picture is variable and more and more patients with an adult-onset are diagnosed. In the majority of countries the only available treatment is plasma, which when administered regularly can efficiently prevent acute disease bouts. The decision to initiate regular prophylaxis is often not easy, as evidence based guidelines and long term outcome data are lacking. Through the hereditary TTP registry (www.ttpregistry.net, ClinicalTrials.gov identifier: NCT01257269), which was initiated in 2006 and is open to all patients diagnosed with Upshaw-Schulman syndrome and their family members, we aim to gain further information and insights into this rare disease, which eventually will help to improve clinical management of affected patients.