Maria Åström

Genetic basis of Congenital Erythrocytosis mutation update and online databases

Congenital erythrocytosis (CE), or congenital polycythemia, represents a rare and heterogeneous clinical entity. It is caused by deregulated red blood cell production where erythrocyte overproduction results in elevated hemoglobin and hematocrit levels. Primary congenital familial erythrocytosis is associated with low erythropoietin (Epo) levels and results from mutations in the Epo receptor gene (EPOR). Secondary CE arises from conditions causing tissue hypoxia and results in increased Epo production. These include hemoglobin variants with increased affinity for oxygen (HBB, HBA mutations), decreased production of 2,3‐bisphosphoglycerate due to BPGM mutations, or mutations in the genes involved in the hypoxia sensing pathway (VHL, EPAS1, and EGLN1). Depending on the affected gene, CE can be inherited either in an autosomal dominant or recessive mode, with sporadic cases arising de novo. Despite recent important discoveries in the molecular pathogenesis of CE, the molecular causes remain to be identified in about 70% of the patients. With the objective of collecting all the published and unpublished cases of CE the COST action MPN&MPNr‐Euronet developed a comprehensive Internet‐based database focusing on the registration of clinical history, hematological, biochemical, and molecular data (http://www.erythrocytosis.org/). In addition, unreported mutations are also curated in the corresponding Leiden Open Variation Database.

Adjustment of Incidence Rates after an Estimate of Completeness and Accuracy in Registration of Acute Leukemias in a Swedish Population

Earlier studies have revealed undernotification of hematological malignancies in Swedish and other Cancer Registries. We present epidemiological data on AML, ALL and unspecified AL in adults diagnosed 1987–1992 in a well-defined population. Blast crises of CML were excluded. The Swedish Cancer Registry and Cause of Death Registry were compared and patient records reviewed for validation. When available, listings of pathology bone marrow reports and inpatient discharge diagnoses were utilized for casefinding. 260 cases of acute leukemias could be verified in a population of 663,135 adults, corresponding to a yearly incidence of 6.5/100,000. The median age of the patients was 69.2 years. 214 cases were AML, 38 ALL and eight unspecified AL. Undernotification in the Cancer Registry was found to be 15.4%, greater for AML and unspecified AL than for ALL. In addition the coding was not uniform, resulting in an incidence rate in adults of 5.3/100,000 for the Cancer Registry which is 18.5% lower than that of our study. A significant survival advantage was seen for notified patients. Combination of the Cancer Registry and Cause of Death Registry gave acceptable coverage, omitting only four patients. As the incidence of acute leukemias in our study is comparatively high, we hypothesize that underestimation of incidence and overestimation of survival are general problems for cancer registries.

High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003–2007

Background A minority of patients with adult acute lymphoblastic leukemia who relapse are rescued. The aim of this population-based study was to assess the results of reinduction treatment and allogeneic stem cell transplantation in patients in second complete remission. Design and Methods Between 2003–2007, 76 adults (<66 years) with relapsed acute lymphoblastic leukemia (Burkitt’s leukemia excluded) were prospectively reported to The Swedish Adult Acute Leukemia Registry and later evaluated. Results Reinduction with: (i) mitoxantrone, etoposide, and cytarabine (MEA); (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor (FLAG-Asp); and (iii) cytarabine, betamethasone, cyclophosphamide, daunorubicin, and vincristine (ABCDV) resulted in complete remission in 6/9 (67%), 10/16 (63%) and 9/21 (43%) of the patients, respectively. Allogeneic stem cell transplantation was performed during second complete remission in 29 patients. Multivariate analysis regarding overall survival after relapse revealed that age over 35 years at diagnosis and relapse within 18 months were negative prognostic factors. Overall survival rates at 3 and 5 years were 22% (95% CI: 13–32) and 15% (95% CI: 7–24). Of 19 patients less than 35 years at diagnosis who underwent allogeneic stem cell transplantation in second remission, ten (53%) are still alive at a median of 5.5 years (range, 4.2–8.3) after relapse, whereas all patients over 35 years old at diagnosis have died. Conclusions Allogeneic stem cell transplantation remains the treatment of choice for young adults with relapsed acute lymphoblastic leukemia. Both (i) mitoxantrone, etoposide, and cytarabine and (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor seem effective as reinduction treatments and should be further evaluated. New salvage strategies are needed, especially for patients over 35 years old at diagnosis.

An investigation into whether deletions in 9p reflect prognosis in adult precursor B-cell acute lymphoblastic leukemia: a multi-center study of 381 patients

The findings of this study suggest that chromosomal abnormalities involving 9p may have a significant negative impact on survival in adult B-precursor acute lymphoblastic leukemia. In acute lymphoblastic leukemia, besides age and white cell count at diagnosis, the cytogenetic abnormalities t(9;22)/BCR-ABL and t(4;11)/MLL-AF4 are important prognostic markers and are often included in the treatment stratification of patients with adult acute lymphoblastic leukemia. Deletions in 9p are seen in about 9% of cases of adult acute lymphoblastic leukemia, but their prognostic impact has been controversial. Cytogenetic data from 381 patients diagnosed with B-precursor acute lymphoblastic leukemia were reviewed. Chromosomal analysis was successful in 240 cases. Of these cases, 18 (8%) had abnormalities in 9p and they were compared with patients with normal karyotypes and patients with t(9;22)/BCR-ABL. Patients with abnormalities of chromosome 9 showed significantly shorter overall survival compared with patients with normal karyotypes. In fact, overall survival was similar to that in the poor prognosis t(9;22)/BCR-ABL-positive group. Our data suggest that chromosomal abnormalities involving 9p may have a significant negative impact on survival in adult B-precursor acute lymphoblastic leukemia.

Erythrocytosis in children and adolescents-classification, characterization, and consensus recommendations for the diagnostic approach.

During recent years, the increasing knowledge of genetic and physiological changes in polycythemia vera (PV) and of different types of congenital erythrocytosis has led to fundamental changes in recommendations for the diagnostic approach to patients with erythrocytosis. Although widely accepted for adult patients this approach may not be appropriate with regard to children and adolescents affected by erythrocytosis. The “congenital erythrocytosis” working group established within the framework of the MPN&MPNr‐EuroNet (COST action BM0902) addressed this question in a consensus finding process and developed a specific algorithm for the diagnosis of erythrocytosis in childhood and adolescence which is presented here. Pediatr Blood Cancer 2013;60:1734–1738.

High relapse rate of T cell acute lymphoblastic leukemia in adults treated with Hyper-CVAD chemotherapy in Sweden

Hyper‐CVAD is widely used to treat acute lymphoblastic leukemia (ALL) and aggressive lymphomas. This multicenter, population‐based study assessed the efficacy of Hyper‐CVAD as first‐line therapy in patients with T‐cell ALL (T‐ALL).

Differences in CD14 and α-naphthyl acetate esterase positivity and relation to prognosis in AML

Alpha-naphthyl acetate esterase (ANAE) and CD14 expression, used for determination of monocytic cells, were compared and related to prognosis in 65 AML patients. Bone marrow aspiration material fro ...

X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: comparisons with primary myelofibrosis.

X‐linked thrombocytopenia with thalassemia (XLTT) is caused by the mutation 216R > Q in exon 4 of the GATA1 gene. Male hemizygous patients display macrothrombocytopenia, splenomegaly, and a β‐thalassemia trait. We describe two XLTT families where three males were initially misdiagnosed as having primary myelofibrosis (PMF) and all five investigated males showed mild‐moderate bone marrow (BM) reticulin fibrosis. Comparative investigations were performed on blood samples and BM biopsies from males with XLTT, PMF patients and healthy controls. Like PMF, XLTT presented with high BM microvessel density, low GATA1 protein levels in megakaryocytes, and elevated blood CD34+ cell counts. But unlike PMF, the BM microvessel pericyte coverage was low in XLTT, and no collagen fibrosis was found. Further, as evaluated by immunohistochemistry, expressions of the growth factors VEGF, AGGF1, and CTGF were low in XLTT megakaryocytes and microvessels but high in PMF. Thus, although the reticulin fibrosis in XLTT might simulate PMF, opposing stromal and megakaryocyte features may facilitate differential diagnosis. Additional comparisons between these disorders may increase the understanding of mechanisms behind BM fibrosis in relation to pathological megakaryopoiesis. Am. J. Hematol. 90:E44–E48, 2015.

Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden

Older/elderly patients with acute lymphoblastic leukemia (ALL) are poorly represented in clinical trials.

Real-world data on first relapse of acute lymphoblastic leukemia in patients >55 years

Emma Bergfelt Lennmyr , Piotr Kozlowski , Lucia Ahlberg, Per Bernell, Erik Hulegårdh, Antonio Santamaria Izarra, Karin Karlsson, Beata Tomaszewska-Toporska, Maria Åstr€ om and Helene Hallb€ o€ ok ; on behalf of the Swedish Adult Acute Lymphoblastic Leukemia Group, SVALL Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden; Department of Medicine, School of Medical Sciences, € Orebro University, € Orebro, Sweden; Department of Hematology, University Hospital of Link€oping, Link€oping, Sweden; Division of Hematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Department of Hematology and Coagulation, Sahlgrenska University Hospital, G€oteborg, Sweden; Department of Hematology, Cancer Center, University Hospital of Umeå, Umeå, Sweden; Department of Hematology and Oncology, Skåne University Hospital, Lund, Sweden