Catherine M. Flynn

Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups

Background Bone marrow has been shown to be superior to peripheral blood, as a stem cell source, in young patients (<20 years of age) with acquired aplastic anemia undergoing a matched sibling transplant. The aim of this study was to test whether this currently also holds true for older patients with acquired aplastic anemia. Design and Methods We analyzed 1886 patients with acquired aplastic anemia who received a first transplant from a human leukocyte antigen identical sibling between 1999 and 2009, with either bone marrow (n=1163) or peripheral blood (n=723) as the source of stem cells. Results In multivariate Cox analysis negative predictors for survival were: patient’s age over 20 years (RR 2.0, P<0.0001), an interval between diagnosis and transplantation of more than 114 days (RR 1.3, P=0.006), no anti-thymocyte globulin in the conditioning (RR 1.6, P=0.0001), a conditioning regimen other than cyclophosphamide (RR=1.3, P=0.008) and the use of peripheral blood as the source of stem cells (RR 1.6, P<0.00001). The survival advantage for recipients of bone marrow rather than peripheral blood was statistically significant in patients aged 1–19 years (90% versus 76% P<0.00001) as well as in patients aged over 20 years (74% versus 64%, P=0.001). The advantage for recipients of bone marrow over peripheral blood was maintained above the age of 50 years (69% versus 39%, P=0.01). Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants. Major causes of death were graft-versus-host disease (2% versus 6% in bone marrow and peripheral blood recipients, respectively), infections (6% versus 13%), and graft rejection (1.5% versus 2.5%). Conclusions This study shows that bone marrow should be the preferred stem cell source for matched sibling transplants in acquired aplastic anemia, in patients of all age groups.

Bone marrow versus peripheral blood sibling transplants in acquired aplastic anemia: survival advantage for marrow in all age groups

Background Bone marrow has been shown to be superior to peripheral blood, as a stem cell source, in young patients (<20 years of age) with acquired aplastic anemia undergoing a matched sibling transplant. The aim of this study was to test whether this currently also holds true for older patients with acquired aplastic anemia. Design and Methods We analyzed 1886 patients with acquired aplastic anemia who received a first transplant from a human leukocyte antigen identical sibling between 1999 and 2009, with either bone marrow (n=1163) or peripheral blood (n=723) as the source of stem cells. Results In multivariate Cox analysis negative predictors for survival were: patient’s age over 20 years (RR 2.0, P<0.0001), an interval between diagnosis and transplantation of more than 114 days (RR 1.3, P=0.006), no anti-thymocyte globulin in the conditioning (RR 1.6, P=0.0001), a conditioning regimen other than cyclophosphamide (RR=1.3, P=0.008) and the use of peripheral blood as the source of stem cells (RR 1.6, P<0.00001). The survival advantage for recipients of bone marrow rather than peripheral blood was statistically significant in patients aged 1–19 years (90% versus 76% P<0.00001) as well as in patients aged over 20 years (74% versus 64%, P=0.001). The advantage for recipients of bone marrow over peripheral blood was maintained above the age of 50 years (69% versus 39%, P=0.01). Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants. Major causes of death were graft-versus-host disease (2% versus 6% in bone marrow and peripheral blood recipients, respectively), infections (6% versus 13%), and graft rejection (1.5% versus 2.5%). Conclusions This study shows that bone marrow should be the preferred stem cell source for matched sibling transplants in acquired aplastic anemia, in patients of all age groups.

Large granular lymphocyte leukemia: natural history and response to treatment

Large granular lymphocyte leukemia (T-LGL) is an indolent T lymphoproliferative disorder that was difficult to diagnose with certainty until clonality testing of the T cell receptor gene became routinely available. We studied the natural history and response to treatment in 25 consecutive patients with T-LGL diagnosed between 2004 and 2008 in which the diagnosis was confirmed by molecular analysis, to define an effective treatment algorithm. The median age at diagnosis was 61 years (range 27–78), with a male to female ratio of 1:1.8 and presenting features of fatigue (n = 13), recurrent infections (n = 9), and/or abnormal blood counts (n = 5). Thirteen patients with symptomatic disease were treated as follows: pentostatin (nine patients), cyclosporine (six patients), methotrexate (three patients), and alemtuzumab in two patients in whom pentostatin was ineffective. Pentostatin was the single most effective therapy, with a response rate of 75% and minimal toxicity. The overall survival (OS) and progression-free survival (PFS) 37 months from diagnosis were 80% and 52%, respectively. Treatment of T-LGL should be reserved for patients with symptomatic disease, but in this series, pentostatin treatment was less toxic and more effective than cyclosporine or methotrexate.

Correlation of the BRAF V600E mutation in hairy cell leukaemia with morphology, cytochemistry and immunophenotype

Hairy cell leukaemia (HCL) has distinct clinical, morphological and immunophenotypic features with no recurrent cytogenetic or molecular abnormalities reported until the recent description of the BRAF V600E mutation in patients with classical HCL. The incidence of this mutation was sought in 27 patients with either classical HCL or HCL variant by an allele‐specific PCR approach and findings related to morphology, cytochemistry and immunophenotype. A high degree of correlation was noted between the presence of BRAF V600E and established diagnostic criteria in 26/27 patients with HCL/HCL variant. Detection of the BRAF V600E mutation is therefore a useful adjunct in the differential diagnosis of HCL and HCL variant and highlights the value of a multifaceted approach to the diagnosis of this malignancy.

Incidence and significance of FLT3-ITD and NPM1 mutations in patients with normal karyotype acute myeloid leukaemia.

BackgroundAcute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic progenitor cells. Approximately half of all adult AML patients have a normal karyotype (NK-AML) and an intermediate risk prognosis.AimsTo determine the incidence and prognostic significance of NPM1 and FLT3-ITD mutations in a population of patients with NK-AML.MethodsFLT3-ITD and NPM1 mutation status was retrospectively sought in presentation samples from 44 NK-AML patients.ResultsFLT3-ITD and NPM1 mutations were detected in 45.5 and 54.5% of patients, respectively, allowing stratification according to genotype.ConclusionsFLT3-ITD and NPM1 mutation status can be defined in NK-AML. Prospective screening for these mutations is advocated in all NK-AML patients, as the genotype is of clinical importance when considering treatment options including stem cell transplantation.

Myelodysplastic Syndrome/Acute Myeloid Leukemia Arising in Idiopathic Erythrocytosis

The term “idiopathic erythrocytosis (IE)” is applied to those cases where a causal clinical or pathological event cannot be elucidated and likely reflects a spectrum of underlying medical and molecular abnormalities. The clinical course of a patient with IE is described manifesting as a persistent erythrocytosis with a low serum erythropoietin level, mild eosinophilia, and with evidence of a thrombotic event. The patient subsequently developed a myelodysplasic syndrome (MDS) and acute myeloid leukemia (AML), an event not observed in erythrocytosis patients other than those with polycythemia vera (PV). Application of a next-generation sequencing (NGS) approach targeted for myeloid malignancies confirmed wild-type JAK2 exons 12–15 and identified a common SH2B3 W262R single-nucleotide polymorphism associated with the development of hematological features of myeloproliferative neoplasms (MPNs). Further NGS analysis detected a CBL L380P mutated clone expanding in parallel with the development of MDS and subsequent AML. Despite the absence of JAK2, MPL exon 10, or CALR exon 9 mutations, a similarity with the disease course of PV/MPN was evident. A clonal link between the erythrocytosis and AML could be neither confirmed nor excluded. Future molecular identification of the mechanisms underlying IE is likely to provide a more refined therapeutic approach.

CALR mutation profile in Irish patients with myeloproliferative neoplasms

Insertion and/or deletion mutations of the CALR gene have recently been demonstrated to be the second most common driver mutations in the myeloproliferative neoplasms (MPNs) of essential thrombocythemia (ET) and primary myelofibrosis (PMF). Given the diagnostic and emerging prognostic significance of these mutations, in addition to the geographical heterogeneity reported, the incidence of CALR mutations was determined in an Irish cohort of patients with MPNs with a view to incorporate this analysis into a prospective screening program. A series of 202 patients with known or suspected ET and PMF were screened for the presence of CALR mutations. CALR mutations were detected in 58 patients. Type 1 and Type 1-like deletion mutations were the most common (n=40) followed by Type 2 and Type 2-like insertion mutations (n=17). The CALR mutation profile in Irish ET and PMF patients appears similar to that in other European populations. Establishment of this mutational profile allows the introduction of a rational, molecular diagnostic algorithm in cases of suspected ET and PMF that will improve clinical management.

A single-centre analysis of 30 patients with relapsed germ cell tumours treated with the TI-CE regimen

A single-centre analysis of 30 patients with relapsed germ cell tumours treated with the TI-CE regimen