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Anticipation in familial hematologic malignancies

We describe a collection of 11 families with ≥ 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P < .0002). This was confirmed in both direct parent-offspring pairs with a mean reduction of 19 years in the age at diagnosis (P = .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P = .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families.

Association between high interleukin-6 levels and adverse outcome after autologous haemopoietic stem cell transplantation.

We studied interleukin-6 (IL-6) levels on the day of transplantation in 31 patients undergoing autologous haemopoietic stem cell transplantation (SCT) (either peripheral blood stem cell transplantation (PBSCT) or bone marrow transplantation (BMT)) for neoplastic diseases to determine if there was a relationship between IL-6 level and rate of haemopoietic recovery, length of stay in hospital, and survival. There was no apparent delay in post-transplant recovery associated with elevated IL-6 levels. However, increased values of IL-6 tended to be associated with an increased length of stay in hospital (P = 0.083). There was a highly significant adverse association between higher IL-6 levels and survival following transplantation (P = 0.0001). This association remained significant (P = 0.013) in the uniform subgroup of patients with malignant lymphoma with chemosensitive disease who had undergone BMT (that is, excluding patients who had undergone PBSCT) (n = 13). Knowledge of IL-6 levels on the day of transplant has the potential to provide valuable prognostic information in patients undergoing autologous haemopoietic SCT. Bone Marrow Transplantation (2001) 28, 929–933.

Cytogenetic investigations of chronic lymphocytic leukemia

This study aimed to determine which culture method would yield the highest culture success rate, mitotic index, banding resolution, and abnormality rate in investigation of patients with chronic lymphocytic leukemia (CLL). A range of culture techniques for conventional cytogenetic (CC) analyses was compared: 24-hour unstimulated, 72 hours incubation with additional fetal calf serum, 72 hours stimulation with interleukin 4, 72 hours stimulation with lipopolysaccharide (LPS), 72 hours stimulation with TPA (12-O-tetradecanoylphorbol 13-acetate), and 72 hours stimulation with CpG-oligonucleotide DSP30 + Interleukin-2 (IL-2). CC abnormality rates were also compared to fluorescence in situ hybridization (FISH) results using probes for CLL (LSI D13S319/13q34/CEP 12: LSI ATM/p53). Forty-five samples from 24 patients (consisting of 11 newly diagnosed and 13 previously diagnosed patients) were included. For CC, a 100.0% culture success rate was achieved (n = 45) by means of an EDTA (ethylenediaminetetraacetic acid) peripheral blood sample with an associated 62.5% CC abnormality rate (n = 24). FISH detected an abnormality rate of 75.0% (n = 24). The combined CC and FISH abnormality rate was 87.5% (n = 24). This study demonstrates that CC that uses TPA and DSP30 + IL-2 on EDTA peripheral blood is effective in the investigation of CLL and may be used as a supplement to FISH studies.

Evidence for a common genetic aetiology in high‐risk families with multiple haematological malignancy subtypes

A family history of a haematological malignancy (HM) is known to be a risk factor for HMs. However, collections of large families with multiple cases of varied disease types are relatively rare. We describe a collection of 12 families with dense aggregations of multiple HM subtypes. Cases were ascertained from a population based study conducted between 1972 and 1980 in Tasmania, Australia. Diagnoses were confirmed through review and re‐examination of stored tissue, pathology reports, Tasmanian Cancer Registry and flow cytometry records. Family trees were generated and kinship coefficients were calculated for all pairs of affected individuals. 120 cases were found in these families. Cases diagnosed with chronic lymphocytic leukaemia (CLL) demonstrated the most significantly increased aggregation (P < 0·0001). There was also significant evidence that those individuals diagnosed at an older age (>53 years), did not aggregate together in families with disease that presented at an earlier age (<20 years) (P = 0·009).

A retrospective examination of mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study

Telomere length has a biological link to cancer, with excessive telomere shortening leading to genetic instability and resultant malignant transformation. Telomere length is heritable and genetic variants determining telomere length have been identified. Telomere biology has been implicated in the development of hematological malignancies (HMs), therefore, closer examination of telomere length in HMs may provide further insight into genetic etiology of disease development and support for telomere length as a prognostic factor in HMs. We retrospectively examined mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study using a quantitative PCR method on genomic DNA from peripheral blood samples. Fifty-five familial HM cases, 191 unaffected relatives of familial HM cases and 75 non-familial HM cases were compared with 758 population controls. Variance components modeling was employed to identify factors influencing variation in telomere length. Overall, HM cases had shorter mean relative telomere length (P=2.9×10−6) and this was observed across both familial and non-familial HM cases (P=2.2×10−4 and 2.2×10−5, respectively) as well as additional subgroupings of HM cases according to broad subtypes. Mean relative telomere length was also significantly heritable (62.6%; P=4.7×10−5) in the HM families in the present study. We present new evidence of significantly shorter mean relative telomere length in both familial and non-familial HM cases from the same population adding further support to the potential use of telomere length as a prognostic factor in HMs. Whether telomere shortening is the cause of or the result of HMs is yet to be determined, but as telomere length was found to be highly heritable in our HM families this suggests that genetics driving the variation in telomere length is related to HM disease risk.

The Familial Tasmanian Haematological Malignancies Study (FaTHMS) : Its origins, its history and the phenomenon of anticipation

We began epidemiological studies of haematological malignancies (lymphomas, leukaemias and related diseases) in Tasmania, the island state of Australia, in 1972. Our work has identified a number of families each containing several cases. In contrast to reports from elsewhere, we recognised familial cases incorporating the range of haematological malignancies, that is, not confined to a single diagnosis. Furthermore the average number of cases per extended family tree has exceeded that of any prior report. An unexpected discovery from the detailed familial analysis was that of anticipation, the phenomenon whereby the symptoms of a disorder become apparent at an earlier age as it is passed on to the next generation. These findings strengthen the case for there being genetic anomalies underlying the development of haematological malignancies at least in some cases, and are the subject of ongoing research.

Use of 'rainy day' autologous haemopoietic stem cells: a single-institution experience over 10 years.

High‐dose chemotherapy and autologous haematopoietic stem cell transplantation is an important therapeutic modality in the treatment of many haematological malignancies. Generally, stem cells are collected close to the time of the transplant, but an alternative is to collect and cryopreserve cells at an early stage of the illness so they are available for later use (‘rainy day harvesting’). Although this practice has been commonplace in Australia, there is little evidence to document eventual use of cells collected in this manner.

A retrospective study of absence of expression of HLA-DR in acute myeloid leukaemia

Aims: To investigate whether absence of expression of HLA-DR on myeloblasts has a predictive value in the diagnosis of acute promyelocytic leukaemia (APML) and other subtypes of acute myeloid leukaemia (AML). Background: From 2000 to 2008, 142 new cases of AML were diagnosed in Tasmania, of which 10–20% are expected to be of the APML subtype according to the Tasmania Cancer Registry. APML has one of the worst prognoses among the AML subtypes on presentation, however with rapid diagnosis and treatment it is the most curable form of AML. Methods: The immunophenotype results from the Flow Cytometry Department of the Royal Hobart Hospital (RHH) of all patients diagnosed with AML in Tasmania from 2000 to 2008 was reviewed and patients were categorised into respective French-American-British classification (FAB) AML subtypes using this data. Confirmation of true APMLs were obtained from the cytogenetics department of the RHH. Results: A total of 110 patients were diagnosed with AML based upon flow cytometry results. There were nine suspected with APML, of which four were confirmed to be APML by cytogenetics. HLA-DR expression was negative on 18 patients, of which only one was an APML. In fact nine (50%) were classified as M2. Conclusions: Preliminary results suggest that absence of expression of HLA-DR does not correlate with a diagnosis of APML; rather it may suggest a diagnosis of AML with maturation (M2).

NEUT-X – A useful predictor for film review in undiagnosed myelodysplastic syndrome

Aim: This retrospective study was to assess whether there is a predictive relationship between the Sysmex XE5000 NEUT-X research parameter and the myeloid lineage dysplasia. Methods: The study period was 14 February to 31 March 2012. The target group consisted of initial patient full blood count with a NEUT-X ⩽1299 and one or more of the following; MCV >96 fL, absolute neutrophils (Neut#) <1.5×109/L, haemoglobin (Hb) <100 g/L or platelet count (Plt) <100 × 109/L. The control group consisted of two match controls for each target patient. A manual neutrophil differential was performed (under oil, ×1000) to determine the percentage of hypogranular neutrophils present. Correlation between the NEUT-X value and microscopically defined hypogranularity of the neutrophils was assessed by simple linear regression. Sensitivity and specificity values were assessed by the use of receiver operating characteristic (ROC) curve analysis. Results: 43 patients had a low NEUT-X value. The area under the ROC curve was 0.863 (95% confidence interval 0.802–0.911) demonstrating that NEUT-X has diagnostic utility irrespective of presence of hypogranular neutrophils. Conclusions: The inclusion of the NEUT-X parameter into film review selection criteria in combination with an alert to the morphologist to perform, if required, a manual neutrophil differential (under oil) to determine the presence of hypogranular neutrophils should aid in the earlier detection of MDS.

Use of ‘rainy day’ haematopoietic stem cells over 10 years

Aim: High dose therapy and autologous haematopoietic stem cell (AHSC) transplantation is an important treatment for many haematological malignancies. AHSCs can be harvested during remission or consolidation treatment for subsequent transplantation if required (‘rainy day’ collection). Although the practice is widespread, evidence base is minimal. We investigated the eventual transplantation of ‘rainy day’ collections, delay to transplantation and patient outcomes. Methods: This was a retrospective audit of practice between 1/1/2001 and 31/12/2010. ‘Rainy day’ harvest was defined as collection of AHSCs where transplantation was not anticipated in the next 6 months. Results: 532 collections were performed in 474 patients for haematological indications. 342 (71%) patients had rainy day AHSCs collected. Disease indications included non-Hodgkin lymphoma (NHL; n = 205, 60%), multiple myeloma (MM; 45, 13%), Hodgkin lymphoma (HL; 38, 11%), acute myeloid leukaemia (AML; 20, 6%), chronic myelogenous leukaemia (CML; 5, 1%), acute lymphoblastic leukaemia (ALL; 6, 2%), other myeloproliferative neoplasms (21, 6%), chronic lymphocytic leukaemia (CLL; 3, 1%). Overall transplantation rate was 14%. For MM collections 27% were transplanted, compared to 16% for HL and 14% for NHL. Only 5% of collections for AML were transplanted and there were no transplants for CML. The median delay to transplantation was 18 months (range 6.3–112); 81% of patients transplanted engrafted within specified limits. Of the 296 patients who had ‘rainy day’ AHSC collections that have not been transplanted, 255 (85%) are still alive Discussion: ‘Rainy day’ AHSC collection is resource intensive. We found high rates of eventual usage for certain indications (MM, HL) and low rates for others (AML, CML). Findings from this study may help to inform guidelines for ‘rainy day’ AHSC collection.