Prognostic impact of blast cell counts in dysplastic bone marrow disorders (MDS and CMML I) with concomitant fibrosis.

In a retrospective study, 43 patients with dysplastic neoplasms of the bone marrow (myelodysplastic syndromes and myelodysplastic/myeloproliferative-overlap neoplasms) associated with marked (grades 2-3) fibrosis were examined. Histopathologic and morphologic findings as well as cytogenetic and molecular results were correlated with clinical endpoints. Multilineage dysplasia (34 of 43 patients, 79 %) and hypercellular bone marrow (64 %) were found in most patients. In ten of 35 patients, poor risk karyotypes according to the International Prognostic Scoring System (IPSS) were recorded. The JAK2 V617F mutation was detected in four of 30 patients (13 %), and the KIT D816V mutation was found in two of 30 patients (6 %). Patients were mainly treated with palliative drugs and best supportive care. After an observation time of 1-41 (median 21) months, ten of 43 patients (23 %) had developed a secondary acute leukemia. The median survival of all 43 patients was 21.4 months (range 1.8-88.2 months). Of all prognostic parameters examined, the blast cell count at diagnosis was found to be a most reliable and most predictive marker concerning survival and leukemia progression. This confirms previous studies in dysplastic bone marrow neoplasms without fibrosis.

Comorbidity as prognostic variable in MDS: comparative evaluation of the HCT-CI and CCI in a core dataset of 419 patients of the Austrian MDS Study Group.

BACKGROUND: The evaluation of comorbidity is of increasing importance in patients with hematologic disorders. PATIENTS AND METHODS: In the present study, the influence of comorbidity on survival and acute myeloid leukemia (AML) evolution was analyzed retrospectively in 419 patients with de novo myelodysplastic syndromes (MDS) (observation period: 1985-2007). The median age was 71 years (range 24-91 years). Two different scoring systems, the hematopoietic stem-cell transplantation-specific comorbidity index (HCT-CI) and the Charlson comorbidity index (CCI) were applied. RESULTS: The HCT-CI was found to be a significant prognostic factor for overall survival (OS, P < 0.05) as well as event-free survival (EFS, P < 0.05) in our patients, whereas the CCI was of prognostic significance for OS (P < 0.05), but not for EFS. For AML-free survival, neither the HCT-CI nor the CCI were of predictive value. A multivariate analysis including age, lactate dehydrogenase, ferritin, karyotype, number of cytopenias, French-American-British groups, and comorbidity was applied. Comorbidity was found to be an independent prognostic factor in patients with low- or int-1-risk MDS (P < 0.05) regarding OS and EFS. CONCLUSIONS: Together, our data show that comorbidity is an important risk factor for OS and EFS in patients with MDS.

Prognostic impact of age and gender in 897 untreated patients with primary myelodysplastic syndromes.

BACKGROUND: The International Prognostic Scoring System (IPSS) is the golden standard to assess prognosis in myelodysplastic syndromes (MDS). The aim of this analysis was to study age and gender as interacting variables for individualized prognostication. PATIENTS AND METHODS: In all, 897 patients with primary MDS treated with supportive care only were examined in a retrospective multicenter study. A Cox model was developed to determine the prognostic impact of age and gender on survival and to examine their modulating influence on IPSS results. Based on main effects and interactions of these variables, we established an individualized age- and gender-adapted scoring system to improve prognostication in MDS. RESULTS: While the risk of a patient in the IPSS is best represented by the values 0 (low), +1 (intermediate-1), +2 (intermediate-2), and +3 (high), these values were found to vary between -1.9 and +3.5 in the same patients when including age and gender. Whereas in low-risk MDS, male patients were found to have a less favorable survival, a particularly high risk (+3.5) was found in younger (< or = 66 years) high-risk female patients. CONCLUSION: The inclusion of age and gender and their respective interactions contribute to improved and individualized prognostication in MDS.

Iron overload in myelodysplastic syndromes (MDS) - diagnosis, management, and response criteria: a proposal of the Austrian MDS platform.

Transfusion-related morbidity is an emerging challenge in chronically transfused patients with low-risk myelodysplastic syndromes (MDS). In these patients, transfusion-induced iron overload may represent a leading medical problem. However, although iron-chelating drugs are available, little is known about optimal diagnostic tools, predisposing factors, and the optimal management of these patients. In the current article, we provide recommendations for the diagnosis, prevention and treatment of iron overload in MDS and propose treatment response criteria. Consensus criteria and resulting recommendations were discussed and formulated by members of the MDS platform of the Austrian Society of Haematology and Oncology in a series of meetings and conferences in 2006 and 2007. These recommendations should facilitate and assist in recognition of iron overload, selection of patients, timing of treatment, drug selection and the measurement of treatment responses.

Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS).

The international prognostic scoring system (IPSS) is considered the gold standard for risk assessment in primary myelodysplastic syndromes (MDS). This score includes several prognostic factors except serum lactate dehydrogenase (LDH). We evaluated the prognostic power of LDH as an additional variable in IPSS-based risk assessment. For this purpose, a total of 892 patients with primary MDS registered by the Austrian-German cooperative MDS study group was analyzed retrospectively. Multivariate analysis confirmed the value of established parameters such as medullary blasts, karyotype and peripheral cell counts and showed that elevated LDH was associated with decreased overall survival (P<0.00005) and increased risk of AML development (P<0.00005), independent of the system used to classify MDS (FAB or WHO). Moreover, elevated LDH was found to be a significant predictor of poor survival within each IPSS risk group and within each FAB group except RAEB-T. To exploit these results for refined prognostication, each IPSS risk group was split into two separate categories (A=normal LDH vs B=elevated LDH). Using this LDH-assisted approach, it was possible to identify MDS patients with unfavorable prognosis within the low and intermediate IPSS risk groups. We propose that the IPSS+LDH score should improve clinical decision-making and facilitate proper risk stratification in clinical trials.

Detection of circulating mammary carcinoma cells in the peripheral blood of breast cancer patients via a nested reverse transcriptase polymerase chain reaction assay for mammaglobin mRNA.

PURPOSE: According to current medical research, mammaglobin (hMAM) is expressed exclusively in the mammary glands of adult women and in mammary tumor cell lines. Therefore, we examined hMAM expression as a marker for the detection of carcinoma cells in the peripheral blood of patients with breast cancer (BC). PATIENTS AND METHODS: Blood samples obtained from 114 BC patients at the various stages of their disease and from 68 individuals without BC were screened for hMAM mRNA by a nested reverse transcriptase polymerase chain reaction (RT-PCR) assay. RESULTS: The assay exhibited a calculated analytical limit of one tumor cell per 10(6) to 10(7) WBCs. None of the samples from peripheral blood of 27 healthy individuals were positive, whereas 29 (25%) of 114 samples from BC patients were positive for hMAM mRNA. hMAM mRNA expression was detected in five (28%) of 18 BC patients at diagnosis, in three (6%) of 53 with no evidence of disease, and in 21 (49%) of 43 with metastatic disease. These results correlate with patients' carcinoembryonic antigen (CEA) plasma level and, to some extent, with estrogen receptor status. Two of 41 samples from patients with malignancies other than BC were also positive. CONCLUSION: In contrast to healthy volunteers, hMAM transcripts were detected in the peripheral blood of BC patients. The percentage of positivity relates to the clinical stages of disease, CEA plasma level, and estrogen receptor status. Aberrant hMAM expression might occur occasionally in malignancies other than BC. The clinical relevance of hMAM RT-PCR-based tumor cell detection in the peripheral blood of BC patients should be further evaluated in prospective studies.

FMS hemizygosity in myeloid dysplasia and acute myeloid leukemia with chromosomal aberration del(5)(q) demonstrated by polymerase chain reaction.

Interstitial deletions of the long arm of chromosome 5 del(5)(q), are recurring aberrations in the myelodysplastic syndrome and acute myeloid leukemia. Several genes located in region (5)(q23-34) have been implicated as being of pathogenic importance. In this study seven samples of six patients with myelodysplastic syndrome and acute myeloid leukemia who have the del(5)(q) aberration were analyzed by polymerase chain reaction (PCR) and Southern blot technique. FMS hemizygosity was demonstrated in all patients. PCR analysis from peripheral blood samples confirmed the observations of this aberration found by semiquantitative Southern blot. PCR-based analysis can be used for primary diagnosis in addition to cytogenetic evaluation and for follow-up in patients with del(5)(q) aberration.

Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM).

A risk-adapted treatment strategy is mandatory for myelodysplastic syndromes (MDS). We refined the World Health Organization (WHO)-classification-based Prognostic Scoring System (WPSS) by determining the impact of the newer clinical and cytogenetic features, and we compared its prognostic power to that of the revised International Prognostic Scoring System (IPSS-R). A population of 5326 untreated MDS was considered. We analyzed single WPSS parameters and confirmed that the WHO classification and severe anemia provide important prognostic information in MDS. A strong correlation was found between the WPSS including the new cytogenetic risk stratification and WPSS adopting original criteria. We then compared WPSS with the IPSS-R prognostic system. A highly significant correlation was found between the WPSS and IPSS-R risk classifications. Discrepancies did occur among lower-risk patients in whom the number of dysplastic hematopoietic lineages as assessed by morphology did not reflect the severity of peripheral blood cytopenias and/or increased marrow blast count. Moreover, severe anemia has higher prognostic weight in the WPSS versus IPSS-R model. Overall, both systems well represent the prognostic risk of MDS patients defined by WHO morphologic criteria. This study provides relevant in formation for the implementation of risk-adapted strategies in MDS.

Efficacy and toxicity of 2-Chlorodeoxyadenosine (Cladribine)--2 h infusion for 5 days--as first-line treatment for advanced low grade non-Hodgkin's lymphoma.

2-Chlorodeoxyadenosine (Cladribine) is a new purine analogue with high activity in pretreated low grade non-Hodgkin's lymphoma (NHL). To evaluate the efficacy of this drug in untreated patients with advanced NHL, we performed a prospective multicentre trial. Cladribine (0.12 mg/kg) was administered intravenously daily for 5 consecutive days in an out-patient setting. The treatment was repeated every 28 days for four cycles. Included were patients with a histological diagnosis of low grade NHL according to the Kiel classification and stage III or IV disease. Stage II patients were included when radiotherapy had failed. 55 patients were entered into the study. 50 patients were evaluable. The remission rate was 44/50 (88%; 95% confidence interval 82-100%), including complete remissions (CR) in 14 (28%) patients. Only 2 patients showed progression while on Cladribine treatment. The estimated overall survival, and time to treatment failure (TTF) were 85% and 51%, respectively, after a median observation time of 92 weeks. 11 (22%) patients showed grade 3 or 4 toxicity according to the WHO grading. Haematological toxicity was responsible for 86% of the overall toxicity and 100% of grade 3 and 4 toxicity. 7 patients (14%) had an infection, two of which were opportunistic. 12 (24%) patients did not experience any toxicity during the treatment. The results of this study clearly demonstrate the safety and considerable activity of this regimen. Cladribine is very effective even at lower doses than have been used so far.

Statistical validation of the mammaglobin-nested RT-PCR assay for tumor cell detection in blood of breast cancer patients.

A stochastic model was developed to validate the results obtained with the mammaglobin-nested RT-PCR assay for tumor cell detection in peripheral blood of breast cancer patients. Since the assay consists of four PCR setups per peripheral blood sample, the probabilities for receiving 0, 1, 2, 3, or 4 positive setups were calculated. In this model, samples with just 500 mammaglobin mRNA molecules are highly probable to result in at least three positive setups, whereas lower quantities shift the probabilities towards one or two positive setups. In the clinical trial, samples with one or two mammaglobin positive setups were detected in 6/143 (4%) patients with benign lesions of the breast, in 41/310 (13%) breast cancer patients with no evidence of disease and in 39/157 (25%) breast cancer patients with metastatic disease. On the contrary, no sample from patients with benign lesions of the breast resulted in three or four positive setups, but 5/310 (2%) breast cancer patients with no evidence of disease and 46/157 (29%) with metastatic disease. These results correspond with the model: an increased number of tumor cells in peripheral blood lead to a higher amount of mammaglobin mRNA molecules, and these samples may result in at least three positive setups. Samples with three orfour positive setups were mainly derived from breast cancer patients with metastatic disease and only occasionally from patients with no evidence of disease. On account of these results, samples with at least three positive setups are of prognostic value and regarded as tumor cell positive.

A randomized study comparing interferon (IFN alpha) plus low-dose cytarabine and interferon plus hydroxyurea (HU) in early chronic-phase chronic myeloid leukemia (CML).

This multicenter randomized phase III study was designed to compare the efficacy and toxicity of IFN alpha-2c (3.5 MU/d) in combination with either araC (10 mg/m(2) d1-10) or hydroxyurea (HU: 25 mg/kg per day) in newly diagnosed CML patients. A total of 114 patients were randomized. Following a median observation period of 36 (range 1-73) months the major cytogenetic response rates were 25 and 27% and the 4-year survival probabilities 62.5 and 63% for the araC and HU group, respectively. While the overall toxicity profile was comparable between both groups, patients in the HU arm exhibited a slightly higher degree of WHO grades 3 and 4 non-hematological toxicities.

Allogeneic bone marrow transplantation for acute leukaemia--IGCI experience. International Group for Chemo-Immunotherapy.

From October 1984 to December 1994, 142 patients from six IGCI-BMT centers (78 acute myelogenous leukemia and 64 acute lymphoblastic leukemia) received allogeneic bone marrow from their HLA-identical sibling. The probability of LFS at 60 months is 41% for AML patients and 39% for ALL patients. A better LFS was documented in patients allografted in first CR compared to the patients treated in advanced stage of the disease. The overall relapse rate is 27% for AML patients and 45% for ALL patients. The relapse rate is higher for patients allografted in advanced stage of the disease (47 vs 26% at 60 months for AML and 55 vs 38% at 60 months for ALL). The incidence of moderate to severe acute GVHD is between 45-50% for both AML and ALL patients. Chronic GVHD was documented in 30% of AML patients and 38% of ALL patients. Transplant-related mortality for both AML and ALL is about 25%. Relapse and GVHD with or without infection are the main causes of death. These results confirmed that allogeneic BMT is very effective therapy for patients with acute leukemia, especially for patients transplanted in first CR.

Is trisomy 22 in acute myeloid leukemia a primary abnormality or only a secondary change associated with inversion 16?

In an attempt to confirm the existence of acute myeloid leukemia (AML) with trisomy 22, we studied three patients in whom trisomy 22 imposed as the sole karyotype abnormality. After revision of the karyotypes, however, we were able to identify an inv(16) as the important primary abnormality in all of them. Based on this experience, we investigated whether at least some of the 17 AML cases with trisomy 22 reported so far might possibly have been misinterpreted. Interestingly, ten out of 16 evaluable cases were classified as M4, some of them with bone marrow eosinophilia. As in cases with inv(16), only few metaphases contained trisomy 22. Furthermore, in at least two out of the only four published karyotypes of cases with trisomy 22, an inv(16) is evident and in the other two cases it cannot be ruled out. We therefore believe that at least some of the trisomy 22 cases mentioned in the literature are in fact only secondary changes occurring in AML with an inv(16) and suggest that future reports of AML with trisomy 22 as a specific primary abnormality can only be accepted as such if inv(16) has been excluded with appropriate methods.

Dose escalation of ara-c may improve response rates in a subgroup of chronic myeloid leukemia patients with poor response to interferon-alpha and low-dose ara-C.

The present analysis was performed to evaluate the impact of cytosine arabinoside (ara-C) dose escalation on hematological and cytogenetic responses in patients with chronic myelogenous leukemia (CML) who failed to respond to low-dose ara-C (LD ara-C) at a dose of 10 mg/m2/d over 10 days per month and interferon-alpha (IFNalpha, 3.5 MU/d). Following the same administration schedule, dose escalation of ara-C to 15 and 20 mg/m2/d 1-10 was performed in 36 of 119 patients (30%) due to inadequate hematological response and/or disease progression. As a result, improvement of hematological and cytogenetic responses was achieved in 22 (61%) and nine (25%) patients, respectively. Escalated ara-C dose levels were usually well tolerated, although some patients experienced deterioration of preexisting side effects. Our results support the critical role of ara-C dose towards a better disease control in CML.

[The clinical significance of the Philadelphia chromosome in acute leukaemia (author's transl)]. / Klinische Bedeutung eines Philadelphia-Chromosoms bei akuter Leukämie.

So-called "Philadelphia-positive acute leukaemias" require varied therapeutic management. Additional chromosome anomalies together with Ph1 indicate an acute transformation of a Philadelphia-positive disease, requiring "non-myelotoxic" treatment and new therapeutic approaches. By contrast, "de novo" acute leukaemias with a Ph1-positive karyotype should be treated with intensive chemotherapy for the induction and maintainance of remission.

[Specific chromosome aberrations in 3 patients with Burkitt-like leukemia (Fab: L3)]. / Spezifische Chromosomenaberrationen bei 3 Patienten mit "Burkitt-ähnlicher" Leukämie (FAB: L3).

Karyotype analysis using the Tri-staining-technique (Chromomycin A3/Distamycin A/DAPI) and subsequent DAPI/AMD staining (Schweizer, 1981) was performed on the bone marrow and peripheral blood of three patients with "Burkitt-like" acute lymphatic leukaemia (FAB: L3). In two patients we found the specific translocation t(8;22). One patient displayed in addition a structural abnormality of chromosome 9, visualized with C-banding using the DA/DAPI stain, and in two patients we found specific abnormalities of chromosome 1. Several patterns of the abnormal chromosome 1 revealed an intercalated DA/DAPI positive C-band in the elongated long arm.

[Prognostic factors in myelodysplastic syndromes: analysis of 72 cases]. / Prognostische Faktoren bei myelodysplastischen syndromen (MDS): eine Analyse von 72 Fällen.

72 patients were diagnosed as suffering from myelodysplastic syndromes (MDS) according to the FAB classification: 16 patients with refractory anaemia (RA), 11 patients with acquired idiopathic sideroblastic anaemia (AISA), 14 patients with refractory anaemia with an excess of blast cells (RAEB), 7 patients with RAEB in transformation (RAEB/t) and 24 patients with chronic myelomonocytic leukaemia (CMML). The duration of the preleukaemic phase was between 2 and 189 months (median: 15 months); RAEB in transformation and CMML showed a median phase of less than 12 months. Transformation into acute leukaemia (AL) occurred in 46 patients (64%). Of the clinical signs only thrombocytopenia was a significant poor prognostic factor (p less than 0.01). Cytogenetic studies were made in 31 patients. 14 had clonal aneuploidy: these patients had a higher risk of AL, but not a significantly shorter preleukaemic phase (p greater than 0.1). Stem cell cultures (CFUc) were carried out in 31 patients. Patients without colony growth or only cluster growth showed a high incidence (10/11 and 8/8) of transformation into AL; preleukaemic phases were significantly shorter than in patients with normal colony growth or cluster + colony growth in all FAB subgroups (p less than 0.001). The bone marrow blast cell count was indirectly proportional to the duration of the preleukaemic phase: thrombocytopenia, cytogenic aberrations and failure of in vitro colony growth are additional poor prognostic factors in MDS.

[Clinical effects of high-dose immunoglobulin therapy in adults with idiopathic thrombocytopenic purpura]. / Klinische Effekte hochdosierter Immunglobulintherapie bei Erwachsenen mit idiopathischer thrombozytopenischer Purpura (ITP).

15 patients suffering from idiopathic thrombocytopenic purpura were treated in our department with high-dosage immunoglobulins. The daily dosage amounted to between 0.13 and 0.4 g/kg body weight, administered for 4 to 15 days consecutively. The platelet count in 10 patients increased within the first week of treatment, but this increase was maintained for more than 4 weeks in only 3 patients. The average age of these 10 patients amounted to 41.2 years and was significantly lower than that of the remaining 5 patients (66.6 years), who failed to respond. Only one of 4 splenectomized patients responded with an increase in platelet count. Two different immunoglobulin preparations were used. No difference in efficacy was found and both preparations were well tolerated.

Monosomal karyotype in MDS: explaining the poor prognosis?

Monosomal karyotype (MK) is associated with an adverse prognosis in patients in acute myeloid leukemia (AML). This study analyzes the prognostic impact of MK in a cohort of primary, untreated patients with myelodysplastic syndromes (MDS). A total of 431 patients were extracted from an international database. To analyze whether MK is an independent prognostic marker in MDS, cytogenetic and clinical data were explored in uni- and multivariate models regarding overall survival (OS) as well as AML-free survival. In all, 204/431 (47.3%) patients with MK were identified. Regarding OS, MK was prognostically significant in patients with ≤ 4 abnormalities only. In highly complex karyotypes (≥ 5 abnormalities), MK did not separate prognostic subgroups (median OS 4.9 months in MK+ vs 5.6 months in patients without MK, P=0.832). Based on the number of abnormalities, MK-positive karyotypes (MK+) split into different prognostic subgroups (MK+ and 2 abnormalities: OS 13.4 months, MK+ and 3 abnormalities: 8.0 months, MK+ and 4 abnormalities: 7.9 months and MK+ and ≥ 5 abnormalities: 4.9 months; P<0.01). In multivariate analyses, MK was not an independent prognostic factor. Our data support the hypothesis that a high number of complex abnormalities, associated with an instable clone, define the subgroup with the worst prognosis in MDS, independent of MK.