Peter Meeus

Further characterization of morphologically defined typical and atypical CLL: a clinical, immunophenotypic, cytogenetic and prognostic study on 390 cases

We analysed a group of 390 patients, diagnosed with chronic lymphocytic leukaemia (CLL). Cases were subclassified as morphologically typical and atypical CLL according to the criteria of the FAB proposal. Typical CLL cases were mostly diagnosed at a low‐risk stage (Binet A/Rai 0), required no immediate treatment and expected a long survival; atypical CLL cases mostly presented at a more advanced risk stage (Binet B/Rai I–II), usually required immediate treatment and their survival was shorter. Moreover, clinical staging was of prognostic significance in typical but not in atypical cases.  In typical CLL, del(11q) was the most common chromosomal abnormality (21%) whereas in atypical CLL trisomy 12 was found in about 65% of the cases documented with an abnormal karyotype. Although chromosomal abnormalities were associated with a poor survival in typical CLL, they are of no prognostic significance in atypical CLL.  Based on these data, we conclude that subtyping CLL by morphology enables the identification of two groups of cases, each characterized by a specific clinical presentation, different cytogenetic abnormalities and prognostic parameters. We speculate that these two groups may represent two related, but different, diseases with different prognostic parameters and a different survival.

Trisomy 12 is uncommon in typical chronic lymphocytic leukaemias

The incidence of trisomy 12 was studied by conventional chromosome analysis in 111 patients referred as B‐cell chronic lymphocytic leukaemia (B‐CLL). Fluorescent in situ hybridization (FISH) was also applied in 34 of those patients with either a normal karyotype or no analysable mitoses. By karyotyping, trisomy 12 was present in 11.7% (13/111), whereas additional FISH increased the incidence to 14.4% (16/111). When subdividing our cases in either typical CLL (n= 90), fulfilling the FAB classification criteria, or atypical CLL (n= 21), with one or more variations from those criteria, the incidence of +12 by metaphase analysis was 3% and 48%, respectively. Additional FISH increased the incidence to 4% and 57%. The most common aberration in atypical CLL was FMC7 positivity (n= 11), followed by CD5 negativity (n= 8), strong surface immunoglobulin staining (n= 7) and atypical morphology (n = 6). Trisomy 12 could only be demonstrated in a small proportion of neoplastic cells in all positive cases. By FISH and/or karyotyping, all available samples at diagnosis of the disease were positive.

Myelodysplastic Syndromes With Bone-marrow Fibrosis - a Myelodysplastic Disorder With Proliferative Features

SummaryWe report on 22 patients with myelodysplastic syndrome (MDS), all of whom showed striking marrow fibrosis. Variable blood counts, often with teardrop poikilocytosis and a leukoerythroblastic picture, were present at diagnosis. Visceral enlargement was detected in 17 patients with a distinct splenomegaly in seven cases. All cases demonstrated dysplasia in at least two cell lineages. No specific cytogenetic abnormality seems to characterize this group of patients. Southern blot analysis showed no breakpoint cluster region rearrangement as observed in classical chronic myeloid leukemia. Ferrokinetic studies revealed quantitatively deficient erythropoiesis in all except two cases and an abnormally high fraction of ineffective erythropoiesis in all. Splenic erythropoiesis was present in eight patients. The median survival was 18 months. At the time of this report, 12 patients had died. The causes of death were disease progression (7 patients) and infection (5 patients). One might speculate that the present series of cases represents a transition between MDS and myeloproliferative disease, thereby dysplaying characteristics of both groups of diseases.

Deletions of the long arm of chromosome 7 in myeloid disorders: loss of band 7q32 implies worst prognosis

Clinical and cytogenetic data were analysed in 54 patients with acute non‐lymphocytic leukaemias (ANLL) or MDS (myelodysplastic syndromes) and deletion of the long arm of chromosome 7 (7q−), in order to determine if there is a commonly deleted region in 7q and to establish possible correlations between karyotypic features, such as karyotype pattern, karyotype complexity, associated anomalies, and/or the type of deleted segments, and outcome of patients with these disorders.

FISH identifies different types of duplications with 12q13-15 as the commonly involved segment in B-cell lymphoproliferative malignancies characterized by partial trisomy 12

Clinical, cytogenetic, fluorescence in situ hybridization (FISH), and Southern blot data of 18 patients with different subtypes of B‐cell non‐Hodgkins lymphoma, cytogenetically characterized by partial trisomy 12, are presented. These chromosomal changes occurred predominantly in clinically progressive chronic lymphocytic leukemia, mixed cell type, and advanced‐stage follicle center cell lymphoma at the time of relapse or transformation into diffuse large cell lymphoma. Partial trisomy 12 consistently included the long arm of chromosome 12, either completely or partially, and resulted from dup(12q) or other rearrangements involving chromosome 12. The duplications were cytogenetically identified as dup(12)(q13q23), dup(12)(q13q22), or dup(12)(q13q15) in follicle center cell lymphoma or t(14;18)‐positive diffuse large cell lymphoma; dup(12)(q13q22) or dup(12)(q13q24) in chronic lymphocytic leukemia; and dup(12)(q13q21) in a case of t(14;18)‐negative diffuse large cell lymphoma. FISH, using library probes and a panel of YAC probes, mapped along the long arm of chromosome 12, confirmed the cytogenetic results in all cases analyzed except for three cases of t(14;18)‐positive follicle center lymphoma or diffuse large cell lymphoma with dup(12q). In these cases, FISH showed similar, possibly identical, duplications, which involved a region more centromeric (12q11‐21) than assumed by karyotypic analysis (12q13‐22 or 12q13‐23) and included alphoid DNA sequences, a combination hitherto unknown. In addition, commonly duplicated regions of chromosome 12 could be defined: 12q11‐21, including alphoid DNA sequences for follicle center cell lymphoma or t(14;18)‐positive diffuse large cell lymphoma, 12q13‐22 for chronic lymphocytic leukemia, and 12p13‐q15 for marginal zone cell lymphoma, all of which overlapped in 12q13‐15. Whether these regions, especially 12q13‐15, may contain genes which are important in malignant transformation or disease progression of B‐cell lymphoproliferative malignancies characterized by complete or partial trisomy 12 remains to be determined. Genes Chromosomes Cancer 20:155–166, 1997.

The kinase inhibitor TKI258 is active against the novel CUX1-FGFR1 fusion detected in a patient with T-lymphoblastic leukemia/lymphoma and t(7;8)(q22;p11)

We report a patient with T-lymphoblastic leukemia/lymphoma and a t(7;8)(q22;p11). CUX1 was identified as the fusion partner of FGFR1 by fluorescence in situ hybridization and 5′ RACE-PCR. We further investigated this novel FGFR1 fusion using the interleukin-3 (IL-3) dependent Ba/F3 cell line and demonstrated IL-3 independent cell growth of CUX1-FGFR1 expressing cells. TKI258 and PKC412 potently inhibited proliferation of CUX1-FGFR1 transformed Ba/F3 cells. This growth inhibition was shown to be mediated by inhibition of CUX1-FGFR1 kinase activity for TKI258 but not PKC412. In summary, we identified a novel CUX1-FGFR1 fusion oncogene in a patient with the 8p11 myeloproliferative syndrome and demonstrated its transforming potential in the Ba/F3 cell line. Our in vitro data support the further investigation of TKI258 for the treatment of constitutively active FGFR1 fusion proteins.

Sustained, clonal karyotype abnormalities in the Philadelphia chromosome negative cells of CML patients successfully treated with Imatinib

Sustained, clonal karyotype abnormalities in the Philadelphia chromosome negative cells of CML patients successfully treated with Imatinib

BCL3 rearrangement and t(14;19)(q32;q13) in lymphoproliferative disorders

Translocation t(14;19)(q32;q13) is a rare but recurrent abnormality in chronic lymphocytic leukemia and small cell lymphoma. It has been associated with rearrangements of the BCL3 gene, which is located at the breakpoint on chromosome 19 and is juxtaposed to the immunoglobulin heavy chain locus on chromosome 14 as a result of the translocation. This results in transcriptional up‐regulation of the BCL3 gene, which encodes a transcription coactivator, an 1‐κB protein, probably contributing to disease progression. We found, among 4,487 cytogenetic analyses of lymphoproliferative disorders, six cases with a t(14;19)(q32;q13), five of which showed the classical t(14;19)(q32;q13) and one of which showed a three‐way translocation t(7;19;14)(q21;q13;q32). The 14;19 translocation never occurred as a single abnormality; additional aberrations included trisomy 12 and several structural abnormalities. The cytogenetic examination was supplemented by molecular analysis using available probes for the BCL3 locus (pα1.4P and pα5B) in 1,150 of the 4,487 patients. Rearrangements of BCL3 involvement could only be confirmed using long‐range restriction mapping, indicating that, with the usually available BCL3 probes, rearrangements of this locus may be missed. Genes Chromosom Cancer 14:00–00 (1995).

Application of the International Prognostic Scoring System for myelodysplastic syndromes

BACKGROUND In March 1997 an international workshop introduced a new International Prognostic Scoring System (IPSS) for MDS. The goal of the present study was to apply the IPSS to a large group of MDS patients from one centre and to compare it to the FAB-classification. PATIENTS One hundred eighty-four MDS patients were included on the basis of similar criteria as used by the workshop but some of them (30) received AML-type therapy. RESULTS The IPSS separated our patients into distinctive prognostic subgroups (P = 0.0001). Median survival was respectively 6.5, 2.6, 1.3 and 0.75 years for the low-risk (22% of patients), the intermediate-1-risk (INT-1) (46%), the intermediate-2-risk (INT-2) (25%) and the high-risk group (7%). The IPSS also discriminated within each of the FAB-categories: RA patients (58 patients) were present in low-risk, INT-1-risk and INT-2-risk subgroups, RARS patients (23) were separated into low-risk and INT-1-risk subgroups. RAEB patients (53) were distributed predominantly between INT-1-risk and INT-2-risk groups, RAEB-t patients (23) between INT-2-risk and high-risk subgroups. CMML patients (27) were present in the low-risk, the INT-1-risk and the INT-2-risk group. CONCLUSIONS Our results confirm the effectiveness of the IPSS in predicting clinical outcome in MDS patients and indicate that it is an improved method compared to the FAB-classification.

Cytogenetic and molecular studies of the Philadelphia translocation in myelodysplastic syndromes:Report of two cases and review of the literature

We report two patients with a myelodysplastic syndrome and the Philadelphia (Ph) chromosome. The first patient was a 73-year-old man who was diagnosed as having a chronic myelomonocytic leukemia in combination with features suggestive of a myeloproliferative syndrome. Chromosomal analysis showed a normal karyotype in the majority of cells, mixed with metaphases containing a standard Ph translocation, t(9;22)(q34;q11), as well as a translocation between chromosome 4 and 6: t(4;6)(p15;p12). Southern blot analysis showed breakpoint cluster region rearrangement as observed in classic chronic myeloid leukemia. The second patient was a 63-year-old man with a myelodysplastic syndrome, type refractory anemia. Cytogenetic study of bone marrow cells at the time of diagnosis revealed a normal karyotype: 46,XY. The initial myelodysplastic syndrome evolved to a myeloproliferative phase with progressive leukocytosis and thrombocytosis. During the terminal phase the Ph chromosome was discovered in 100% of the examined cells. We discuss the correlation between MDS and myeloproliferative diseases, the de novo acquisition of the Ph chromosome during the course of a myelodysplastic syndrome, and review the literature.