Hans Josef Weh

Results of chromosome studies and their relation to morphology, course, and prognosis in 120 patients with de novo myelodysplastic syndrome

Cytogenetic studies were performed in 120 patients with de novo myelodysplastic syndrome (MDS) classified according to FAB criteria. Twenty-eight patients had refractory anemia (RA), 14 had refractory anemia with ring sideroblasts (RARS), 45 had refractory anemia with blast excess (RAEB), 19 had refractory anemia with blast excess in transformation (RAEB-t), and 14 had chronic myelomonocytic leukemia (CMMoL). Fifty patients (42%) had clonal chromosome anomalies at initial analysis. The most common cytogenetic anomalies were: 5q- (11 patients), trisomy 8 (nine patients), -7/7q- (6 patients), 12p- (five patients), followed by structural anomalies of chromosome 17 (four patients), and loss of Y chromosome (three patients). The prognostic value of chromosome anomalies was examined by comparison of the significance of single chromosome anomalies (34 patients) versus multiple cytogenetic changes (16 patients). Patients with multiple anomalies had a shorter survival (8 months) than patients with single anomalies (18 months) or those with a normal karyotype (36 months). All these differences were significant. The incidence of multiple anomalies was higher in patients with RAEB and RAEB-t than in those with RA, RARS, and CMMOL (p less than 0.05). However, no chromosome anomaly was specifically associated with any group of FAB classification. Transformation to acute leukemia was observed in 25% of patients with normal karyotype, 41% of patients with single anomalies, and 50% of patients with multiple changes. The incidence of leukemic transformation was significantly higher in patients with multiple anomalies than in those with a normal karyotype (p less than 0.05). Thus, in the present study, FAB classification and chromosome anomalies were of independent prognostic significance. Sequential cytogenetic studies were performed in 23 patients to correlate the cytogenetic and clinical findings during the course of the disease. Six of seven patients with transformation to acute leukemia showed a karyotypic evolution. These findings agree with the view that an unstable karyotype can be associated with a poor prognosis.

Karyotype in multiple myeloma and plasma cell leukaemia

Between October 1988 and October 1991, 104 patients with multiple myeloma and 6 with plasma cell leukaemia were studied cytogenetically. Abnormal karyotypes were found in bone marrow cells of 33 patients (30%). Most pathological karyotypes were complex with numerous modal and structural anomalies. Numerical anomalies most frequently involved chromosome 11 and structural aberrations occurred most often in chromosomes 1, 11 and 14. The most consistent structural aberration was a 14q+ chromosome (10 patients) resulting from a t(11;14)(q13;q32) in 4 patients and a t(8;14)(q24;q32) in 1 patient. Sequential cytogenetic studies were performed in 15 patients. In 5 of 8 cases with a normal karyotype at diagnosis, chromosomal anomalies were detected when disease progressed. In concomitant cytogenetic/cytological studies it was found that in the majority of patients with normal karyotype the mitoses originated from contaminating normal bone marrow cells. Pathological karyotypes were detected more frequently in pretreated than in untreated patients, in patients with plasma cell leukaemia than in patients with multiple myeloma, in patients with stage III and dense bone marrow infiltration than in patients with stage I. Patients with abnormal karyotype, irrespective if pretreated or not, had a significantly shorter median survival than those with normal karyotype. These findings suggest that karyotype is an independent prognostic factor in multiple myeloma.

Cytogenetic studies in 69 patients with myelodysplastic syndromes (MDS)

Cytogenetic studies were performed in 69 patients with myelodysplastic syndromes classified according to the FAB proposals. Overall incidence of chromosomal anomalies was 48% with 5q‐, +8, 12p‐,‐7/7q‐ being the aberrations most often found. The 12p‐ chomosome showed a close correlation with a prior exposure to mutagenic agents and CMML. Although there were no group‐specific cytogenetic anomalies, FAB classification strongly influenced their incidence. They were lower (36%) in RA/RA‐S than in RAEB/RAEB‐T/CMML (53%). Chromosomal anomalies were significantly more often found in patients with a prior exposure to carcinogenic agents (80%) than in unexposed patients (33%). The presence of chromosomal anomalies did not predict a higher risk of leukemic transformation.

Prognostic significance of chromosome analysis in de novo acute myeloid leukemia (AML)

Since the first report by Sakurai and Sand-berg [1] in 1973, indicating a better prognosis for patients with a normal karyotype (NN) or a mixture of normal and abnormal mitoses (AN) than for patients with only abnormal mitoses (AA), several other large cytogenetic studies [2–4] have confirmed these prognostic findings in patients with de novo acute myeloid leukemia (AML). But there are also some reports denying such a prognostic value of the chromosomal status NN, AN, AA [5–7] and in more recent studies [8–10] the prognostic value of the types of chromosomal aberrations rather than the NN-AN-AA classification has been emphasized.

Cytogenetics in multiple myeloma and plasma cell leukemia: simultaneous cytogenetic and cytologic studies in 51 patients

SummaryCytogenetic studies in patients with multiple myeloma (MM) and plasma cell leukemia (PCL) have in general been largely unsuccessful. The investigation of mitoses of nonmalignant hematopoietic precursor cells, rather than mitoses of malignant plasma cells might account for the low percentage of pathological genetic findings. We investigated bone marrow (BM) cells of 51 patients both cytogenetically and cytologically. In patients with a normal karyotype (n=39) nearly all mitoses examined cytologically (107/117) derived from granulopoietic or erythropoietic cell lineages. In contrast, 20/27 metaphases in patients with a pathological karyotype (n=12) were found to be plasma cell mitoses. These findings may explain the low rate of chromosomal rearrangements in MM and may suggest that the real abnormality rate is considerably higher.

Low-dose cytosine-arabinoside in the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)

SummaryTen AML- and two MDS-patients in whom conventional chemotherapy was contraindicated or ineffective were treated with low dose ARA-C, 10 mg/m2 per 12hs.c. for 2–4 weeks. Seven patients obtained a complete and two a partial remission. Our findings suggest that low dose ARA-C may act both by induction of differentiation and/or inhibition of proliferation.

Is trisomy 11 another nonrandom chromosomal anomaly in acute nonlymphocytic leukemia and myelodysplastic syndromes

Four cases with trisomy 11 as the sole chromosomal anomaly are reported, three with de novo acute nonlymphocytic leukemia (ANLL) and one with a myelodysplastic syndrome (MDS) after treatment for multiple myeloma. In reviewing the literature, we found 19 additional cases with trisomy 11 as the sole cytogenetic defect. All patients except one were reported to have ANLL or MDS. Thus, it seems that trisomy 11 is another rare but nonrandom chromosomal anomaly in ANLL and MDS. So far, no apparently characteristic clinical or cytologic signs have been found in these cases.

Cytogenetic studies in malignant fibrous histiocytoma

Among soft tissue sarcomas, malignant fibrous histiocytoma is considered to be the most commonly encountered tumor-type of late adult life. Cytogenetic data are, however, sparse and contradictory, without any specific anomalies. We are describing the results of cytogenetic studies in 20 malignant fibrous histiocytomas of various subtypes and gradings. Although we saw two single and therefore possibly primary rearrangements, t(13;14) and t(5;7), most tumors had complex rearrangements without sharing any characteristic aberrations. In our opinion, the heterogeneity of these findings supports the concept that malignant fibrous histiocytoma is not a distinctive entity but merely a name for a group of as yet poorly defined sarcomas.

Trisomy 8 preceding diagnosis of acute nonlymphocytic leukemia by 2 years in a patient with multiple myeloma without cytological evidence of myelodysplasia

A case of acute nonlymphocytic leukemia (ANLL) occurring 2 years after the diagnosis of multiple myeloma (MM) that had been treated by only one course of melphalan/prednisone chemotherapy is reported. Cytogenetic and fluorescence in situ hybridization analysis of peripheral blood cells revealed trisomy 8 as the sole cytogenetic defect at the time of diagnosis of ANLL. Two years earlier, when MM was diagnosed without any cytological evidence of co-existent myelodysplasia, chromosomal analysis of bone marrow cells showed the same pathological karyotype 47, XY, +8 in 14 of 20 mitoses studied. Our interpretation of this unusual cytogenetic finding is that at the time of diagnosis of MM, in spite of lacking cytological signs of myelodysplasia, an unrecognizable myelodysplastic syndrome must have been present which then evolved to ANLL.

Phase II trial of 5-fluorouracil and recombinant interferon alfa-2B in metastatic colorectal carcinoma

Between February 1990 and April 1991, 59 previously untreated patients with progressive and/or symptomatic metastatic colorectal carcinoma were enrolled in a phase II study of 5-fluorouracil (5-FU) and interferon alfa-2b (IFN-alpha). 5-FU 750 mg/m2/day was administered as continuous infusion for 5 days, then weekly in a dose of 750 mg/m2 as intravenous push injection starting on day 15. IFN-alpha 9 MU was given subcutaneously three times a week. Treatment was given for a maximum of 6 months. 55 patients are evaluable for response and 51 for toxicity. 17 patients (31%) achieved a partial remission, 15 (27%) had stable disease and 21 patients (38%) had progressive disease. Median duration of remission was 5 months and median survival for all patients 10 months. Toxicity was important with two treatment-related deaths and severe leukopenia, fever, diarrhoea and mucositis in about one third of the patients. In our opinion, this regimen is effective but rather toxic in metastatic colorectal carcinoma.