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.     

A chromosomal profile of polycythemia vera

One hundred four patients with a diagnosis of polycythemia vera and a variable period of follow-up had one or more cytogenetic investigations. Chromosome abnormalities were found in 13% of untreated patients, in 56% of cases treated with radioactive phosphorus (32P) or cytotoxic drugs, and in 85% of patients in which transformation of the disease had occurred. Nonrandom chromosome abnormalities found before treatment included +8, +9, 13q-, 20q-; their prognostic value is little, as they are often associated with longstanding, stable disease. In contrast, 5q- anomaly and the appearance of subclones in patients with an abnormal karyotype were found to be poor prognostic signs, as they are usually coincidental with evolution of the disease to myelofibrosis or leukemia. Chromosomally two patterns of acute leukemia were observed in polycythemia vera patients. The first type resembles de novo acute leukemia, in that the clinical and cytologic characteristics of the disorder are easily defined by FAB criteria and the chromosome changes compatible with the types usually found in those conditions. In the second type, assignment to a FAB morphologic subgroup was more difficult, myelodysplastic changes were often present, and the karyotype showed complex abnormalities frequently involving chromosomes #5 and #7. All these features suggest the occurrence of secondary leukemia.     

Correlation between soluble serum CD16 (sCD16) levels and disease stage in patients with multiple myeloma

CD16, the type III receptor for IgG, is expressed on neutrophils, natural killer cells, and some T lymphocytes, mast cells, and activated monocytes but not on cells of the B-lymphocyte lineage including plasma cells. It is also produced in a soluble form found in serum. We analyzed sera from 165 multiple-myeloma patients, 29 patients with monoclonal gammopathies of unknown significance, and 20 normal disease-free donors. We found that the level of soluble CD16 was significantly decreased in sera from patients with multiple myeloma compared to sera from healthy and monoclonal gammopathies of unknown significance donors (P=0.0001). In addition, a stage-dependent decrease in soluble CD16 was observed, with a highly significant difference (P=0.004) between stage I and stage II+III myeloma patients. The correlation between the myeloma stage and the serum level of soluble CD16, which is related to the host response, was found to be more sensitive than that of ₂-microglobulin, which reflects the tumor burden. The concomitant evaluation of the serum levels of these two markers allows better staging and therefore has a more precise prognostic value.     

MLL amplification in myeloid leukemias: A study of 14 cases with multiple copies of 11q23

We here report the clinical, cytogenetic, fluorescence in situ hybridization (FISH), and Southern blot data on 14 patients with a myeloid malignancy and structural aberration of chromosome band 11q23 associated with overrepresentation or amplification of the MLL gene. The number of copies of MLL varied from three (two cases) to a cluster consisting of multiple hybridization spots. Together with previous reports, available data indicate that amplification of 11q23/MLL is a recurrent genetic change in myeloid malignancy. It affects mainly elderly patients and is often associated with dysplastic bone marrow changes or with complex karyotypic aberrations, suggestive of genotoxic exposure. It is associated with a poor prognosis. In addition, FISH analysis of nine cases with additional 11q probes showed that the overrepresented chromosomal region is generally not restricted to MLL, and Southern blot analysis indicated that amplification does not involve a rearranged copy of this gene. The significance of MLL amplification and the mechanisms by which it could play a role in leukemogenesis and/or disease progression remain to be elucidated.     

3q−, 3q+ anomaly in malignant proliferations in humans

Anomalies of both No. 3 chromosomes, of the t(3q?; 3q+) type can be observed in human malignancy as reported previously. It is our experience that this anomaly is found predominantly in myeloproliferative disorders, as a rather rare event, though occurring more frequently than similar exchanges between other homologous chromosomes. Previous claims about a relationship between this anomaly and thrombocytosis could not be confirmed, but the features found in a few patients indicate that further research should be undertaken to clarify this point.     

CLONAL MONOSOMY 7 AND 5q IN A CHILD WITH MYELODYSPLASTIC SYNDROME

The authors report the case of a 5-year-old boy referred for thrombocytopenia and neutropenia. Bone marrow examination showed a myelodysplasia with clonal monosomy7. The acceleration of the disease was marked by the appearance of an additional cytogenetic abnormality, i.e., the deletion of the long arm of chromosome 5 in the clonal cells. RAS genemutationwas not detected. Chemotherapy was started to achieve complete remission before a bone marrow transplatation. This treatment was complicated by a prolonged a plasia and the patient died of systemic mycotic infection.     

Epstein-Barr virus-associated lymphoproliferative disease occurring in a patient with sarcoidosis treated by methotrexate and methylprednisolone

We describe the case of a 51-yr-old man with systemic sarcoidosis, complicated by the occurrence of a lymphoproliferative disease following a 36-month (duration) immunosuppressive treatment with methotrexate (MTX) and methylprednisolone. Four years after the onset of sarcoidosis, the patient presented a large necrotizing anal fistula. Pathological examination of this lesion showed a diffuse polymorphic infiltrate containing large Epstein-Barr virus (EBV)-positive lymphoid cells associated with areas of necrosis, all features similar to classical B-cell lymphoproliferative disorders occurring in immunosuppressed solid-organ recipients. MTX has been recently implicated in the development of lymphoproliferative disease in connective tissue diseases. This case supports the hypothesis that immunosuppression therapy may contribute to an increased risk for the development of EBV-associated lymphoproliferative disorders in patients suffering from sarcoidosis.     

2-Chlorodeoxyadenosine with or without daunorubicin in relapsed or refractory acute myeloid leukemia

 2-Chlorodeoxyadenosine (2-CdA) is a purine analogue which has proved to be active in acute myeloid leukemia (AML), especially in children. In adults, results yielded by 2-CdA alone or with ara-C were less encouraging. Here we report on the efficacy of 2-CdA with or without daunorubicin (DNR) in 19 relapsing or refractory adult AML patients, with a median age of 57 years. 2-CdA was administered as a continuous infusion to all patients at a dose of 0.1 mg/kg per day for 7 days. For 14 patients, DNR was added at a dose of 50 mg/m² per day on days 5, 6, and 7. Antileukemic activity was observed in all the patients, but no single complete remission was achieved. One patient had a long-lasting partial response (response rate=5%). The remaining patients died of progressive AML (n=7), uncontrollable infection with persistent disease (n=10), and cerebral hemorrhage (n=1). Median survival from start of 2-CdA therapy was 56 days. Long-lasting neutropenia and transfusion-dependent thrombopenia were encountered in all 16 evaluable patients. Grade 4 hepatic toxicity occurred in one patient. Other side effects included nausea in six, mucositis in three, and mental disturbances in three patients. Compared with 2-CdA alone, the addition of DNR to 2-CdA changed neither the response rate nor the toxicities. In conclusion, our data do not support the use of 2-CdA ± DNR for relapsing or refractory adult AML patients, at least as used in the present regimen. Received: 21 July 1997 / Accepted: 18 November 1997