Timing of acquisition of deletion 13 in plasma cell dyscrasias is dependent on genetic context

Background

Multiple myeloma, monoclonal gammopathy of undetermined significance and smoldering multiple myeloma harbor common chromosomal abnormalities but the prevalence and relative association of aberrations in these diagnostic groups remains controversial. We investigated these aspects in a large series of patients.

Design and Methods

Chromosome 13 deletion (Δ13), deletion of TP53, ploidy status and immunoglobulin heavy chain (IgH) translocations were evaluated by fluorescence in situ hybridization in patients with monoclonal gammopathy of undetermined significance (n=189), smoldering multiple myeloma (n=127) and multiple myeloma (n=400).

Results

Overall, Δ13 (25%, 34% and 47%), 16q23 deletions (6%, 8% and 21%) and 17p13 deletions (3%, 1% and 10%) were less frequent in patients with monoclonal gammopathy of undetermined significance and smoldering multiple myeloma than in those with multiple myeloma. When distinct genetic groups were considered, no differences in the prevalence of Δ13 were found with t(4;14)(p16;q32) and t(14;16)(q32;q23) among the three diagnostic groups; in contrast Δ13 was rarer in t(11;14)(q13;q32) in patients with monoclonal gammopathy (1/28) and smoldering myeloma (2/13) than in those with multiple myeloma (40%). Similar results were seen for the few t(6;14)(p21;q32) cases: 0/3 patients with monoclonal gammopathy or smoldering myeloma had the Δ13, whereas 4/6 (67%) patients with multiple myeloma and this translocation also had the deletion. In multiple myeloma patients with both an IgH translocation and Δ13, the proportions of cells affected by the two abnormalities were similar, as was the case for t(4;14) and t(14;16) monoclonal gammopathy patients positive for Δ13. In contrast, in monoclonal gammopathy patients with t(14;20)(q32;q11), the translocation was present in almost all cells, while the Δ13 was present in only a sub-population.

Conclusions

These results indicate that the presence and time of occurrence of Δ13 depends on the presence of specific concurrent abnormalities. The observation that Δ13 was extremely rare in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma with translocations directly involving cyclin D genes (CCND1 and CCND3) suggest a possible role of Δ13 in the progression of the disease specifically in these genetic sub-groups. (clinicaltrials.gov identifier: ISRCTN 68454111; UKCRN ID 1176).     

Chromosome aberrations in a series of 120 multiple myeloma cases with abnormal karyotypes

We identified 120 multiple myeloma (MM) cases with satisfactory cytogenetic evaluation and abnormal karyotypes. Hyperdiploid karyotype was found in 77 cases (64%), hypodiploid in 30 cases (25%), and the remaining 13 cases (11%) had a pseudodiploid karyotype. The most common numerical abnormalities were gains of chromosomes 15, 9, 3 followed by chromosomes 19, 11, 7, 21, and 5. Whole chromosome losses were also frequent involving primarily chromosomes X/Y, 8, 13, 14, and 22. Most cases showed also structural rearrangements leading to del(1p), dup(1q), del(5q), del(6q), del(8p), del(9p), del(13q), and del(17p). Chromosome 13/13q deletion was found in 52% of cases; complete loss of 13 was observed in 73% of cases, whereas 27% had interstitial deletions. In addition, 13/13q deletions occurred in 75% of nonhyperdiploid myeloma but only 39% of the hyperdiploid had 13/13q deletions. Translocations affecting 14q32/IGH region was seen 40 cases; t(11;14)(q13;q32) in 17 cases, t(14;16)(q32;q23) and t(8;14)(q24;q32) in three cases each, and t(6;14)(p21;q32) and t(1;14)(q21;q32) in two cases each. The remaining 14q32 translocations had various t(V;14) partners or of an undetermined origin. Remarkably, the 14q32/IGH translocations were less frequent in the hyperdiploid karyotypes than the nonhyperdiploid karyotypes (17 vs. 63%). Fourteen cases showed break at 8q24/CMYC site; seven of those had Burkitt's-type translocations. Our results revealed that conventional cytogenetics remains an important tool in elucidating the complex and divers genetic anomalies of MM. Cytogenetics identifies two distinct groups of MM, hyperdiploid and nonhyperdiploid, and establishes the presence of prognostic chromosomal markers such as 13/13q, 17p, 8q24, and 16q aberrations.     

Relationship of patient survival and chromosome anomalies detected in metaphase and/or interphase cells at diagnosis of myeloma

The clinical efficacy of evaluating genetic anomalies in metaphase cells versus interphase nuclei for multiple myeloma (MM) is poorly understood. Therefore, survival for 154 patients with newly diagnosed untreated MM was compared with results from analysis of metaphase and interphase cells. Metaphases were studied by conventional cytogenetics and fluorescent-labeled DNA probes (fluorescence in situ hybridization [FISH]), whereas inter-phase nuclei were evaluated only by FISH. All FISH studies were done using DNA probes to detect t(4;14)(p16;q32), t(11;14)(q13;q32), t(14;16)(q32;q23), del(17) (p13.1), and chromosome 13 anomalies. Metaphases were abnormal by cytogenetics and/or metaphase FISH in 61 (40%) patients. Abnormal interphase nuclei were observed in 133 (86%) patients, including each patient with abnormal metaphases. FISH was a necessary adjunct to cytogenetics to detect t(4;14) and t(14;16) in metaphase cells. Patient survival was especially poor for patients with greater than 50% abnormal interphase nuclei, although this result was more likely due to level of plasma cells than specific chromosome anomalies. For metaphase data, patients with t(4;14), t(14;16), del(17) (p13.1), and/or chromosome 13 anomalies (primarily monosomy 13) had poor survival. A different outcome was observed for interphase data as patients with t(4;14) or t(14;16) had poor survival, whereas patients with chromosome 13 anomalies had intermediate survival: interphase FISH did not substitute for metaphase analysis.     

Nonrandom chromosomal rearrangements of 14q32.3 and 19p13.3 and preferential deletion of 1p in 21 patients with multiple myeloma and plasma cell leukemia

Structural chromosomal abnormalities and their break-points were characterized in 17 patients with multiple myeloma (MM) and 4 with plasma cell leukemia by banding. Chromosome 14q32 translocations with a variety of partners were detected in 13 patients, and a variant translocation t(8;22)(q24.1;q11) was detected in 1. Three recurrent 14q32 translocations have been identified: t(6;14)(p21.1;q32.3) occurring in 3 cases, and t(11;14)(q13;q32.3) and t(14;18) (q32.3;q21.3) each occurring in 2 cases. Translocations t(1;14)(q21;q32.3), t(3;14)(p11;q32),t(7;14)(q11.2;q32.3), and t(11;14)(q23;q32.3) were found in each patient, whereas in the remaining 2 patients, partner chromosomes could not be determined. The band 19p13.3 was newly delineated as a recurrent breakpoint involved in translocations in MM. Chromosomes 1 and 6 were also commonly involved in structural abnormalities (14 and 10 patients, respectively), although no particular bands were noted. However, the short arm of chromosome 1 was preferentially involved in deletion, suggesting a certain antioncogene on 1p associated with the development of myeloma. In addition; fluorescence in situ hybridization was successfully applied to determine the nature of the structural abnormalities in a patient with t(8;22) translocation. The present findings suggest that there may be subsets of 14q32 translocations specific to MM.     

Interphase Fluorescence In Situ Hybridization Detection of Cytogenetic Abnormalities in B-Cell Chronic Lymphocytic Leukemia

The most frequent chromosomal abnormalities in B-cell chronic lymphocytic leukemia (B-CLL) are deletions on 13q14 and 17p13, trisomy 12, and 14q32 rearrangement. Conventional cytogenetic analysis underestimates the frequency of specific chromosome aberrations in B-CLL because of the low rate of spontaneous mitoses and the poor response to mitogen stimulation. We used interphase fluorescence in situ hybridization (I-FISH) to explore the incidence of chromosomal changes in the peripheral blood cells of B-CLL patients. Probes for 13q14 (D13S319), 17p13 (p53), the centromere of chromosome 12 (CEP12), and 14q32 (IGHC/IGHV) were applied to detect chromosomal aberrations in peripheral blood samples from 83 B-CLL patients (60 men, 23 women). Molecular cytogenetic aberrations were found in 61 cases (73.5%), and 8 patients (9.6%) showed 2 kinds of abnormalities. The most frequent abnormality was deletion of 13q14 (41.0%), followed by +12 (19.3%), deletion of 17p13 (12%), and 14q32 rearrangement (9.6%). FISH results were analyzed for correlation with Binet stages. The percentages of patients who showed abnormalities by FISH were 73.0%, 73.3%, and 80% for Binet stages A, B, and C, respectively, and the percentages of patients with abnormalities who showed 2 anomalies were 7.9%, 27.3%, and 0% for Binet stages A, B, and C, respectively. We noted no consistent pattern among the various Binet stages in the distribution of either the types of FISH-detected anomalies or the numbers of FISH anomalies. I-FISH was found to be a rapid, exact, and sensitive technique for analysis of chromosome aberrations in CLL. FISH could provide accurate information regarding the molecular cytogenetic features of CLL.     

Splenic marginal zone B-cell lymphomas: two cytogenetic subtypes, one with gain of 3q and the other with loss of 7q

BACKGROUND AND OBJECTIVES: Splenic marginal zone B-cell lymphoma (SMZBCL) has clinical, immunophenotypic and histologic features distinct from other B-cell malignancies, but few chromosome studies have been previously reported. In the present study we performed conventional cytogenetics and in situ hybridization studies in 47 patients with SMZBCL. DESIGN AND METHODS: We studied 47 cases of splenic marginal zone B-cell lymphoma combining conventional cytogenetics and in situ hybridization (ISH) techniques using centromeric probes (chromosomes 3 and 12), locus specific probes (7q31 and 17p13) and cross-species color banding fluorescent ISH probes (RxFISH). The diagnosis of SMZBCL was ascertained in all cases after studying, morphologically and immunologically, peripheral blood and splenectomy specimens. RESULTS: A clonal chromosome abnormality detected by conventional cytogenetics and/or FISH was found in 33/47 patients (70%) being identified in 18 (18/33, 55%) as a complex abnormality. The most frequently recurrent abnormalities were: gain of 3q (10 cases), del(7q) (12 cases), and involvement of chromosomes 1, 8 and 14. No patient showed translocation t(11;14) (q13;q32) or t(14;18) (q21;q32). Trisomy 3 was detected in eight cases (8/47, 17%). Two novel cytogenetic abnormalities involving 14q32, t(6;14)(p12;q32) and t(10;14) (q24;q32) were reported. Deletion of 17p13 (P53) was observed by FISH in one case. Only one patient showed a gain of 3q or trisomy 3 and deletion 7q in the same karyotype. INTERPRETATION AND CONCLUSIONS: Our findings support the interpretation that two forms of SMZBCL could be considered, one with gain of 3q and the other with deletions at 7q.     

Abnormalities of chromosome 1p/q are highly associated with chromosome 13/13q deletions and are an adverse prognostic factor for the outcome of high-dose chemotherapy in patients with multiple myeloma

The prognostic value of chromosomal abnormalities was studied in untreated multiple myeloma patients who were registered into a prospective randomised multicentre phase 3 study for intensified treatment (HOVON24). A total of 453 patients aged less than 66 years with stage II and III A/B disease were registered in the clinical study. Cytogenetic analysis was introduced as a standard diagnostic assay in 1998. It was performed at diagnosis in 160 patients and was successful in 137/160 patients (86%). An abnormal karyotype was observed in 53/137 (39%) of the patients. Abnormalities of chromosome 1p and 1q were found in 19 (36% of patients with an abnormal karyotype) and 21 patients (40%). There was a strong association between chromosome 1p and/or 1q abnormalities and deletion of chromosome 13 or 13q (n = 27, P < 0.001). Patients with karyotypic abnormalities had a significantly shorter overall survival (OS) than patients with normal karyotypes. Complex abnormalities, hypodiploidy, chromosome 1p abnormalities, chromosome 1q abnormalities, and chromosome 13 abnormalities were associated with inferior OS on univariate analysis, as well as after adjustment for other prognostic factors. In conclusion, chromosome 13 abnormalities and chromosome 1p and/or 1q abnormalities were highly associated, and are risk factors for poor outcome after intensive therapy in multiple myeloma.     

Comparison of chromosome analysis and BCL-1 rearrangement in a series of patients with multiple myeloma

Translocation (11;14)(q13;q32) is a recurring chromosome abnormality which is found non-randomly in non-Hodgkin's lymphoma, especially of follicular type, as well as in B-cell chronic lymphocytic leukaemia, Waldenström's macroglobulinaemia and multiple myeloma. To define further the prevalence of this abnormality in multiple myeloma, we studied a series of 17 patients with this disease with concomitant chromosome analysis and Southern blotting, using a probe specific for the major translocation cluster of the BCL-1 oncogene which is located at chromosome Hq13. Karyotype analysis of 14 evaluable patients revealed three cases with abnormalities of chromosome 11q13, two of them with t(11;14)(q13:q32) and one with del (11)(q13). Southern blot analysis showed no rearrangements in BclI and HindIII digests of DNA from 17 patients including the three patients with anomaly of chromosome 11q13, using a BCL-1 specific probe. A possible restriction length polymorphism was detected in EcoRI cut DNA of five out of 11 patients studied. Therefore the chromosomal break point in our cases with abnormality of chromosome 11q13 must lie outside the major translocation cluster of the BCL-1 gene. However, in centrocytic lymphoma rearrangement of the BCL-1 oncogene has been detected in up to 50% of cases. Location of the break point may therefore be dependent on the differentiation of the transformed B-cell.     

Chromosome 13 abnormalities in multiple myeloma are mostly monosomy 13

Chromosome 13 abnormalities are frequently observed in multiple myeloma (MM). Several reports recently demonstrated the strong prognostic value of these abnormalities, associated with a short survival. Cytogenetic studies have shown that most of these abnormalities are complete monosomies. In order to define the common minimal deletion, we analysed a series of 234 patients with MM using fluorescence in situ hybridization (FISH) with a panel of five probes mapping along the whole chromosome 13. A chromosome 13 abnormality was observed in 98 patients (42%), 90 of whom (92%) displayed a complete monosomy. In seven of the eight remaining patients presenting partial deletions, the three probes specific for the 13q14 region were deleted. Only one patient (1%) displayed a small deletion of the D13S319 locus. In conclusion, FISH should be used for the analysis of chromosome 13 abnormalities, using probes mapping in the 13q14 region.     

Multiple myeloma with deletion of chromosome 13q is characterized by increased bone marrow neovascularization

Anti-angiogenesis therapy with thalidomide has been reported to have marked activity in multiple myeloma (MM). As cytogenetics is an independent prognostic factor in MM, we analysed bone marrow (BM) angiogenesis and cytogenetic abnormalities in 34 patients with active MM. BM microvessel density (MVD), as determined by staining with anti-CD34, was significantly higher in MM (MVD: 221 +/- 94 per mm2) than in controls (80 +/- 36; P < 0.0001). In patients with the presence of at least one unfavourable cytogenetic abnormality (deletion of 13q14, deletion of 17p13, aberrations of 11q), a significantly increased BM MVD was observed (254 +/- 93 vs. 160 +/- 60 in patients with absence of these abnormalities; P = 0.0035). Further analyses indicated that increased BM MVD was significantly correlated with deletion of 13q14 (259 +/- 96 vs. 188 +/- 80; P = 0. 026), but not with other cytogenetic, clinical and laboratory MM parameters. We conclude that BM neovascularization is particularly high in MM with deletion of 13q14, which provides a rationale for use of anti-angiogenic strategies in the treatment of MM with high-risk cytogenetics.     

Monosomy 13 in metaphase spreads is a predictor of poor long-term outcome after bortezomib plus dexamethasone treatment for relapsed/refractory multiple myeloma

We retrospectively investigated the prognostic impact of high-risk cytogenetic abnormalities (CAs) on the outcome of treatment with bortezomib plus dexamethasone (BD) in 43 relapsed/refractory (Rel/Ref) multiple myeloma patients. Fluorescence in situ hybridization (FISH) analysis identified del(13q) in 25 patients, t(4;14) in 14, t(14;16) in 4, 1q21 abnormality in 12 and del(17p) in 2, while G-banding also detected chromosome 13 monosomy (-13) in metaphase spreads from 7 patients. Eighteen of 25 patients with FISH-detected chromosome 13 abnormalities also exhibited other abnormalities. Median observation period was 510 days, and median overall survival (OS) and progression-free survival (PFS) were 912 days and 162 days, respectively. Detection of del(13q), t(4;14), t(14;16) or 1q21 abnormalities by FISH and co-occurrence of chromosome 13 abnormality with other abnormalities were not associated with poorer outcomes. In contrast, detection of -13 by G-banding in metaphase spreads showed significant association with shorter OS, although the overall response rate and PFS were not inferior to those for patients without -13 detected by G-banding. BD therapy may be a potent weapon for overcoming most classical high-risk CAs, while the detection of -13 in metaphase spreads may serve as a predictor of highly progressive disease, even when treated with BD.     

Fluorescent in situ hybridization studies in multiple myeloma

Abstract

Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) results of bone marrow samples of 36 multiple myeloma (MM) patients at the time of diagnosis have been evaluated. Three probes for chromosome 13q (RB1, D13S319, D13S25), one for 14q32 (IgH) and one for 17p13 (p53) have been used for hybridization with fixed cells. Twenty patients (55·5%) had normal karyotypes, whereas eight (22·2%) had numerical or structural chromosomal abnormalities. We did not find metaphases for chromosome analysis in eight (22·2%) patients. Fluorescence in situ hybridization analyses revealed at least one or more abnormal results in 25 (69·5%) cases, whereas 11(30·5%) cases had no abnormal findings. 14q32 rearrangement was the most common finding in FISH analyses and has been detected in 21 cases (58·3%). 13q deletion and 17p deletion have been detected in 11 (30·5%) and 5 (13·9%) cases, respectively. Fluorescence in situ hybridization studies including 14q32 and 17p13 chromosome regions may yield quite significant results during clinical follow-up of MM.     

Frequency and prognostic value of chromosome abnormalities in multiple myeloma

Chromosomal aberrations have been shown to significantly affect survival in multiple myeloma (MM), but few cytogenetic analyses among Japanese MM patients have been reported. Using a commercial laboratory, we performed interphase fluorescent in situ hybridization (FISH), as well as a conventional metaphase cytogenetic study (G-banding), among 106 of 131 patients between April 1997 and February 2007. Karyotype abnormalities were found in 21.2% (21 of 99 patients). Del(13q), del(17p), del(11q), t(11;14) and t(4;14) were detected by FISH in 36.0% (31/86), 24.7% (19/77), 7.6% (5/64), 18.2% (12/66) and 10.4% (7/67) of patients, respectively. The prevalence of abnormalities detected by G-banding was lower than that reported in European countries, but when compared with FISH studies, no difference was observed. Prognostic analyses of patients with these abnormal chromosomes revealed that those with abnormal karyotype and del(13q), t(4;14), as detected by FISH, had significantly poorer survival. This study suggests that the prevalence of chromosome abnormalities among Japanese patients is similar to that for European populations, and that chromosome studies by G-banding and FISH are essential to predict survival.     

21例多发性骨髓瘤分子遗传学异常的FISH检测的意义

目的：为探讨间期荧光原位杂交（FISH）在检测多发性骨髓瘤（MM）间期细胞13q14缺失、1q21、p53缺失以及免疫球蛋白重链（IgH）基因重排中的意义。方法：采用组合探针（1q21/RB1、D13S319/p53、IgH）对21例MM患者骨髓进行FISH检测,分析其分子遗传学异常,比较其与常规染色体检查及临床指标的相关性。结果：21例MM患者中,19例（90.48%）检测出1种或1种以上的细胞遗传学异常,15例（71.43%）同时检测出2种及以上的异常。其异常比例从高到低分别为：＋1异常（66.67%）,IgH基因重排（57.14%）,13号染色体缺失（47.62%）和p53基因丢失（23.81%）。3例（14.29%）通过G-显带常规染色体检查发现异常,与FISH比较两者差异有统计学意义（P〈0.01）。结论：＋1、IgH基因重排及13q14缺失在MM中的发生率较高。FISH技术能提高MM分子遗传学异常的敏感性。     

Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2

A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum β(2)-microglobulin level and International Staging System stages II and III, incorporating high β(2)-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.     

Value of comparative genomic hybridization and fluorescence in situ hybridization for molecular diagnostics in multiple myeloma

Chromosomal abnormalities, such as 13q deletions, are emerging as important prognostic factors in multiple myeloma. Fluorescence in situ hybridization (FISH) using specific DNA probes is the technique most widely used for the determination of genomic aberrations in this disease. The utility of comparative genomic hybridization (CGH) for molecular diagnostics in plasma cell malignancies has not been systematically analysed. We investigated tumour samples of patients with multiple myeloma (n = 43) or plasma cell leukaemia (n = 3) using CGH and FISH with five DNA probes localized to chromosome bands 1p22, 6q21, 11q22-q23, 13q14 and 17p13. By CGH, the most frequent genomic changes were gains on chromosomes 1q, 9q and 11q, as well as losses on chromosomes 13q, 6q, Xp and Xq. By FISH, trisomy 11q was identified at a similar frequency to the 13q deletion (42%). Compared with FISH data, the sensitivity of CGH was 80.7% and the specificity was 97.5%. Thirty-two aberrations found by FISH were not identified by CGH, mostly as a result of the proportion of cells carrying the respective aberrations, or because of the limited spatial resolution of CGH. Our data indicate that, for clinical molecular diagnostics in multiple myeloma, FISH with a disease-specific DNA probe set is superior to CGH analysis.     

Molecular cytogenetic aberrations in 21 Chinese patients with plasma cell leukemia

Plasma cell leukemia (PCL) is a rare malignant plasma cell disorder. Cytogenetic studies performed on plasma cell disorders are scarce and difficult because of the low proliferation rate of plasma cells (PCs). Fluorescence in situ hybridization (FISH) analysis is an attractive alternative for evaluation of chromosomal changes in PCL. To explore the molecular cytogenetic abnormalities in Chinese patients with PCL, interphase FISH studies with three probes for the regions containing 13q14.3 (D13S319), 14q32 (IGHC/IGHV) and 1q12(CEP1) were retrospectively performed in 21 PCL patients. FISH with LSI IGH/CCND1 and LSI IGH/FGFR3 probes were used to detect t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with 14q32 rearrangement. Among 21 PCL patients, molecular cytogenetic aberrations were found in 18 (81.8%) patients, four (19.0%) patients simultaneously had 13q14 deletion, illegitimate IgH translocation and 1q abnormality. 13q14 deletion was detected in 13 (61.9%) cases and illegitimate 14q32 rearrangement in 16 (76.2%) including six with t(11;14) and three with t(4;14). Chromosome 1 abnormality was found in seven (33.3%) patients, one with deletion of 1q, six with at least three copies amplifications of 1q12 (Amp1q12). 14q32 rearrangement and 13q14 deletion were found concurrently in 11 (52.4%) cases. It was showed that most PCL had chromosomal abnormalities, 14q32 rearrangement, 13q14 deletion and chromosome 1 abnormality are the frequent abnormalities, and over half of the 14q32 rearrangement were t(11;14) or t(4;14). t(4;14) and 13q14 deletion were correlated in PCL. FISH is a highly sensitive technique at detecting molecular cytogenetic aberrations in PCL and should be used in the routine evaluation of PCL.     

Cytogenetic and molecular cytogenetic characterization of 6 new cases of idiopathic hypereosinophilic syndrome

BACKGROUND AND OBJECTIVE: Idiopathic hypereosinophilic syndrome (HES) is defined as a peripheral blood eosiniphilia greater than 1, 500 cells/microL for longer than 6 months, absence of other apparent etiologies for eosinophilia and signs and symptoms of organ involvement. HES may be a reactive condition or a chronic myeloproliferative disorder but scanty information is available concerning its cytogenetic profile. DESIGN AND METHODS: Six patients with HES were studied by cytogenetic analysis. To increase the sensitivity of cytogenetic analysis, interphase FISH studies were performed to detect some cryptic chromosomal lesions involving the regions known to be frequently involved in myeloproliferative disorders (i.e. BCR/ABL, 5q31, 7q31.1, 11q23, 13q14, 17p13). Clinical parameters were recorded in all patients. RESULTS: A 3q deletion was detected in one patient; two unrelated clones with +14 and +11 were present in another patient who had a cryptic 5q31 deletion as disclosed by FISH; both patients had a mild clinical course. The 5q31 deletion was shown to involve the eosinophilic lineage and not the lymphoid cells. No chromosome abnormalities were found by karyotyping or interphase FISH in the remaining 4 cases. In two of these cases the clinical course was aggressive, with progressive leukocytosis and marked splenomegaly in one patient, central nervous system and cardiac involvement as well as bone marrow failure in the other. INTERPRETATION AND CONCLUSIONS: The 3q deletion, +11 and +14, and a cryptic 5q31 deletion involving the cells of the eosinophilic lineage are three novel chromosome abnormalities occurring in HES. We did not find a correlation between evolving or aggressive disease and the presence of chromosome anomalies. Our data confirm that HES is a clinically and biologically heterogeneous condition and suggest that more cases need to be studied to identify clinically significant chromosome changes in this rare condition. Some patients may benefit from treatment with interferon.     

The clinical significance of cytogenetic studies in 100 patients with multiple myeloma, plasma cell leukemia, or amyloidosis

Chromosome studies were done on 82 patients with multiple myeloma, 11 with amyloidosis, 2 with multiple myeloma and amyloidosis, and 5 with plasma cell leukemia to investigate their chromosomal abnormalities and to determine the usefulness of cytogenetic studies. A chromosomally abnormal clone was found in 29 patients but was observed most often in those with active disease: in 18% of patients with newly diagnosed multiple myeloma, in 63% with aggressive disease, and in 40% with plasma cell leukemia. Survival among the newly diagnosed patients was significantly shorter (P = .0089) for those in whom an abnormal clone was identified (median survival, six months) than for those in whom only normal metaphases were observed (median survival, greater than 12 months). Among all of the patients, survival from the time of chromosome analysis was shorter for those in whom a chromosomally abnormal clone was found: the median survival was three months for patients with all abnormal metaphases and eight months for patients with normal and abnormal metaphases and has not yet been reached for patients with only normal metaphases. The most common anomalous chromosomes in patients with a plasma cell proliferative disorder were 1, 11, and 14: 11 patients had an abnormality involving chromosome 14q32 and nine patients had an anomalous chromosome 11. The single most common abnormality, a t(11;14)(q13;q32), occurred in three patients. Among the patients who developed preleukemia or acute nonlymphocytic leukemia, the most common anomaly involved chromosome 7. The results suggest that cytogenetic studies are useful for identifying patients who have a poor prognosis and can help distinguish patients with a cytopenia because of preleukemia from those with an aggressive plasma cell proliferative process.