Cytogenetic Abnormalities In Patients Research Articles

Treatment of myelodysplastic syndromes in elderly patients

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal neoplasms with the median age at diagnosis being in the seventh decade. If left untreated, the disease progresses to acute myeloblastic leukemia (AML). There are many options for the management of MDS, but the only potentially curative treatment is allogenic hematopoietic stem cell transplantation (allo-HSCT), which is often not an option because of advanced age or comorbidities at diagnosis or lack of a human leukocyte antigen-identical donor. MDS in the elderly should be managed similar to that in young patients, but the fact that many advanced age patients cannot undergo allo-HSCT precludes any chance of cure. Despite the main objective of prolonging overall survival and the time to progression to AML, the key is to improve quality of life for the longest possible time. To achieve these objectives, supportive care is essential. Likewise, immunomodulatory drugs, such as lenalidomide, can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients with MDS with chromosome 5q deletion. Elderly patients with high-risk MDS can benefit from 5-azacitidine (5-AZA), with efficacy and safety profiles comparable with those found in patients under 75 years of age. In any patient, predictive drug response scores are required in order to ensure more rational use of these medications.

Gene methylation and cytogenetic abnormalities in patients (pts) with higher-risk myelodysplastic syndromes.

6606 Background: Inactivation of tumor-suppressor genes by DNA hypermethylation of CpG islands in gene promoter regions occurs frequently in MDS. We explored the relationship between methylation in...

Cytogenetics and Clinical Outcomes of Plasma Cell Leukemia Patients: A Single Institution Experience.

Abstract 4932 IntroductionPlasma cell leukemia (PCL) is a rare, poorly understood and clinically aggressive plasma cell dyscrasia that can originate from multiple myeloma (sPCL) or de novo as primary PCL (pPCL). Historically, median survival of patients with PCL has been reported to be 1 and 11 months for patients with secondary and primary PCL, respectively (Tiedemann, Leukemia 2008). The impact of novel agents and transplantation strategies on outcomes of patients with PCL remains unclear. In addition, few have reported extensively on the cytogenetics abnormalities seen in patients with PCL especially with respect to outcomes with novel therapies (proteasome inhibitor or immunomodulator). Accordingly, we thought to evaluate the clinical, cytogenetic features and outcomes of patients with PCL treated at H. Lee Moffitt Cancer Center in the era of novel agents and transplant strategies. Materials and MethodsRetrospective review of records of patients with PCL diagnosed after 2003. The diagnosis of PCL was according to the IMWG criteria (specifically peripheral blood plasma cells ≥ 20% or 2 ×109/L). Clinical data reviewed included basic demographic, laboratory, pathologic, treatment and outcomes variables. Cytogenetics was reviewed by metaphases and FISH. Overall survival was defined as the time from diagnosis of PCL to death or last follow-up. Response criteria was according to the IMWG. Treatment was at the discretion of the treating physician. ResultsTwenty four patients with PCL were identified: 15 patients had pPCL and 9 had sPCL. The median age of all patients was 58 years (range 37-77years). The median peripheral WBC was 15×109/L (range 3-102 ×109/L) and the median percent of peripheral plasma cells was 40% (15-93%). The median β2 microglobulin was 3 mg/L (range 1.4-23). Nine patients (38%) had renal failure (creatinine>2.0mg/L) at diagnosis of PCL and 11/19 (58%) had a serum LDH greater than the institution's upper limit of normal. Two patients had CNS disease and 6 patients had extramedullary disease.Regarding metaphase cytogenetics: One patient had a novel translocation involving 3 separate breakpoints, which included: ins(6;14)(p22;q32q32)t(6;11)(p22;q13), der (14) ins (11)(q32;q13q13)?? t(6;14)(p22;q32), 3 patients (2 with pPCL) had a translocation between chromosomes 1 and 16 including t(1;16)(q21;q24), t(1;16)(q21;22) and t(1;16)(break points not reported). 14/23 patients with PCL (61%) had deletion of chromosome 13 by either FISH or cytogenetics; while 80% of patients with pPCL (12/15) had 13q deletion. Only one patient had deletion 17p. 11 patients received bortezomib based therapy and 19 patients received a novel agent, 5 had an allogeneic transplant, 19 had high dose therapy and autologous transplantation). Best response to therapy was as follows: 9 CR, 4 VGPR, 4PR, 1MR, 2 Non evaluable (PR and better: 77%). After a median follow up of 13 months, 5 remain alive (all had autologous transplant and 3 had an allogeneic transplant) (median follow up 2 years; range 2-34 months). The median overall survival for pPCL compared to sPCL via Kaplan-Meier was 28.4 vs. 3.5 months, respectively (p=0.0018). See Figure 1. ConclusionWe herein report novel cytogenetic abnormalities in patients with PCL (1 unique translocation involving chromosomes 6, 11 and 14 as well as 3 patients with t(1; 16) which has rarely been reported). Despite generally poor outcomes with traditional therapies, patients treated with novel agents and allogeneic transplant may enjoy a longer survival than previously reported. [Display omitted] DisclosuresOff Label Use: Lenalidomide in newly diagnosed myeloma. Baz:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Cytogenetic abnormalities in essential thrombocythemia at presentation and transformation

Cytogenetic abnormalities in patients with essential thrombocythemia (ET) are infrequent. Their role in survival of patients and disease transformation is not extensively studied. We describe cytogenetic abnormalities in 172 patients with ET at a single institution. At presentation nine (5.2%) patients had cytogenetic abnormality and three (1.7%) additional patients acquired them during follow-up. Survival of patients with cytogenetic changes at presentation did not differ when compared to the patients with normal karyotype. The more common were abnormalities of chromosome 9 (n = 4), 20 (n = 2), 5 (n = 2), and complex abnormalities (n = 2). Forty-one patients (23.8%) had additional cytogenetic tests performed for monitoring purposes during follow-up. Five patients (2.9%) with normal karyotype transformed to myelofibrosis (MF) without developing new cytogenetic changes at transformation. Two patients (1.2%) with normal karyotypes at presentation transformed to myelodysplastic syndrome and acute myeloid leukemia, respectively. Both acquired complex cytogenetic changes at the time of transformation. There is no rationale for repeating cytogenetic tests in ET patients on follow up, unless blood cell count changes suggest possible transformation.

Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis

Light chain amyloidosis is a rare plasma cell dyscrasia. Interphase fluorescence in situ hybridization (FISH) coupled to cytoplasmic staining of specific Ig (cIg-FISH) on bone marrow plasma cells has become well established in the initial evaluation of multiple myeloma, a related disorder. Little, however, is known about cytogenetic abnormalities in patients with light chain amyloidosis. We reviewed 56 patients with light chain amyloidosis who had cIg-FISH performed as part of their routine clinical testing using the standard screening panel employed in multiple myeloma at our institution. Seventy percent of patients had abnormal cIg-FISH, with the most common abnormalities being IgH translocations [48%]--including t(11;14) [39%], and t(14;16) [2%]--and del13/del13q [30%]. No t(4;14) or deletions of 17p (p53) were observed. Patients with t(11;14) had the lowest levels of clonal plasma cells, and those with del13 had the highest. The risk of death for patients harboring the t(11;14) translocation was 2.1 (CI 1.04-6.4), which on multivariate analysis was independent of therapy. Although preliminary, our data would suggest that cIg-FISH testing is important in patients with light chain amyloidosis and that t(11;14) is an adverse prognostic factor in these patients.

Impact of Age on Transfusion Independence Response, Survival, and Transformation to Acute Myeloid Leukemia in Patients with Deletion 5q: A Sub-Analysis of the MDS-003 Study

Introduction: Recent data have demonstrated that lenalidomide reduced transfusion requirements and reversed cytologic and cytogenetic abnormalities in patients who have myelodysplastic syndrome (MDS) with the chromosome 5q31 deletion (List et al NEJM 2006). Previous studies have demonstrated that age may impact on survival rates in cancer patients, but the impact of age on patients treated with lenalidomide for deletion 5q [del(5q)] MDS has not been investigated. This sub-analysis investigated the impact of age on transfusion independence (TI) response, survival, transformation to acute myeloid leukemia (AML), and cytopenias in patients with deletion 5q who were treated with lenalidomide.Methods: Transfusion-dependent, Low/Int-1-risk patients with primary MDS and del(5q) with/without additional cytogenetic abnormalities were treated with lenalidomide 10 mg daily or for 21 days every 28 days. Patients were treated until disease progression, treatment failure, or treatment-limiting adverse events. For this analysis, patients were subdivided into two categories: ≤75 and >75 years of age. The relationship between age and TI response, survival, progression to AML, and cytopenias were analyzed.Results: A total of 148 patients were included in the study: 103 patients aged ≤75 years and 45 patients aged >75 years (Table). The TI response was 68% for patients aged ≤75 years and 60% for patients aged >75 years (P=0.35). As expected, median survival was shorter for older patients (P=0.01). There was no difference in the progression to AML with 22% progressing for patients aged ≤75 years and 16% for patients aged >75 years (P=0.65). Cytopenias were reported in 84% and 76% of patients aged ≤75 and >75 years, respectively (p=0.42).Conclusion: Patients aged >75 years had a similar TI response to patients aged ≤75 years of age. Survival was shorter as is to be expected in an older age group with a lower average life expectancy. There was no difference in the rate of progression to AML when compared with patients aged ≤75 years. The rates of cytopenias were not influenced by patient age.≤75 years (n = 103)>75 years (n = 45)PTI response, n/N (%)70/103 (68)27/45 (60)0.35Median survival, years (95% CI)NA (3.186–NA)2.52 (2.13–3.09)0.01AML progression, n/N (%)23/103 (22)7/45 (16)0.65Cytopenias, n/N (%)87/103 (84)34/45 (76)0.42CI, confidence interval; NA, not yet reached.

Impact of Baseline Renal Function on Transfusion-Independence Response, Survival, and Transformation to Acute Myeloid Leukemia in Patients with Deletion 5q: A Sub-Analysis of the MDS-003 Study

Introduction: Lenalidomide reduced transfusion requirements and reversed cytologic and cytogenetic abnormalities in patients who have myelodysplastic syndrome (MDS) with the chromosome 5q31 deletion del(5q)] (List et al., NEJM 2006). Dose-adjusted lenalidomide is safe and effective in MDS patients with del(5q) and severe renal impairment (Knop et al., Leuk Lymph 2008), but the impact of baseline renal function on outcomes has not been specifically studied. This MDS-003 clinical trial sub-analysis investigates the impact of baseline renal function on the transfusion-independence (TI) response, overall survival, and transformation to acute myeloid leukemia (AML).Methods: Transfusion-dependent, Low/Int-1-risk patients with primary MDS and del(5q) with/without additional cytogenetic abnormalities were treated with lenalidomide 10 mg daily for 21 days every 28 days. Patients were treated until disease progression, treatment failure, or treatment-limiting adverse events. This sub-analysis included patients with normal renal function (creatinine clearance [CrCl] >80 mL/min) and patients with mild (CrCl 50–80 mL/min), moderate (30–50 mL/min), or severe renal impairment (CrCl <30 mL/min). CrCl was calculated according to the Cockcroft-Gault formula. Red blood cell (RBC) transfusion-dependent anemia was defined as having received ≥2 units of RBCs within 8 weeks of the first day of study treatment. Neutropenia was defined as a baseline absolute neutrophil count of <1,000/μL. Thrombocytopenia was defined as a baseline platelet count of < 100,000/μL. TI response, overall survival, and transformation to AML were assessed.Results: Of 148 patients enrolled in the study, 70 patients had normal renal function and 70 patients had renal impairment (47 mild, 19 moderate and 4 severe impairment; with renal data missing for 8 patients). The TI response was 44/70 (63%) for patients with normal renal function and 48/70 (69%) for patients with impaired renal function (P=0.47). In the subcategories, the TI responses were 79%, 53% and 25% for mild, moderate and severe impairment, respectively (P=0.07, P=0.42 and P=0.13 vs. normal function). Renal impairment resulted in shorter median overall survival compared with no renal impairment (hazard ratio of 2.88, 95% confidence interval, 2.24–3.45). The transformation to AML rate was 19% for normal patients and 20% for patients with renal impairment.Conclusion: In this analysis, baseline renal function does not have a significant impact on achieving transfusion independence or transformation to AML. Patients with moderate to severe renal impairment had a shorter survival than patients with normal renal function.

Fluorescent in situ hybridization with a panel of probes detects molecular cytogenetic abnormalities in patients with chronic lymphocytic leukemia

To explore the characteristics and prognostic significance of molecular cytogenetic aberrations in Chinese patients with chronic lymphocytic leukemia (CLL) and the significance thereof in diagnosis of CLL. A panel of probes (LSI D13S319, LSI p53, LSI ATM, CEP 12, LSI MYB, and LSI IGHC/IGHV) and interphase fluorescence in situ hybridization (FISH) were used to prospectively detect the cytogenetic abnormalities in 106 CLL patients, 82 males and 24 females, aged 62 (34 - 86). Molecular cytogenetic aberrations were found in 79 of the 106 CLL patients (74.5%) and 35 patients (33.0%) showed more than two kinds of abnormalities. The most frequent abnormality detected was del (13q14) in 48 cases (45.3%), followed by trisomy of chromosome 12 in 27 patients (25.5%), IgH translocation in 25 patients (23.6%), del (17p13) in 17 patients (16.0%), del (11q22) in 11 patients (10.5%) and del (6q23) in 5 patients (4.7%). The Del (13q14) rate of the group younger than 60 was 56.5%, significantly higher than that of the group aged > or = 60 (36.7%, P = 0.033). There was no significant relationship between molecular cytogenetic aberrations and sex and Binet stages (both P > 0.05). Kaplan-Meier survival analysis showed that the survival time was shorter in the patients with p53 or ATM gene deletion. Patients with sole Del (13q14) had longer survival time than those with other abnormalities. The frequencies of the chromosomal abnormalities in Chinese CLL patients are similar to those in Western countries. Panel FISH has greatly increased the sensitivity of cytogenetic analyses. Del (13q14) is the most frequent abnormality in CLL. Molecular cytogenetic aberrations detected with FISH have important prognostic significance in CLL.

Myelodysplastic Syndrome in Fanconi Anemia: Morphologic and Cytogenetic Findings Are Strongly Correlated.

Predisposition to myelodysplastic syndrome (MDS) and acute leukemia is a hallmark of Fanconi anemia (FA). Morphologic criteria for MDS in FA are not well established. The presence of some degree of bone marrow (BM) dysplasia, especially dyserythropoiesis, as background in these patients can confound the diagnosis. Similarly, the significance of cytogenetic abnormalities in patients with the chromosomal instability syndrome of FA has been debated. To address both the morphologic diagnosis of MDS in FA and the relationship between morphologic and cytogenetic (CG) findings, we reviewed 169 BM biopsies and CG results from 118 FA patients referred to University of Minnesota from 1991-2006. Peripheral blood and BM smears, sections, iron and immunoperoxidase stains were reviewed by a single hematopathologist without knowledge of CG. MDS was diagnosed and classified according to WHO criteria. Dyserythropoiesis alone was considered diagnostic of MDS only if present in an arbitrarily determined level of at least 50% of cells, or if more than 15% ring sideroblasts (RS) were identified. A borderline MDS category was also defined. G-banding, FISH, and/or array based CGH were performed for detection and characterization of clonal chromosomal abnormalities. Twenty-two patients (18.6%) had morphologic evidence of MDS: RCMD and RCMD-RS were predominant, with RAEB-1 and 2, MDS-unclassifiable, RA and RARS accounting for the remainder. Of the 22 patients with MDS, 20 (91%) had clonal abnormalities; 2 patients, one with RA and one with RARS, showed normal cytogenetics. Of the abnormalities observed, 80% involved gain of 1q, gain of 3q, and/or loss of 7q, and most patients had more than one abnormality. Six patients had borderline MDS; all but one of these had clonal abnormalities. Eight patients with AML were identified, all of whom showed complex cytogenetic abnormalities. Eighty-six patients showed insufficient abnormalities for MDS, but most had some degree of dyserythropoiesis. Cytogenetics was normal in 75 of these patients (87.2%) and abnormal in 11 (12.8%). Most of these patients had clones with a single abnormality. In summary, 37.3% of all FA patients showed chromosomal abnormalities. The presence of MDS as diagnosed by WHO criteria is strongly correlated with the presence of a clonal chromosomal abnormality. With respect to morphologic findings, the diagnosis of MDS in FA is highly dependent upon the detection of myeloid dysplasia, megakaryocytic dysplasia and/or increased blasts. Dyserythropoiesis per se, even if present in excess of 50% of cells, does not correlate with a clonal cytogenetic abnormality. The finding that most patients with borderline MDS also had CG abnormalities suggests that the clonal abnormalities in such cases may herald evolution to MDS. Interpretation of the finding of a clonal abnormality in FA patients without morphologic evidence of MDS requires consideration of the particular chromosomal abnormality involved, the size of the clone, and the presence or absence of clonal evolution. The strong correlation between morphologic and CG findings has implications for monitoring patients with FA.

Transmitted cytogenetic abnormalities in patients with mental retardation: Pathogenic or normal variants?

Knowing the origin of cytogenetic abnormalities detected in individuals with mental retardation and dysmorphic features is essential to genetic counselling of affected families. To illustrate this, we report on six families with transmitted cytogenetic abnormalities and discuss the genotype–phenotype correlations, including the possibility of the abnormalities being normal genomic variants. The abnormalities were detected using metaphase HR-CGH; their size was estimated to range from 1.6 to 7.5 Mb using tiling path array-CGH and real-time PCR. The abnormalities were transmitted through two to four generations and included interstitial deletions of 1p31.3-p32.1, 2q13, 10q11.21-q11.23, and 13q31.1; a duplication of 1p34.1-p34.2; and in one family both a deletion of 18q21.1 and a duplication of 4q35.1-q35.2. The probands were mentally retarded and had nonspecific dysmorphic features except for one patient with the Bohring–Opitz syndrome. We considered the abnormalities in two families to be clinically significant: In one family, the proband's brain abnormality was comparable to previously reported abnormalities in individuals with a similar duplication of 1p31-p32. Congenital heart disease was previously mapped to the chromosomal region of 18q that was affected in the proband of another family. The carrier parents in both families had mild clinical features. In two families the abnormalities were considered as coincidental findings, and in two further families the abnormalities were insufficient to explain the phenotypes of the probands but possibly were related to a milder phenotype in other family members. These cases illustrate the need for careful assessment of the extended family in order to interpret the phenotypic consequences of abnormalities identified using array-CGH.

Prognostic relevance of cytogenetics determined by fluorescent in situ hybridization in patients having myelofibrosis with myeloid metaplasia

In chronic myelofibrosis (MF), distinct recurrent cytogenetic aberrations have been identified but their true prognostic relevance remains uncertain. In this disease, cytogenetic studies as assessed by conventional metaphase karyotyping are limited due to the inherent difficulties in obtaining adequate bone marrow aspirates and the low proliferative capacity of the clonal cells. Interphase fluorescent in situ hybridization (FISH) can partly overcome these limitations and increase the sensitivity of cytogenetic assessment in MF. We retrospectively analyzed formalin-fixed, paraffin embedded bone marrow sections of 107 MF patients by FISH and correlated cytogenetic findings with clinical presentation and survival. Chromosomal aberrations were detected in 56% of patients, with 20q- (24.3%) and 13q- (16.8%) being the most frequent ones. Importantly, cytogenetic abnormalities were found in 8/17 patients displaying a normal karyotype as assessed by conventional cytogenetics. Cytogenetic abnormalities in patients with MF can be detected reliably using FISH. Rare abnormalities confer an adverse outcome, but the main recurrent chromosomal aberrations do not correlate with clinical features and prognosis.

Various distinctive cytogenetic abnormalities in patients with acute myeloid leukaemia aged 60 years and older express adverse prognostic value: results from a prospective clinical trial

Diagnostic cytogenetic abnormalities are considered important prognostic factors in patients with acute myeloid leukaemia (AML). However, the prognostic assessments have mainly been derived from patients with AML aged <60 years. Two recent studies of AML patients of 60 years and older proposed prognostic classifications with distinct discrepancies. To further study the prognostic value of cytogenetic abnormalities in this patient population, we have evaluated cytogenetic abnormalities in a series of 293 untreated patients with AML aged 60 years and older, included in a randomised phase 3 trial, also in relation to patient characteristics and clinical outcome. The most frequently observed cytogenetic abnormality was trisomy 8 (+8), in 31 (11%) patients. Abnormalities, such as -5, 5q-, abn(17p) and abn(17q), were almost exclusively present in complex karyotypes. A relatively favourable outcome was only observed in five patients with core-binding factor abnormalities t(8;21) and inv(16)/del(16)/t(16;16). However, most of the other evaluated cytogenetic abnormalities, such as 5q-, -7, +8, abn(17p), abn(17q), and complex aberrations expressed a more adverse prognosis when compared with patients with AML aged 60 years and older with a normal karyotype. Large studies to confirm the prognosis of individual cytogenetic aberrations are warranted.

Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion

Severe, often refractory anemia is characteristic of the myelodysplastic syndrome associated with chromosome 5q31 deletion. We investigated whether lenalidomide (CC5013) could reduce the transfusion requirement and suppress the abnormal 5q31- clone in patients with this disorder. One hundred forty-eight patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily. Hematologic, bone marrow, and cytogenetic changes were assessed after 24 weeks of treatment by an intention-to-treat analysis. Among the 148 patients, 112 had a reduced need for transfusions (76%; 95% confidence interval [CI], 68 to 82) and 99 patients (67%; 95% CI, 59 to 74) no longer required transfusions, regardless of the karyotype complexity. The response to lenalidomide was rapid (median time to response, 4.6 weeks; range, 1 to 49) and sustained; the median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. The maximum hemoglobin concentration reached a median of 13.4 g per deciliter (range, 9.2 to 18.6), with a corresponding median rise of 5.4 g per deciliter (range, 1.1 to 11.4), as compared with the baseline nadir value before transfusion. Among 85 patients who could be evaluated, 62 had cytogenetic improvement, and 38 of the 62 had a complete cytogenetic remission. There was complete resolution of cytologic abnormalities in 38 of 106 patients whose serial bone marrow samples could be evaluated. Moderate-to-severe neutropenia (in 55% of patients) and thrombocytopenia (in 44%) were the most common reasons for interrupting treatment or adjusting the dose of lenalidomide. Lenalidomide can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients who have the myelodysplastic syndrome with the 5q31 deletion. (ClinicalTrials.gov number, NCT00065156 [ClinicalTrials.gov].).

Additional chromosomal abnormalities in patients with a previously detected abnormal karyotype, mental retardation, and dysmorphic features

The detection of chromosomal abnormalities in patients with mental retardation (MR) and dysmorphic features increases with improvements of molecular cytogenetic methods. We report on six patients referred for detailed characterization of chromosomal abnormalities (four translocations, one inversion, one deletion) detected by conventional cytogenetics, in whom metaphase CGH revealed imbalances not involved in the initially detected rearrangements. The detected abnormalities were validated by real-time PCR. Parents were investigated by CGH in four cases. The genomic screening revealed interstitial deletions of 2q33.2-q34, 3p21, 4q12-q13.1, 6q25, 13q22.2-q31.1, and 14q12. The estimated minimum sizes of the deletions ranged from 2.65 to 9.27 Mb. The CGH assay did not reveal imbalances that colocalized with the breakpoints of the inversion or the translocations. The deletion of 6q included ESR1, in which polymorphisms are associated with variation of adult height. FOXG1B, known to be involved in cortical development, was located in the 14q deletion. The results illustrate that whole-genome molecular cytogenetic analysis of phenotypically affected patients with abnormal conventional karyotypes may detect inapparent molecular cytogenetic abnormalities in patients with microscopic chromosomal abnormalities and that these data provide additional information of clinical importance.

Correlation of Cytogenetic Findings with Morphology, Clinical Course and Prognosis in 2124 Patients with MDS.

Cytogenetic abnormalities are observed in 30%–80% of MDS pts and correlate with morphologic features, clinical course, prognosis, and response to therapy. Cytogenetic heterogeneity hampers investigation, and little is known about rarer abnormalities and combinations of abnormalities. Furthermore, it has not yet been possible to compare the effects of different therapies within cytogenetic entities. To address such issues, we have generated a large, unique database comprising morphologic, clinical, cytogenetic, and follow-up data from MDS pts at 8 institutions in Austria and Germany. So far, we have data on 2124 pts with a median age of 65.7 yr and a male: female ratio of 1.29. 1981 pts (93.3%) had primary and 143 had secondary MDS. FAB classification of pts: RA 589 (27.7%); RARS 256 (12.1%); RAEB 424 (20%); RAEB-T 311 (14.6%); CMML 287 (13.5%); MDS-AL 132 (4.2%). WHO classification (available in 595 pts): 5q- syndrome 71 (11.9%); RA 46 (7.7%); RARS 26 (4.4%); RCMD 164 (27.6%); RSCMD 77 (12.9%); RAEB-I 90 (15.1%); RAEB-II 121 (20.3%). Cytogenetic analyses were successful in 2072 pts (97.6%) with a mean of 21.9 completely analyzed metaphases. The mean number of aberrations per case was 1.52. 1080 pts (52.1%) had clonal abnormalities. Cytogenetic characteristics are shown in Figure 1. IPSS cytogenetic risk: good 1217 pts (58.7%); intermediate 401 (19.4%); unfavorable: 454 (21.9%). Follow-up data were available in 1841 pts for a mean of 29.2 mo. Supportive care was given to 1286 pts (60.6%), chemotherapy to 462 (21.8%), amifostine to 22 (0.1%), and therapeutic data were unavailable in 354. Median survival by IPSS cytogenetic risk, karyotype complexity, and influence of additional cytogenetic abnormalities in patients with isolated 5q deletion and trisomy 8 are shown in Table 1. Prognostic data of other isolated and combined abnormalities (-7,-20/20q-,-Y) as well as rarer abnormalities (3q, 9q-, +11, -12/12p-, -13/13q-, -17/17p-, +21 and others) will be presented, as will the influence of different therapies on survival in genetic entities. By FAB classification, there were no significant differences in the distribution of cytogenetic risk groups between RA and RARS and between RAEB and RAEB-T. By WHO classification, the 5q- syndrome exclusively displayed favorable karyotypes; no unfavorable abnormalities were observed in RARS (WHO) in contrast to RARS (FAB), and no significant differences were observed between RAEB-I and RAEB-II. In conclusion, additional abnormalities modulate the prognostic value of the primary cytogenetic changes in different ways that have to be delineated for each abnormality. Since novel therapies such as IMiDs/lenalidomide are effective in distinct cytogenetic entities, a better knowledge of cytogenetically defined subgroups is urgently needed. [Display omitted]

A set of commercially available fluorescent in-situ hybridization probes efficiently detects cytogenetic abnormalities in patients with chronic lymphocytic leukemia

Purpose: To investigate a simplified panel of fluorescent in-situ hybridization (FISH) probes for evaluation of patients with chronic lymphocytic leukemia (CLL) and to correlate results from this technique with known prognostic factors.Methods: We retrospectively reviewed the FISH and conventional cytogenetic results, and clinical and laboratory data of 44 patients with CLL.Results: FISH was more sensitive than conventional cytogenetics in detecting genomic aberrations (75% vs. 16%, P < 0.0001). Trisomy 12 was significantly correlated with the cell surface marker of CD38 expression (P = 0.0017).Conclusion: This FISH panel reliably detects prognostically important genomic abnormalities in CLL and is suitable for widespread use.

Molecular cytogenetic abnormalities in patients with concurrent chronic lymphocytic leukemia and multiple myeloma shown by interphase fluorescence in situ hybridization: evidence of distinct clonal origin

The coexistence of chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) is rare, and there is no consensus about the clonal relationship of the two disorders when they occur in the same individual. We investigated chromosomal abnormalities in two patients with concurrent CLL and MM using interphase fluorescence in situ hybridization (FISH) with a panel of region-specific DNA probes. In patient 1, the clonal plasma cells harbored IgH translocations (14q32); however, FISH with probes for the four most frequent IgH partner genes in MM ( CCND1, FGFR3, MAF, and MYC) did not detect translocations involving any of them. The CLL cells were characterized by deletions of 13q14, 11q23, and 17p13, as well as trisomy 12, none of which were found in the MM cells. In patient 2, deletions of 13q14 and 17p13 were detected in CLL cells, but no cytogenetic abnormalities were found in the MM cells. Both patients had relapsed MM following chemotherapy and had autologous stem-cell transplant, whereas their CLL has been stable and not requiring treatment. Our results show that the cytogenetic profiles differ between CLL and MM within the same patients, and provide evidence for two distinct malignant clones in both patients.

Trisomy 4 and Double Minutes in Acute Myeloid Leukemia: Further Evidence that Double Minutes can Occur as the Primary Cytogenetic Abnormality

The specific association of trisomy 4 and double minutes (dmin) is rare and is usually reported in patients with acute myeloid leukemia (AML), primarily M2 and M4 subtypes. Several previous reports describing this combination suggested that trisomy 4 was the primary cytogenetic abnormality, and that the presence of the dmin was secondary. We describe a 79-year-old male who presented with myelodysplasia, transforming to AML-M2. Cytogenetic analysis of bone marrow aspirate cultures showed a 46,XY,dmin [12]/47,XY,+4,dmin [7]/46,XY [6] karyotype. The number of dmin ranged from 1 to 150. Fluorescence in situ hybridization (FISH) analysis showed that the dmin were derived from amplification of the MYC oncogene. Dual-color interphase FISH analysis was performed with D4Z1 and MYC probes and showed no evidence of a clone containing trisomy 4 without dmin. These data suggest that dmin may also occur as the primary cytogenetic abnormality in patients with trisomy 4 and dmin.

Neuroblastoma and related tumors in Turner’s syndrome

Objectives: The identification of constitutional cytogenetic abnormalities in patients with cancer may indicate loci of genes, abnormalities of which are responsible for tumor development or progression. This study was undertaken to determine whether girls with Turner’s syndrome (TS) (partial or complete deletion of an X chromosome, short stature, gonadal dysgenesis) are at increased risk of neural crest-derived tumors.Study Design: Medical records of 394 patients with TS who were followed up at Thomas Jefferson Hospital and Children’s Hospital of Pittsburgh were reviewed for documentation of TS phenotype, constitutional cytogenetics, and history of neuroblastoma or related tumors. Informative cases were reviewed for tumor pathology, primary site, disease stage, associated symptoms, treatment, and outcome.Results: Three patients were found to have neuroblastoma. A fourth child who died of neurofibrosarcoma was found to have extensive areas of ganglioneuroma, the benign counterpart of neuroblastoma, at autopsy. An additional four girls with TS and neuroblastoma were identified in the literature, as were two more patients with ganglioneuroma. These 10 patients ranged in age from 1 week to 16 10/12 years (median age, 3 years), and all but two of the children had localized lesions. Two of the seven children with neuroblastoma had courses complicated by opsoclonus-myoclonus, a syndrome found in fewer than 5% of all patients with neuroblastoma.Conclusions: These data strongly suggest that girls with TS are predisposed to the development of neuroblastoma and related tumors. Because these tumors are often of limited stage and may be underdiagnosed, screening of urine of patients with TS for elevated catecholamine metabolite levels may strengthen this association. (J Pediatr 1997;131:666-70)

Improved Cytogenetics in Multiple Myeloma: A Study of 151 Patients Including 117 Patients at Diagnosis

Between December 1990 and January 1994, bone marrow (BM) samples from 151 patients with multiple myeloma (MM), including 117 patients evaluated at diagnosis, were collected for cytogenetic analysis. A total of 129 patients had assessable metaphases (100 patients at diagnosis). Cytogenetic studies were performed on BM cells after longterm cultures (6 days) with stimulation of cultures by granulocyte-macrophage colony-stimulating factor (GM-CSF), GM-CSF plus interleukin (IL)-6, IL-3 plus IL-6, or GM-CSF plus IL-3 plus IL-6 to improve myeloma cell growth, and 91 patients had an additional unstimulated culture. Sixty-six patients (51%) had cytogenetic abnormalities, including 47 of 100 patients at diagnosis (47%) and 17 of 24 patients at relapse (71%; P = .04). The aberration rate increased with stage (P = .007), BM plasmacytosis (P = .003), beta 2 microglobulin level (P = .001), C-reactive protein (CRP) level (P = .001), and Ki-67 (P = .007). The abnormality detection rate was higher in stimulated than unstimulated cultures, and the difference was statistically significant (P < .01). Hyperdiploidy was observed in 39 patients (30% of patients with an assessable karyotype) and hypodiploidy in 19 patients (15%). Among numeric changes, gains predominantly involved chromosomes 3, 5, 7, 9, 11, 15, 19 and losses, chromosomes 8, 13, 14, and X. The most frequent loss was loss of chromosome 13, observed in 22 patients (15%), including 18 patients at diagnosis (12%). We observed frequent structural changes of chromosomes 1 (15%) and 14 (10%) but also a 5% incidence of 19q13 abnormality and two patients with translocation t(1;16)(p11;p11). By using the proportional hazard univariate model, patients with abnormal karyotypes were demonstrated to have 2.5-fold greater chance of death than patients with normal karyotypes (P < .014). Despite a multivariate approach with the same model, the respective roles of karyotype abnormality, age, stage, and beta 2 microglobulin level could not be clearly ascertained. From these results we conclude that cytogenetic analysis using stimulation of cultures by cytokine(s) may be a promising method to identify about 50% of cytogenetic abnormalities in patients with newly diagnosed MM. Cytogenetic analysis may help to define a high-risk population that would benefit from intensive therapeutic approaches.