Correlation between Immunoglobulin Gene Rearrangements and Chromosomal Abnormalities in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4771-4771
Author(s):  
Giovanna Piras ◽  
Maria Monne ◽  
Antonella Uras ◽  
Laura Pilo ◽  
Luciana Arca ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosomal Abnormalities ◽  
Normal Karyotype ◽  
Fish Analysis ◽  
Immunoglobulin Gene ◽  
Cytogenetic Aberrations ◽  
Oncogenic Pathways ◽  
Clonality Analysis ◽  
Conventional Cytogenetics ◽  
Clonogenic Cell

Abstract Background: Multiple Myeloma (MM) is characterized by frequent and complex genetic abnormalities that contribute to the pathogenesis and its prognostic eterogeneity. There is evidence for two oncogenic pathways in the early development of clonal plasma cell disorder: i) non-hyperdiploid carring translocation of the immunoglobulin heavy-chain locus and various oncogenes ii) hyperdiploid tumors with infrequent IgH translocation. The MM clonogenic cell is positively selected during the development and reaction of the germinal center. The immunoglobulin gene (IG) repertoire in MM follows a pattern similar to that of the normal repertoire. However, available data from analysis of IGH and IGK/L genes according to cytogenetic aberrations are limited. In the present study we investigated the frequency and characteristics of IGK and incomplete DJH as well as complete VDJH rearrangements in parallel with chromosomal abnormalities in a series of untreated MM patients. Materials and Methods. Bone marrow aspirates were collected from 53 MM patients with a mean age of 69.6 (range 48–84) between 2003–2007. The serum monoclonal component was IgG and IgA in the 77% and 22% patients respectively; 1 patient presented with IgD k MM. Cytogenetics and FISH analysis were performed simultaneously in 37 MM. In 18 (50.5%) samples kariotype analysis was successful. Interphase FISH analysis was perfomed using a set of probes specific for RB-1 (13q14), D13S319 (13q14.3), IgH (14q32), and p53 (17p13.1) loci, t(4;14), t(14;16), t(11;14) and a multicolor probe set for detection of aneuploidy (Vysis, Downers Grove, IL, USA). Genomic DNA was isolated for clonality analysis. IGHV-J, IGHD-J, IGKV-J, IGKV-KDE, IGKJ-C-INTRON-KDE rearrangements were amplified by PCR and analyzed following the BIOMED-2 protocol. Results: Conventional cytogenetics allowed to detect 16 patients with a normal kariotype, 1 hyperdiploid kariotype with monosomy 13, 1 hyperdiploid kariotype with 3q21 deletion. FISH panel analysis resulted in 4 patients with hyperdiploid kariotype and 7 with abnormalities for RB-1 and/or D13S319. IGH rearrangements were detected in 3 patients and the t (4;14) was found in 1 case. The p53 deletion, t(11;14) and t(14;16) were not detected. The overall detection rate of clonality by amplifying VDJH and DJH rearrangements using family-specific primers was 90%. We found a high frequency (71.7%) of DJH rearrangements with DH3 segment under represented (4%). The DH7 segment was rearranged in the 15% of MM. Incomplete DJH and complete VDJH rearrangements were present at frequencies of 20% and 29.5%, respectively. IGK locus rearrangements were detected in 38 out of 53 MM and the 60% presented the non-productive IGKV-KDE and IGKJ-C-INTRON-KDE rearrangements. Parallel analysis of clonality pattern and chromosomal abnormalities showed that complete VDJH rearrangements were present in all hyperdiploid MM and in a small proportion (4/16) of the MM with normal karyotype. Conclusions: Our results confirm previous estimations about IgH repertoire usage. Despite the small numbers, our findings indicate that complete Ig rearrangements might be correlated with hyperdiploid MM. Combining cytogenetics and IgH clonality studies might help to identify distinct subgroups of MM and provide a framework for dissection of disease prognosis and clinical management. Research funded by Regione Autonoma Sardegna.

FISH Reveals Abnormalities of Unsuspected Regions in Chromosomally Normal De Novo Myelodysplastic Syndromes (MDS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2599-2599
Author(s):  
Paolo Bernasconi ◽  
Irene Dambruoso ◽  
Marina Boni ◽  
Paola Maria Cavigliano ◽  
Ilaria Giardini ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Low Risk ◽  
Fish Analysis ◽  
Disease Evolution ◽  
Therapeutic Decisions ◽  
Conventional Cytogenetics

Abstract Abstract 2599 Poster Board II-575 In de novo MDS the chromosomal pattern is a mandatory step for an accurate diagnosis, predicts overall survival (OS) and the risk of MDS/AML evolution, guides therapeutic decisions. However, conventional cytogenetics (CC) studies show a normal un-informative chromosomal pattern in about half of MDS patients, especially in low-risk disease. FISH with probes pinpointing the chromosomal regions most frequently affected in MDS can increase the incidence of abnormal karyotypes up to 60%, but the percentage of normal karyotypes remains high and makes the search of novel cytogenetic/molecular markers a urgent need. A fundamental contribution to overcome CC and FISH shortcomings, has been recently provided by array CGH (aCGH) studies which have revealed that, independently of the cytogenetic pattern, MDS patients may harbour novel abnormalities involving unsuspected chromosomal regions. Based on this assumption, we decided to investigate whether FISH with probes already employed in aCGH studies can truly unmask cryptic lesions in chromosomally normal MDS patients, whether these defects are either chromosomal gains/losses or balanced rearrangements and whether these chromosomal abnormalities influence OS and disease evolution. FISH analyses were carried out in thirty-five patients examined between January 2005 and June 2008. There were thirteen females and twenty-two males, whose median age was 66 years (range 24–78). According to WHO classification, 6 patients were classified as RA, 13 as RAEB-1 and 16 as RAEB-2. According to IPSS score, 7 patients were considered low-risk, 14 intermediate-1 risk and 14 intermediate-2 risk. Median follow-up was nine months (range 1–46). At the time of the analyses no patients has died; 6 have progressed to RAEB-2 and 3 to AML. Probes for FISH analysis were chosen following two criteria: the frequency of their involvement in chromosomal abnormalities identified by aCGH studies and their Mb position on Human Mar. 2003 assembly according to the UCSC genome browser. All probes, obtained from BACPAC Resources Center at C.H.O.R.I. (Oakland, USA), were labelled and applied as previously reported. The following probes were applied: RP11-912d8 (19q13.2); RP11-196p12 (17q11.2); RP11-269c4 (14q12); RP11-351o1 (10q21.3); RP11-144g6 (10q11.2); RP11-122a11 (7q34); RP11-951k18 (5q13.1); RP11-100m20 (4p14); RP11-544h14 (2q33). The cut-off values for interphase FISH (i-FISH) were obtained from the analysis of 300 nuclei from ten normal samples and were fixed at 10%. An abnormal FISH pattern was revealed in eighteen patients (51.4%). It was observed in 3/6 RA patients, in 7/13 RAEB-1 and in 8/16 RAEB-2 and in 2/7 IPSS low-risk, in 7/14 intermediate-1 risk and in 9/14 intermediate-2 risk MDS patients. Seven presented a 19q13.2 deletion, three a 14q12 deletion, four an amplification of band 4p14, two a defect of band 10q21.3, two a potential amplification and one a deletion of band 10q11.2, two a deletion of band 5q13.1 and one a deletion of band 17q11.2. Cryptic defects were also revealed in six of the nine patients who experienced disease evolution on FISH analyses. This event occurred in 2/3 RA, in 2/7 RAEB-1 and in 2/8 RAEB-2 patients with an abnormal FISH pattern. Despite these data, the prognostic significance of an abnormal FISH pattern needs to be assessed on additional patients. In conclusion, our data show that i) FISH can truly reveal novel lesions involving unsuspected chromosomal regions in 51% of MDS patients with a normal karyotype; ii) most of these lesions consist of chromosomal gains/losses; iii) an abnormal FISH pattern seems to correlate with disease progression, but this correlation needs to be tested on additional patients. Disclosures: No relevant conflicts of interest to declare.

Multiple Myeloma: Clinical Implications of Cytogenetic Aberrations on Selected Plasma Cells on Conventional Cytogenetics and Interphase Flourescence In Situ Hibridization (FISH)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4987-4987 ◽  
Author(s):  
Rakesh Verma ◽  
Lalit Kumar ◽  
Ashutosh Halder ◽  
Atul Sharma ◽  
Ritu Gupta ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Response To Therapy ◽  
Novel Agents ◽  
Cytogenetic Aberrations ◽  
Bone Marrow Plasma ◽  
Conventional Cytogenetics

Abstract Abstract 4987 Purpose: We prospectively studied patients of multiple myeloma (MM) for presence of t(14q32), and del13q14 on FISH and numerical chromosomal abnormalities on conventional cytogenetics(CC). Methods: Between February 2007 and June 2009, 90 previously untreated patients of MM were enrolled, Patient's median age was 55 years (range, 34 to 75 years) and 67 were males (M: F: 2.9: 1). 24 patients had ISS stage I, stage II-46 & 20 patients had stage III. Purified bone marrow plasma cells, using magnetic activated cell sorter with CD138 micro beads were used. Conventional cytogenetics for numerical chromosomal abnormalities and FISH for deletion 13q14 (RB-1) and 14q32 (IgH) translocations was carried out on these purified plasma cells. 65/90 (72%) patients received therapy; using novel agents, n=54 (thalidomide-dexamethasone (n=50), Lenalidomide-dexamethasone (n=4)) and melphalan, prednisolone and thalidomide (MPT, n=11). Response was evaluated post 4 cycles using EBMT response criteria. Results: Metaphases could be obtained on CC in 53/90 patients (58%); with numerical abnormalities in 21: hyperdiploid -16 & hypodiploid in 5. Del 13q14 and t (14q32) by FISH was present in 51 (56%) and 75 (83%) patients, respectively. t (14q32) was present more in patients with ISS-III (p<.008). Presence of del13q14 correlated with BM plasma cells >40% (P<.007) and Hb ≤9.2G/dl (p=.06). Following therapy, 49/65 patients (75.2%) achieved significant response (CR+VGPR+PR). Patients aged ≤55 years (P = 0.07), those with ISS- I (P <0.05), IgG-kappa (P<0.04) and with absence of del13q14 (P = 0.04) responded better. The median overall survival (OS) has not reached yet, median event-free survival (EFS) is 33 months (95% CI 18–48). Estimated OS and EFS at 2 years is 77% and 50 %, respectively. Durie Salmon stage IIIB (HR 3.6) and response to therapy (HR 7.8) were significant predictors of OS. For EFS - del13q14 (HR 2.7, P <0.036), response to therapy (HR 2.7,P<0.01) and use of novel agents (HR 3.1, (P<0.008) were important predictors. Conclusion: Chromosomal abnormalities including IgH translocations and del13q14 with numerical chromosomal abnormalities are common in MM patients at diagnosis and can predict the treatment outcome and survival. Disclosures: No relevant conflicts of interest to declare.

Retrospective analysis of cytogenetic and clinical characteristics on 65 patients with multiple myeloma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5075-5075
Author(s):  
Li Yang ◽  
Jingsong He ◽  
Xiaojian Meng ◽  
Guoqing Wei ◽  
Wenjun Wu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Retrospective Analysis ◽  
Clinical Features ◽  
Elevated Serum ◽  
Serum Levels ◽  
Fish Analysis ◽  
Molecular Cytogenetic ◽  
Cytogenetic Aberrations ◽  
Conventional Cytogenetics

Abstract Abstract 5075 Multiple myeloma (MM) is a malignant disorder characterized by abnormal proliferation of monoclonal, immunoglobulin producing plasma cells in the bone marrow. Studies with large samples have shown that molecular cytogenetic changes play an important role in the prognosis of MM. Based upon these findings, we tested cytogenetic aberrations of 65 patients with MM by conventional cytogenetics analysis and FISH technique in this study. Retrospective study was done on these cases for clinical features. Methods: This is a retrospective analysis of 65 patients with MM diagnosed between June 2007 and May 2010 including 13 relapsed cases and 52 newly diagnosed patients. Patients received bortezomib-based combination chemotherapy including bortezomib plus dexamethasone (BD) and the triplet combinations (bortezomib, adriamycin, dexamethasone (BAD), bortezomib, cytoxan, dexamethasone (BCD) and bortezomib, melphalan, prednisone (BMP) or traditional chemotherapy including doxorubicin, vincristine plus dexamethasone (VAD), melphalan plus dexamethasone (MP), melphalan, dexamethasone plus thalidomide (MPT)). To further clarify the correlation between cytogenetic and clinical features on patients with multiple myeloma, we used conventional cytogenetics analysis with R-banding technique and interphase fluorescence in situ hybridization (FISH) to describe the molecular cytogenetic characterization of bone marrow nucleated cells from 65 patients. SPSS (version 18.0) software was used for data analysis, χ2 tests or Fisher's exact test was used for betweengroup comparison of the discrete variables and Log- Rank was used for survival analysis. p<0.05 reflects the remarkable significance. Results: 16.9% of patients (11/65) showed abnormal cytogenetic aberrations including 90.9% (10/11) cases with ultra complex aberration and complex aberration via conventional cytogenetics. In addition, we were able to show aberrations in 49.2% (32/65) of patients by interphase FISH analysis. Abnormalities of 13q14, 1q21, 14q32 and 17p13 were detected in 27.7% (18/65), 13.8% (9/65), 16.9% (11/65), and 29.2% (19/65) by FISH, respectively. 1q21 amplification is strongly associated with 13q14 mutation (P=0.008), demonstrating significant correlation between two. Abnormality of 13q14 deletion or 1q21 amplification were associated with lower levels of albumin (P<0.05). Patients with 13q14 deletion frequently had stage III disease by DS and ISS staging, and compared with patients not detected on FISH analysis, they tended to have elevated serum levels of β2-microglobulin at diagnosis (P<0.05). 17p13 deletion coexistent with 13q14 deletion frequently correlate with elevated serum levels of β2-microglobulin and advanced clinical staging. The median progression-free survival (PFS) of patients with 17p13 deletion or 17p13/13q14 aberrations were both 11.0m, significantly lower than patients with no detected abnormality (median PFS 19.0m) (P<0.05). The median overall survival (OS) of patients with FISH negtive results was 38.0m, significantly higher than those with 13q14, 14q32 or 1q21 abnormality and 17p13/13q14 or more than three abnormalities (P<0.05). Conclusions: This study validates myeloma cells are prone to show complex aberration and FISH is superior in the detection of cytogenetic aberrations to conventional cytogenetics analysis for patients with multiple myeloma. 1q21 had significant correlation to 13q abnormality. 17p13 deletion coexist with 13q14 deletion and 14q32 rearrangeent were used to associate with poor prognosis. 17p13 deletion or 17p13/13q14 deletion was associated with poorer PFS while abnormality of 13q14, 1q21,14q32, 17p13/13q14 or more than 3 abnormalities were correlate with poorer OS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Complex cytogenetic research of cryptic chromosomal aberrations in patients with multiple myeloma

2019 ◽  
Vol 18 (1) ◽  
pp. 50-59
Author(s):  
A. A. Solodovnik ◽  
А. S. Mkrtchyan ◽  
V. A. Misyurin ◽  
L. A. Kesaeva ◽  
N. N. Kasatkina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosomal Aberrations ◽  
Plasma Cells ◽  
Chromosomal Abnormalities ◽  
Partial Trisomy ◽  
Fish Analysis ◽  
National Medical ◽  
Clonal Proliferation ◽  
Cytogenetic Aberrations ◽  
Wide Range

Background . Multiple myeloma (MM) is a malignant lymphoproliferative B-cell disease characterization by clonal proliferation of plasma cells in the bone marrow and beyond its borders. Currently, a wide range of cytogenetic anomalies and molecular-biological parameters are studied as prognostic factors.Objective: a comparative study of the frequency, features and clinical significance of chromosomal abnormalities in MM by conventional cytogenetic and fluorescent in situ hybridization (FISH) methods.Materials and methods . 77 patients with MM, which admitted in N.N. Blokhin National Medical Research Center of Oncology, were included in the study from 2016 to 2017.Results . Chromosomal alterations were detected only in one case (1/77) by conventional cytogenetic method G-banding. However cytogenetic aberrations were revealed in 26 % of cases (20/77) using FISH. Deletions of different regions of chromosomes, indicating the possible presence of a hypodiploid clone or loss of some regions, were found in one patient in the second FISH analysis after 6 months. In the cohort of patients with chromosomal abnormalities (n = 20) a partial trisomy 11q, a deletion of the region q32 of the chromosome 14, a translocation t(4;14)(p16;q32) and IGHV gene rearrangement were determined in 30 % (6/20) as sole anomalies. Two or more cytogenetic aberrations were identified in the remaining 14 patients. Our study confirms that chromosomal abnormalities are more likely detected at later stages of MM (IA и IIA – 0 %, IIIA и IIIВ – 27 and 47 % respectively).Conclusion . FISH allows to detect chromosomal changes in tumor plasma cells regardless of the mitosis phase. In MM, it becomes particularly important in connection with low proliferative activity of plasma cells. Additionally, in the fourth of MM patients in the study submicroscopic chromosomal aberrations were discovered using FISH. The improvement of the probe panel and the widespread use of locus specific FISH don’t replace G-banding that allows to see damages of all chromosomes at once.

Cytogenetic Abnormalities in Histologically Confirmed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5082-5082
Author(s):  
Anwar N. Mohamed ◽  
Gail Bentley ◽  
Michelle L. Bonnett ◽  
Margareta Palutke ◽  
Ayad M. Al-Katib
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Chromosomal Abnormalities ◽  
Molecular Genetic ◽  
Fish Analysis ◽  
Abnormal Karyotype ◽  
Proliferation Activity ◽  
Genetic Techniques ◽  
Conventional Cytogenetics ◽  
Monitor Treatment Response

Abstract In multiple myeloma, conventional cytogenetics is limited by low proliferation activity of plasma cells in culture. Despite that, nonrandom chromosomal abnormalities have been reported in one third of cases. Recently, the karyotype has emerged as an important prognostic factor in multiple myeloma. In this study, we identified 104 histologically confirmed multiple myeloma cases with satisfactory cytogenetic evaluation and abnormal karyotype. FISH analysis was used to evaluate certain chromosome abnormalities or to monitor treatment response. Hyperdiploid karyotype was found in 67 cases (64%), hypodiploid in 25 cases (24%), and the remaining 12 cases (12%) had a pseudodiploid karyotype. The most common numerical abnormalities were gains of chromosomes 9, 15, 3 followed by chromosomes 19, 21, 11, 7, and 5. Whole chromosome losses were also frequent involving primarily chromosomes 13, 8, 14, 22, and 16. In the hypodiploid cases, loss of chromosome 13 was more evident, seen in 19/25 (76%) cases. Most cases showed also structural rearrangements leading to del(1p), dup(1q), del(6q), del(9p), del(13q), del(17p), del(8p), 3p/3q abnormalities, and 11p/11q abnormalities. Translocations affecting 14q32/IGH region was the most frequent seen 36 times in 34/104 (33%) cases; t(11;14)(q13;q32) in 13 cases, t(1;14), t(6;14), and t(8;14) in 2 cases each, and the remaining cases had various t(V;14) partners or of an undetermined origin. The 14q32/IGH translocations were less frequent in the hyperdiploid karyotypes than the hypodiploid and pseudodiploid karyotypes (18% vs 60%). Nine cases showed break at 8q24/CMYC site; six of those had Burkitt’s-type translocations. Other non-random translocation was t(1;16) seen in three cases. Coventional cytogenetic remains an important tool in elucidating the complex and diverse genetic anomalies of multiple myeloma. Acccordingly well defined cytogenetic subgroups can be identified. At the present time, FISH and other molecular genetic techniques are important adjuncts, but should not be a substitute for conventional karyotyping. The clinical and hematological correlates of the karyotype in our series is being evaluated.

scholarly journals ANALYSIS OF COMPLEX CHROMOSOMAL ABNORMALITIES IN A CASE OF MULTIPLE MYELOMA USING SPECTRAL KARYOTYPING

2018 ◽  
Vol 11 (9) ◽  
pp. 9
Author(s):  
Perumal Govindasamy ◽  
Pooja S Kulshreshtha ◽  
Prabu Pandurangan ◽  
Anil Tarigopula ◽  
Jayarama S Kadandale ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Cells ◽  
Spectral Karyotyping ◽  
Multicolor Fish ◽  
Genetic Abnormalities ◽  
Prognostic Outcome ◽  
Conventional Cytogenetics ◽  
Marrow Cells

Objective: It was proposed to determine the chromosomal abnormalities in a 49-year-old male patient with multiple myeloma (MM) employing both conventional and advanced molecular cytogenetic techniques.Methods: GTG-banding and spectral karyotyping (SKY) on fixed metaphases obtained from LPS-stimulated bone marrow cells and interphase fluorescence in situ hybridization (iFISH) on unsorted marrow cells were carried out to identify genetic markers of prognostic significance.Results: The abnormal chromosomes observed through conventional cytogenetics could be resolved with SKY technique. The translocation t(4;14) (p16;q32) indicating FGFR3/IGH fusion and deletion of 13q14.3 was noticed using iFISH. The genetic abnormalities confirmed a poor prognostic outcome in the patient who died within 6 months of diagnosis.Conclusion: This report emphasizes the need for multicolor FISH techniques besides iFISH to resolve complex abnormalities and to identify cryptic aberrations of importance in risk stratification of MM patients.

Influence of Cytogenetics in Patients with Relapsed and Refractory Multiple Myeloma (MM) Treated with Carfilzomib (CFZ).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1827-1827 ◽  
Author(s):  
Andrzej Jakubowiak ◽  
Luhua Wang ◽  
Robert Z Orlowski ◽  
Sundar Jagannath ◽  
David Siegel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Single Agent ◽  
Entire Group ◽  
Fish Analysis ◽  
Advisory Committees ◽  
Minor Response

Abstract Abstract 1827 Poster Board I-853 Background It is now well established that cytogenetic abnormalities can affect the responses to therapies in multiple myeloma (MM) patients. Bortezomib, used alone or in combination with other agents, has been shown to overcome the adverse impact of several common unfavorable cytogenetic features. More recently, responses with lenalidomide and dexamethasone have been reported in patients with some types of unfavorable cytogenetics. Carfilzomib (CFZ) is a novel proteasome inhibitor that has demonstrated single agent activity in relapsed and/or refractory MM patients. The objective of this analysis was to provide the first preliminary information on the influence of cytogenetics in patients (pts) with relapsed and/or refractory MM treated with CFZ. Methods We evaluated 79 pts treated on two single agent CFZ studies (PX-171-003 and PX-171-004) in relapsed and/or refractory myeloma in which metaphase cytogenetics and/or FISH analysis for del 13q, t(4:14), and t(14;16) chromosomal abnormalities were available. Metaphase cytogenetics was conducted for all pts in the analysis; fluorescence in situ hybridization (FISH) results were available for 28 of the 79 pts. Twenty-one pts with relapsed and refratory MM (PX-171-003) and 58 pts with relapsed or refractory MM (PX-171-004) received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 in a 28-day cycle for up to 12 cycles. For this analysis, responders were defined as pts who achieved at least a Minor Response (MR) [MR + Partial Response (PR) + Very Good Partial Response (VGPR) + Complete Response (CR)] by IMWG and EBMT criteria. Results The median age of analysed pts was 63 yrs and 100% of pts were relapsed, with 70% refractory to their last therapy. Analysis of their histories demonstrated prior thalidomide treatment in 75% of pts, prior lenalidomide treatment in 57%, prior bortezomib treatment in 55%, and prior stem cell transplantation in 84%. The response rate (≥MR) for the entire group of patients was 40.5%. Twenty three of 79 pts had at least one of the abnormalities. The presence of del 13q, t(4;14), or t(14;16) did not significantly change the response rates, with 43.5% of pts with one or more abnormalities responding compared to 39.3% with none. The median time to progression (TTP) for all patients in this analysis was 203 days. The TTP for pts with one or more of the abnormalities was 195 days and was not significantly different from the TTP of 208 days for pts with none of the abnormalities (Figure; P > 0.05). Conclusion In this preliminary analysis, CFZ showed comparable activity in relapsed and relapsed/refractory MM with del 13q and/or t(4:14), and/or t(14;16) versus none of these abnormalities, with ≥MR in 43.5% vs. 39.3% of patients, and a TTP of 195 vs. 208 days, respectively. Updated efficacy data and TTP data will be presented at the meeting. Disclosures Jakubowiak: Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang:Proteolix, Inc.: Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Kukreti:Celgene: Honoraria. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. McDonagh:Proteolix: Research Funding. Vallone:Proteolix, Inc.: Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix: Research Funding.

Myelodysplastic Syndromes: A Multidisciplinary Integrated Diagnostic Work-up for Patients' Risk Stratification

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5579-5579
Author(s):  
Elena Ciabatti ◽  
Maria Immacolata Ferreri ◽  
Angelo Valetto ◽  
Alice Guazzelli ◽  
Veronica Bertini ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Mutational Analysis ◽  
Conflicts Of Interest ◽  
Normal Karyotype ◽  
Diagnostic Workup ◽  
Fish Analysis ◽  
Rt Pcr ◽  
Risk Scoring ◽  
Conventional Cytogenetics ◽  
Work Up

Abstract Conventional cytogenetics continues to have a fundamental role in the classification and risk scoring of myelodysplastic syndromes (MDS). Nevertheless, non-informative karyotypes represent up to 20% of cases. Some different molecular methods, not included in the routinary diagnostic workup, such as aCGH or mutational analysis, could be able to detect new abnormalities and improve the subtyping of MDS. The aim of this study was to propose a new diagnostic workup to determine the eventual adjunctive value offered by FISH, aCGH, and somatic mutation assays in respect of the the conventional cytogenetics only. In this study, we analyzed 50 patients: 29% female and 71% male, median age 71 (range 30-88 years), 66% at low/int1 IPSS risk, 54% at very-low/low R-IPSS risk, 33% with RCMD, 15% with RA, 14% with RARS, 14% with RAEB, 8% 5q-, and 16% with MMCL. We assessed these new MDS cases by different techniques: i) conventional cytogenetics; ii) FISH for chromosome 5, 7, PDGFRa, and PDGFRb; iii) aCGH, and iiii) specific RT-PCR for ASXL1, EZH2, TP53, and TET2 mutations. Conventional cytogenetics showed 42% of patients with at least one chromosomal aberration, including +8, del(11), del(7), del(5), -Y, +6, del(13), +14, del(20), and complex karyotypes (6% of cases). After FISH analysis, we were able to correctly classify as affected by the 5q- syndrome 2 cases who then received lenalidomide. The aGCH allowed to detect quantitative chromosomal aberrations in 44% of cases (del(13), -7, del(12), del(16), del(17), del(11), del(8), dupl(14), 5q-), including 10 cases (20%) showing a normal karyotype. After the RT-PCR, 32% of patients resulted mutated, with highest frequency for TP53 (22%). Four of these TP53-mutated patients showed normal karyotype, and resulted unmutated also by FISH and aCGH; in a case TP53 mutated we added treatment with steroid. Other 3 patients TP53-mutated did not respond to azacitidine Four low-risk patients (8%) showed ASXL1 gene mutation, three of them not earlier detected by cytogenetics or aCGH. One of these patients died after progression into acute leukemia. The identification of TP53 or ASXL1 mutations after RT-PCR and of dupl(14) by the aCGH prompted us to strictly follow patients at high risk of transformation. Only one case showed TET2 mutation; although TET2 mutations have been related to a better survival in patients receiving 5-azacitidine, this patient resulted not-responsive after 9 cycles. In conclusion, these results sustain the necessity of an integrated work-up for the diagnosis and the correct risk scoring of MDS patients. Disclosures No relevant conflicts of interest to declare.

The usefulness of interphase fluorescence in situ hybridization at diagnosis of myeloma in addition to metaphase cytogenetics

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19558-e19558
Author(s):  
S. Park ◽  
C. Kim ◽  
H. Kim ◽  
D. Hong ◽  
S. Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Plasma Cells ◽  
Chromosomal Abnormalities ◽  
Chromosome Abnormalities ◽  
Interphase Fish ◽  
Conventional Cytogenetics ◽  
Igh Rearrangement

e19558 Background: Multiple myeloma is characterized by the accumulation of malignant plasma cells within the bone marrow and regarded as incurable, but remissions may be induced with steroids, chemotherapy, thalidomide and stem cell transplants. The clinical heterogeneity of myeloma is dictated by the cytogenetic aberrations present in the clonal plasma cells. Fluorescence in situ hybridization (FISH) overcomes the limitations of standard cytogenetics and allows for the detection of numerical and structural chromosomal abnormalities in both metaphase spreads and interphase nuclei. Methods: We evaluated the chromosome abnormalities in 34 MM patients using conventional cytogenetics and interphase FISH with 6 probes such as IGH/CCND1, IGH/FGFR3, IGH/MAF, DS13S319/LAMP1, IGH/BAP, and p53/CEP17. Results: Cytogenetic abnormalities were found in 24 (70.6%) of the 28 MM patients. 10 (35.7%) patients had abnormal metaphases by conventional cytogenetics. Interphase FISH results were abnormal in 21 (61.8%) patients and 11 (52.3%) patients had abnormal interphase FISH but normal metaphases. The evidence of the loss of D13S319 with or without loss of LAMP1 was found in 6 (21.4%) patients, and loss of p53±CEP17 for 2 patients, IGH-BAP for 9 (26.5%) patients, IGH/FGFR3 for 2 patients, and IGH/CCND1 for 7 (20.6%) patients, respectively. However, there were none positive for IGH/MAF. Chromosome 13 abnormalities and IGH rearrangement is correlated with poor clinical outcome. Conclusions: Interphase FISH can provide useful information to evaluate the presence of prognostic chromosome abnormalities in addition to metaphase cytogenetics. And it should be used in the routine evaluation of multiple myeloma. No significant financial relationships to disclose.

Impact of t (11;14) on the outcome of autologous hematopoietic cell transplantation (Auto-HCT) in multiple myeloma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8040-8040
Author(s):  
Koji Sasaki ◽  
Gary Lu ◽  
Chitra Hosing ◽  
Uday R. Popat ◽  
Sairah Ahmed ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Chromosomal Abnormalities ◽  
Normal Karyotype ◽  
Cancer Center ◽  
Induction Treatment ◽  
High Dose ◽  
Significant Difference ◽  
The Impact

8040 Background: Approximately 15-20% of patients with multiple myeloma (MM) present with t(11;14)(q13;q32) involving IgH and CCND1-XT genes. In this study, we report the impact of the t(11;14) on the outcome of patients with MM. Methods: We performed a retrospective chart review on patients with MM who underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between 2/2000 and 8/2010, and had conventional cytogenetic (CC) or fluorescent in situ hybridization (FISH) results available before transplant. The primary objective was to compare the progression free survival (PFS) and overall survival (OS) of patients with t(11;14) to patients without chromosomal abnormalities. Results: CC or FISH studies were available for 1239 patients: 863 normal, 28 with t(11;14), 348 with other abnormalities. Concurrent high-risk abnormalities on CC or FISH were seen in 15/28 patients with t(11;14): del(13q) in 11 , del(17p) in 3, and t(14;16)(q32;q23) in 1. Induction treatment in patients with t(11;14) was: bortezomib + dexamethasone +/- thalidomide/lenalidomide : 15 (53%), thalidomide or lenalidomide + dexamethasone: 11 (39%), others 2 (8%); they received auto-HCT after a median of one line (1-7) of therapy. Median follow up in surviving patients was 39 months. There was no significant difference in median time from diagnosis to auto-HCT from diagnosis (6.9 vs. 7.7 months, p=1.0), disease status at auto HCT (>PR1: 82 vs. 76%, <PR1: 7 vs. 11%, relapsed 10 vs. 13%), complete remission (CR: 21% vs. 32%; p=0.30), very good partial remission (VGPR: 29% vs. 21%; p=0.23) or overall response (75% vs. 85%; p=0.18) between patients with t(11;14) and normal karyotype. Median PFS in patients with t(11;14) and normal karyotype was 15.7 months and 35.9 months, respectively (p=0.017). Median OS in patients with t(11;14) and normal karyotype was 51.4 months and 88.4 months, respectively (p=0.03). There was no difference in PFS (p=0.25) or OS (p=0.71) in patients with t(11;14), with or without other high-risk chromosomal abnormalities. Conclusions: In this large single center study with a long follow up, we demonstrated that t(11;14) in MM is associated with a shorter PFS and OS in the context of auto-HCT.

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