Jumping Translocations of the Long Arms of Chromosome 1 (1qJT) in Myeloproliferative Neoplasms (MPNs) and Myelodysplastic Syndromes (MDS) Are Associated with High Risk of Transformation to Acute Myelogenous Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1567-1567
Author(s):  
Vesna Najfeld ◽  
Joseph Tripodi ◽  
Steven Fruchtman ◽  
Lewis R. Silverman ◽  
Richard T. Silver ◽  
...  
Keyword(s):  
High Risk ◽  
Copy Number ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Chromosomal Rearrangements ◽  
Patient Characteristics ◽  
Myelogenous Leukemia ◽  
Chromosome 1 ◽  
Genetic Event

Abstract Abstract 1567 Poster Board I-591 Jumping translocations (JT) are rare cytogenetic events where by a part of one chromosome is translocated to several recipient chromosomes creating multiple related clones within a single patient (pt). Over two-thirds of the already ∼70 reported cases with JTs had multiple myeloma (JR Sawyer et al, 2005). The most frequent donor chromosome involved in JT is the long arm of chromosome 1 (+1q). Although abnormalities of 1q are the 4th most common recurrent rearrangements in both MPN and MDS, 1qJT have been rarely reported in these disorders. Their role in the pathogenesis of MPN and MDS remains unknown. We report a study of 23 pts with myeloid malignancies to determine the role of 1qJT in MPN and MDS. Patient characteristics are shown in Table 1. Of 512 MPN pts (PV=361, PMF=151) cytogenetically evaluated at our institution, we identified 3 pts (PV=2, PMF=1) at diagnosis with 1qJT (0.6% incidence). Additionally 4 of 169 (PV=96, PMF=69) pts with MPN acquired 1qJT during the serial follow up studies over a period of 11 years (the overall incidence was 1.3%, and 4.2% in pts with cytogenetically abnormal karyotypes). Table 1 Characteristics of 23 pts with 1qJT at baseline and sequential studies *One patient had stem cell transplantation The median follow up time was 78 months (mos) and the average time to acquire 1qJT was 58 mos. usually only one or two cells with +1q were initially identified but over time the number of partner chromosomes increased. In 4 pts who acquired 1qJT, this genetic event occurred an average after 5 years while in 1 pt it occurred after 11 years. However, once 1qJT was acquired, 3 of 4 pts developed AML, within an average time of 8 months. The transformation to AML was associated with an increased 1q translocated copy number, suggesting that 1qJT may be a marker of disease progression. By contrast, the incidence of 1qJT at diagnosis of MDS was 0.04% (4 of 1,000). Each of 4 pts, who presented with 1qJTs, had up to three different related clonal populations, all characterized by +1q translocated to 3 different chromosomes. The presence of 1qJT at diagnosis was associated with transformation to AML (3 of 4 pts) after less than 4 mos. Additionally of the 300 pts who were sequentially studied for over a period of 34 mos, 12 pts acquired 1qJT within 27 months (the overall incidence 4%, or 8% among the cytogenetically abnormal). Once 1qJT was acquired, transformation to AML occurred after 8 months (range 0-32) in 10 of 12 pts (83%). This was accompanied with an increased number of JT partner chromosomes. Overall, trisomy 1q, was “jumping” to as many as 11 different chromosomes, creating 11 related clonal populations. All chromosomes except 2, 10 and 12, were recipients of 1qJT, with a greater frequency affecting acrocentric chromosomes (55%). More importantly, 81% of the breakpoints in recipient chromosomes were in the pericentromeric regions. This study represents the largest series of pts with MPN and MDS characterized by 1qJT. The presence of 1qJT at diagnosis or the subsequent acquisition of 1qJT was associated with transformation to AML in 86% of MPN cases and 83% of MDS cases after an average of 8 months. The prognosis of pts with 1qJT tends to be dependent on the translocated 1q copy number: the higher the number of “jumping” 1q being translocated to different partner chromosomes the shorter the time to transformation to AML. These data strongly indicate that 1qJT in MPN and MDS patients represents clonal chromosomal rearrangements associated with a high risk of imminent transformation to AML. Disclosures No relevant conflicts of interest to declare.

Recurrent Amplified Regions on the Long Arm of Chromosome 1 (1q) Are Associated with Disease Progression In Ph-Negative Myeloproliferative Neoplasms (MPN)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3087-3087
Author(s):  
Vesna Najfeld ◽  
Joseph Tripodi ◽  
Timothy Best ◽  
Mingjiang Xu ◽  
Ronald Hoffman ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Snp Array ◽  
Normal Karyotype ◽  
Myelogenous Leukemia ◽  
Chromosome 1 ◽  
Abnormal Karyotype ◽  
Chromosome 1Q

Abstract Abstract 3087 Trisomy of all or part of the long arm of chromosome 1 (1q) is a recurrent abnormality frequently observed at diagnosis in myeloproliferative neoplasms (MPN). Recently, we reported that jumping translocations involving duplications of chromosome 1q (1qJT) represent a clonal marker associated with high risk of transformation to acute myelogenous leukemia (AML) in both MPN and myelodysplastic syndrome (MDS). Breakpoints are often found at either 1q12 or 1q21 (Najfeld et al BJH 2010). Consequently, we hypothesized that these regions are likely to contain a gene or cluster of genes under selection for amplification associated with disease progression. To investigate this, we karyotyped 13 patients (7 males and 6 females) with MPN (primary myelofibrosis [MF]=7, essential thrombocythemia [ET]=2, ET->polycythemia vera- [PV]=1, ET or PV->MF=2, ET->MF->AML=1). Ten of these 13 patients (pts) had an abnormal karyotype, while 3 patients had a normal karyotype. Of pts with an abnormal karyotype, four had trisomy 1q and two had duplication 1q (q12 to q31). The breakpoint 1q12 was observed in 3 pts while the breakpoint 1q21 was identified in 4 pts. One pt had two different populations of cells with a 1q duplication (1q): 36% of cells had a 1q21 breakpoint while 6% cells had a 1q12 breakpoint as identified by FISH using 1q12 and 1q21 specific FISH probes. Additionally, one pt had trisomy for chromosomes 8 and 9, and one had a balanced t(1;9)(p36;p24.1) abnormality. JAK2V617F, an activating mutation implicated in MPN, was present in 6 pts. Of the 13 pts six progressed to AML or had an aggressive disease course that required stem cell transplantation. To map the boundaries of the minimally amplified regions on chromosome 1q associated with disease progression, DNA was isolated from the MPN cells of these 13 patients and genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0. Copy number abnormalities were assessed by Genomic Segmentation (Partek Genomic Suite, St Louis, MO). This analysis revealed seven regions that were recurrently amplified (amplified in at least 4 MPN cases but not in normal controls). Of these regions, three were in 1q21.1 and the rest were telomeric to 1q21. We identified six patients with amplifications in 1q21.1, in contrast to the four identified by karyotype analysis. Of these, one pt had a normal karyotype and was JAK2V617F negative. Intriguingly, the region on 1q21 amplified in this patient was also amplified in the relapse sample of another patient at the time of progression to AML. Of note, this region includes PDE4DIP, which had previously shown to be part of a t(1;5)(q23;q33) translocation in MPN associated with eosinophilia. Of the other recurrent amplifications four pts had a gain of 1q32.1 which includes MDM4, a known regulator of the p53 tumor suppressor. Thus, these data suggest that fine mapping of recurrently amplified regions of chromosome 1q may reveal genes under pressure for amplification in high-risk MPN or that may be involved in the high-risk 1qJT found in both MPN and MDS. Disclosures: No relevant conflicts of interest to declare.

Post-Transplant Therapy Is More Important Than Induction Regimen Choice in Autologous Hematopoietic Cell Transplantation (AHCT) Recipients for Multiple Myeloma (MM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 396-396 ◽  
Author(s):  
Robert Frank Cornell ◽  
Luciano J Costa ◽  
Adetola A. Kassim ◽  
Racquel Inns-Shelton ◽  
Amrita Krishnan ◽  
...  
Keyword(s):  
High Risk ◽  
Hematopoietic Cell Transplantation ◽  
Chromosomal Abnormalities ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
Chromosome 1 ◽  
Disease Stage ◽  
Similar Response ◽  
Induction Regimen

Abstract Background: Modern therapies incorporating bortezomib (V), lenalidomide (R), cyclophosphamide (C) and dexamethasone (D) constitute the most common doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens for transplant eligible MM in the US. These regimens produce an overall response rate of >80% but their impact on longer term post-AHCT outcomes are largely unknown. Patient and Methods: We evaluated the relative impact of pre- and post-AHCT treatment on 693 patients receiving upfront AHCT after induction with RD (178), VD (161), CVD (84) or VRD (270) using data prospectively reported to the CIBMTR from 2008-2013. Analysis was limited to those receiving one line of induction chemotherapy and a single transplant with 200 mg/m2 melphalan as conditioning regimen no later than 12 months from treatment initiation. Survival endpoints were evaluated from time of AHCT and the planned use of post-AHCT maintenance incorporating R or V was also considered. Results: The table shows patient characteristics. Median number of induction cycles were 4 (range, 2 to 16) and median time to transplant was 6.5 months. Median follow up was 36 months (3 to 82) from time of transplant. Age, disease stage, disease status at transplant and cytogenetic risk were similar between the 4 cohorts. Fourteen percent had high-risk chromosomal abnormalities [17pdel, t(4;14), t(14;16), chromosome 1 abnormalities and hypodiploidy]. CVD and VD were used more frequently in patients with renal failure. Doublet use was more common before 2010 (55%) and triplets after 2010 (85%). Use of R or V post-AHCT chemotherapy was higher in with VRD (79%) and CVD (81%) cohorts vs. RD (53%) and VD (67%). No differences in pre- or post-AHCT responses were seen with regard to choice of induction agents. Pre-AHCT responses ≥VGPR were 57% for VRD vs. 45/42/51% for CVD/RD/VD respectively. Corresponding post AHCT responses at day 100 were 65% for VRD and 58/63/65% respectively. In multivariate analysis of relapse, progression free (PFS) and overall survival (OS), there was no overall difference in these outcomes based on induction regimen. High risk cytogenetics (HR = 0.57, p=0.0004 for non-high risk) and absence of planned maintenance (HR=1.55, p=0.0008) were associated with higher risk of relapse. VRD was associated with a marginal benefit in relapse risk vs. CVD (HR=0.68, p=0.04). Non-relapse mortality was similar across cohorts. Those not receiving planned post-AHCT maintenance (HR 1.69, p<0.001) and high-risk MM had higher risk of progression/death (HR in non-high risk 0.58, p<0.001); OS was lower in those with low stage (DSS or ISS I/II) vs. stage III (HR 0.6, p=0.006) and with non-high risk cytogenetics (HR 0.5, p=0.001). Patients receiving planned post-AHCT therapy had significantly improved 3-year PFS vs. no post-AHCT therapy (55% vs. 39%, log-rank p=0.0001) (figure). Conclusions: Modern induction doublets and triplets induce similar response rates and post AHCT outcomes at a median follow-up of 36 mo. Although there is an increase in use of triplets after 2010 in transplant eligible patients, our analysis suggests that the choice of induction regimen is less important than the decision to use vs. not use planned post-AHCT maintenance therapy. Figure 1. Patient characteristics. Figure 1. Patient characteristics. Figure 2. PFS by planned post-AHCT therapy vs. not: Figure 2. PFS by planned post-AHCT therapy vs. not: Disclosures Krishnan: Janssen: Consultancy; BMS: Consultancy; Jazz: Consultancy; Millenium: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Onyx: Speakers Bureau. Gasparetto:Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hari:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy.

scholarly journals Whole-genome optical mapping of bone-marrow myeloma cells reveals association of extramedullary multiple myeloma with chromosome 1 abnormalities

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eva Kriegova ◽  
Regina Fillerova ◽  
Jiri Minarik ◽  
Jakub Savara ◽  
Jirina Manakova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Copy Number ◽  
Optical Mapping ◽  
Chromosome 1 ◽  
Gene Copy ◽  
Whole Genome ◽  
Myeloma Cells ◽  
Genomic Architecture

AbstractExtramedullary disease (EMM) represents a rare, aggressive and mostly resistant phenotype of multiple myeloma (MM). EMM is frequently associated with high-risk cytogenetics, but their complex genomic architecture is largely unexplored. We used whole-genome optical mapping (Saphyr, Bionano Genomics) to analyse the genomic architecture of CD138+ cells isolated from bone-marrow aspirates from an unselected cohort of newly diagnosed patients with EMM (n = 4) and intramedullary MM (n = 7). Large intrachromosomal rearrangements (> 5 Mbp) within chromosome 1 were detected in all EMM samples. These rearrangements, predominantly deletions with/without inversions, encompassed hundreds of genes and led to changes in the gene copy number on large regions of chromosome 1. Compared with intramedullary MM, EMM was characterised by more deletions (size range of 500 bp–50 kbp) and fewer interchromosomal translocations, and two EMM samples had copy number loss in the 17p13 region. Widespread genomic heterogeneity and novel aberrations in the high-risk IGH/IGK/IGL, 8q24 and 13q14 regions were detected in individual patients but were not specific to EMM/MM. Our pilot study revealed an association of chromosome 1 abnormalities in bone marrow myeloma cells with extramedullary progression. Optical mapping showed the potential for refining the complex genomic architecture in MM and its phenotypes.

scholarly journals Pre-Enucleation Chemotherapy in Advanced Intraocular Retinoblastoma. Central America Follow Up: AHOPCA II

2016 ◽  
Vol 2 (3_suppl) ◽  
pp. 75s-75s
Author(s):  
Sandra Luna-Fineman ◽  
Soad L. Alabi ◽  
Mauricio E. Castellanos ◽  
Yessika Gamboa ◽  
Ligia Fu ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Central America ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
High Risk Group ◽  
Globe Rupture ◽  
Neo Adjuvant Chemotherapy ◽  
Standard Risk

Abstract 57a Purpose: A significant percentage of patients in Central America present with buphthalmos, carrying a high risk of globe rupture and orbital contamination. In 2007, AHOPCA introduced chemotherapy before enucleation in children with buphthalmos. Methods: Patients with advanced intraocular disease were considered standard-risk and underwent enucleation. Those with diffuse invasion of choroid, postlaminar optic nerve, or anterior chamber invasion received 4-6 cycles of adjuvant chemotherapy (vincristine, carboplatin, etoposide). Patients with buphthalmos or perceived to be at risk for abandonment were considered high-risk, given 2-3 cycles of chemotherapy before enucleation to compete 6 cycles regardless of pathology. All cases were discussed via online meetings. Results: From 2007 to 2014, 396 patients were enrolled; 240 had IRSS stage I (174 unilateral). 143 had upfront enucleation, 95 had pre-enucleation chemotherapy, 1 is pending enucleation and 1 abandoned before enucleation. The standard-risk group 69 had risk pathology and 76 had no risk factors; 125 had no events, 5 abandoned 11 relapsed/progressed and 2 died of toxicity. Of 95 high-risk group, 8 abandoned, 20 relapse/progressive, 6 had toxic deaths and 61 are alive at last follow-up (median time of 4 years). Of high risk group, 55 were unilateral, 82% are alive. At 7 years OS (abandonment-censored) was 95±0.02 and 79±0.04 for standard-risk and high-risk (p=0.008). Conclusion: AHOPCA addressed advanced intraocular disease with an innovative approach. In eyes with buphthalmos and patients with risk of abandonment, neo-adjuvant chemotherapy is effective, when followed by post-enucleation chemotherapy. This approach avoids ocular rupture and intensified therapy, and reduces refusal/abandonment rate. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: No COIs from the authors.

Comparing Toxicities and Survival Outcomes with Total Therapy 4 (TT4) for 70-Gene (R70)-Defined Low-Risk Multiple Myeloma (MM) to Results Obtained with Total Therapy 3 Protocols TT3A and TT3B

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 368-368 ◽  
Author(s):  
Elias J. Anaissie ◽  
Frits van Rhee ◽  
Antje Hoering ◽  
Sarah Waheed ◽  
Yazan Alsayed ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Low Risk ◽  
Phase Iii ◽  
Survival Outcomes ◽  
Phase Iii Trial ◽  
Baseline Characteristics ◽  
Total Therapy ◽  
Timing Of Onset

Abstract Abstract 368 Background: TT3, incorporating bortezomib and thalidomide with induction prior to and consolidation after melphalan 200mg/m2-based transplants and 3 year maintenance with VTD (year 1) and TD (years 2+3) in TT3A and with VRD for 3 years in TT3B resulted in a high CR rate of ∼60% and, in the 85% of patients with GEP-defined low-risk MM, 5-yr OS/EFS of 80%/78%; 5-year CR duration estimate was 88%. Patients and Methods: Phase III trial TT4 for low-risk MM randomized patients between standard (S) and light (L) arms. TT4-L applied 1 instead of 2 cycles of induction therapy with M-VTD-PACE prior to and 1 instead of 2 cycles of consolidation with dose-reduced VTD-PACE after tandem transplantation. M-VTD-PACE comprised melphalan, bortezomib, thalidomide, dexamethasone and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide. TT4-S applied standard single dose melphalan 200mg/m2, while TT4-L used a 4-day fractionated schedule of melphalan 50mg/2 on days 1–4. VRD maintenance for 3 years was identical in both arms. Here we report, for both TT4 arms combined, on grade >2 mucosal toxicities, applying CTCAE version 3.0, and on efficacy (CR, EFS, OS) in relationship to TT3 in low-risk MM. At the time of analysis, median follow-up on TT4 is 10.7 months and on TT3A/B 62.3/33.4 months. To facilitate comparisons between trials with different follow-up times, TT3 data were backdated to follow-up time comparable to TT4 as of this reporting time. Results: Baseline characteristics were similar in TT3 (n=364) and TT4 (n=165) in terms of B2M both >=3.5mg/L and >5.5mg/L, and elevated levels of CRP, creatinine, and LDH. Presence of cytogenetic abnormalities (CA) overall and in terms of CA13/hypodiploidy was similar in both. Fewer TT4 patients had ISS-1 (31% v 43%, P=0.010) and more had hemoglobin <10g/dL (35% v 26%, P=0.029). While neither trial had GEP-defined high-risk in the 70-gene model (R70), the more recently validated R80 distribution showed 7% high-risk in TT4 v 3% in TT3 (P=0.031). DelTP53 was more prevalent in TT4 than TT3 (39% v 10%, P<0.001), and MY favorable subgroup designation pertained to 3% in TT4 v 12% in TT3 (P=0.002). Toxicities are reported per protocol phase. During induction (TT4, n=160; TT3, n=364), grade >2 mucosal toxicities included colitis in 0%/1% (P=0.32), esophagitis/dysphagia in 0%/1% (P=0.33), GI mucositis, NOS in 1%/1% (P=0.99) and stomatitis/pharyngitis in 0%/1% (P=0.99). With transplant-1, (TT4, n=139; TT3, n=344), grade >2 mucosal toxicities included colitis in 3%/1% (P=0.24), esophagitis/dysphagia in 1%/5% (P=0.03), gastritis in 1%/0% (P=0.29), GI mucositis, NOS in 1%/2% (P=0.73) and stomatitis/pharyngitis in 0%/5% (P=0.008); with transplant-2 (TT4, n=105; TT3, n=294), grade >2 mucosal toxicities included colitis in 4%/3% (P=0.77), esophagitis/dysphagia in 0%/2% (P=0.20), GI mucositis, NOS in 2%/3% (P=0.99) and stomatitis/pharyngitis in 0%/1% (P=0.58). With consolidation (TT4, n=85; TT3, n=280), grade >2 mucosal toxicities included colitis in 0%/3% (P=0.36) and GI mucositis, NOS in 0%/1% (P=0.99). Timing of onset and final levels of CR differed substantially between TT4 and TT3 in favor of TT4 (P=0.006); no differences were observed in OS (P=0.36), EFS (P=0.66), and CR duration (P=0.12). Conclusion: TT4 (both arms combined) provided, despite higher proportions of patients with unfavorable characteristics than in TT3, superior CR rate and comparable survival outcomes to TT3's low-risk population. GI toxicities were reduced in TT4 v TT3. Results of TT4 arms will be presented. Disclosures: No relevant conflicts of interest to declare.

Improved Outcome with Total Therapy 3 (TT3) In Comparison with Total Therapy 2 (TT2) Can Be Traced to GEP70-Defined High-Risk Disease with Trisomy of 1q21 and Modest but Not Marked Hyper-Activation of the Proteasome Gene PSMD4

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 303-303
Author(s):  
John Shaughnessy ◽  
Pingping Qu ◽  
Erming Tian ◽  
Bijay Nair ◽  
Sarah Waheed ◽  
...  
Keyword(s):  
High Risk ◽  
Copy Number ◽  
Risk Model ◽  
Conflicts Of Interest ◽  
Dramatic Improvement ◽  
Proteolytic Fragment ◽  
Poor Outcome ◽  
High Risk Disease ◽  
Total Therapy ◽  
High Level

Abstract Abstract 303 Background: Gene expression profiling (GEP) of purified plasma cells identifies 15% of newly diagnosed MM as high-risk with a median survival of 2yr compared to 10+yr for the remainder. A validated 70-gene GEP risk model (GEP70) making such determinations is related to copy number increases in chromosome 1q21. Moreover, FISH-defined gains of 1q21 at diagnosis are associated with poor outcome and serial studies have shown that both the percentage of cells with 1q21 gains and 1q21 copies in these cells invariably increase at relapse. Combined with the fact that 1q21 is the only recurrent high-level amplicon in MM, these data suggests that 1q21 harbors a copy number sensitive gene or genes that confer resistance to apoptosis. PSMD4 and CKS1B are the only genes in the GEP70 model that map to the 1q21 amplicon. PSMD4 is the polyubiquitin receptor for the proteasome and the only component of the proteasome that exists free of the proteasome complex. High levels of free cytoplasmic PSMD4 and a small proteolytic fragment of PSMD4, known as anti-anti-secretoy factor, may be able to reduce proteasome load thereby reducing sensitivity of MM cells to proteasome inhibition-induced apoptosis. Patients and Method: In TT3, we added BOR to TT2 and performed GEP at baseline and 48hr after BOR test-dosing (1.0mg/m2). We correlated post BOR GEP (TT3), baseline GEP (TT2 and TT3), and baseline 1q21 FISH (TT2 and TT3) with outcomes in over 600 cases. Result: PSMD4 and 14 other proteasome genes were among 80 genes in a post-BOR GEP model (GEP80) created in TT3 and validated in TT3B, whose post-BOR elevated expression was related to poor outcome. The absence of hyper-activation of PSMD4 and proteasome genes after in-vivo thalidomide, dexamethasone or lenalidomide test dosing suggested that this effect was BOR-specific. There was strong but not complete overlap between risk designations by the GEP70 and GEP80 models in TT2 and TT3. We combined the risk predictions of the two models in baseline samples creating four risk combinations. Kaplan Meier analysis revealed a dramatic improvement in outcomes of GEP70 high-risk/GEP80 low-risk cases in TT3 relative to TT2. Similarly, while a significant improvement in outcomes were observed in cases with 3 copies of 1q21, there was no difference for cases with 4+ copies of 1q21. To determine if 1q21 copy number-driven expression changes could account for these differences, we correlated GEP of candidate genes with the presence of 2, 3 or 4+ copies of 1q21. Using FISH-defined tertiles we discovered that intermediate levels of PSMD4, corresponding to 3 copies of 1q21, was associated with significant improvement in outcome in TT3. Conclusion: BOR incorporated into TT3 overcomes GEP70 high-risk disease with 3, but not 4+ copies of 1q21. PSMD4, is a copy number dependent gene at 1q21 and appears to be a strong prognostic biomarker for BOR-containing therapies. We propose that TT3-like therapies can overcome the anti-apoptotic effects of modest increases in PSMD4 levels in MM, but that novel therapeutic strategies specifically targeting PSMD4 function might be needed to improve the currently dismal outcomes associated with high-level expression of PSMD4. Disclosures: No relevant conflicts of interest to declare.

Significance of Bone Marrow Karyotype and Morphology in Patients with Inherited Bone Marrow Failure Syndromes,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3431-3431
Author(s):  
Neelam Giri ◽  
Blanche P Alter ◽  
Helkha Peredo-Pinto ◽  
M. Tarek Elghetany ◽  
Irina Maric ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Disease Progression ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Myelogenous Leukemia ◽  
Monosomy 7 ◽  
Cytogenetic Abnormalities ◽  
Bone Marrow Failure Syndromes ◽  
Number Of Patients

Abstract Abstract 3431 Recurring clonal cytogenetic abnormalities have been described in patients with Fanconi anemia (FA) and Shwachman-Diamond syndrome (SDS). In FA, gains of 3q and monosomy 7 (−7) imply progression to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). In SDS, isochromosome 7q and deletion (del) 20q are usually benign. Dyskeratosis congenita (DC) and Diamond-Blackfan anemia (DBA) do not have unique clones. We report here the types and frequencies of cytogenetic clones and their association with morphologic MDS or AML in the major inherited bone marrow failure syndromes (IBMFS), in a prospective/ retrospective study of patients with FA, SDS, DC and DBA enrolled in the NCI IBMFS cohort from 2002–2010. Bone marrow (BM) morphology and cytogenetics (G-banding; selected FISH, CGH, SKY) performed at our institute and all outside cytogenetics reports were centrally reviewed. Cytogenetic abnormalities were defined and karyotypes designated according to ISCN (2009). Two independent blinded hematopathologists reviewed BM morphology. Diagnosis of morphologic MDS was based on a modification of WHO 2008 and required ≥10% dysplasia in 2 cell lineages. Data analysis was both cross-sectional and longitudinal. P values are global comparing all 4 disorders using Fisher's exact test.ParameterAll IBMFSFASDSDCDBAP valueTotal number (N)12835113646–N with clone ever2817 (49%)4 (36%)4 (11%)3 (7%)<0.01N with MDS ever105 (14%)3 (27%)1 (3%)1 (2%)0.01N with clone + MDS75 (14%)2 (18%)00<0.01N with clone alone2112 (34%)2 (18%)4 (11%)3 (7%)<0.01N with MDS alone301 (9%)1 (3%)1 (2%)0.3N with clone at 1st BM179 (26%)4 (36%)3 (8%)1 (2%)<0.01N with clones at follow-up118012<0.01N with follow-up BMs591791716–Median follow-up in years3 (0–19)6 (1–16)2 (1–6)3 (0–19)2 (0–10)– More FA and SDS patients had clones and/or MDS compared with DC or DBA (Table). MDS was always associated with clones in FA but not in the other IBMFS. In FA, bone marrow transplant (BMT) or death occurred with similar frequencies in those with or without clones. Among 17 patients with clones, follow-up cytogenetics were unavailable in 5; of these, 2 with clone alone [one with del 7q and 18p and one with t(3;6)(q?25;p?21)] progressed to AML, while one with clone and MDS died from other causes. Recurring abnormalities in 12 FA patients with clones followed for up to 16 years, included gains of 1q in 4, −7 or del 7q in 3, and deletions of 6p, 13q, 18p and 20q in 2 patients each; only one had gain of 3q. These patients showed fluctuation or disappearance of clones, new appearance of clones, stable clone, or clonal evolution. Progression to MDS occurred with gain of 1q and 6p deletion, gain of 3q, or −7 in 3 patients, respectively; one patient with MDS had clonal persistence. No disease progression was seen in 5 FA patients with clone alone. All 5 SDS patients with clones and/or MDS are alive with no disease progression. The 4 with a clone had stable persistent del 20q as a sole abnormality; 2 had MDS and 2 did not. One had MDS with a normal karyotype. Four DC patients had abnormal clones including 2 with gain of 1q only. One patient with 1q gain died from pulmonary fibrosis. Three others are alive; 2 with stable clones at 7 and 19 years' follow-up, respectively. One additional DC patient has morphologic MDS but no clone. All 3 DBA patients with clones had del 16q, 2 alone and 1 with del 9p; none had MDS. The clones were transient in 2, disappearing within 1–2 years; the third was recently identified. None of these had disease progression. One patient with morphologic MDS alone died from complications of iron overload. This study shows that clonal chromosome abnormalities occur more frequently in FA and SDS than in DC and DBA. Gain of 3q in FA was not as common here as reported by others. This is the first comprehensive study of clones and MDS in DC and DBA. Strengths of this study include the large number of patients, and central review of cytogenetics and morphology. It is unbiased compared with FA literature reports that include many patients referred for BMT. Limitations include a relatively small number of patients with each diagnosis and short follow-up in most. The study demonstrates that clones may fluctuate or disappear, and may not per se portend a bad prognosis. Progression to clinically significant MDS or AML may be related to the severity of cytopenias and not to clone alone, and warrants more extensive long-term studies. Disclosures: No relevant conflicts of interest to declare.

Tet2 Loss Accelerates The Myeloproliferative Neoplasm (MPN) Phenotype Of Jak2V617F Knockin Mice But Is Insufficient To Cause Leukemic Transformation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4095-4095
Author(s):  
Edwin Chen ◽  
Lawrence J Breyfogle ◽  
Rebekka K. Schneider ◽  
Luke Poveromo ◽  
Ross L. Levine ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Myeloproliferative Neoplasm ◽  
Conditional Knockout ◽  
The Other ◽  
Myelogenous Leukemia ◽  
Leukemic Transformation ◽  
The Impact

Abstract TET2 mutations are early somatic events in the pathogenesis of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPN) and are one of the most common genetic lesions found in these diseases. In MPN, TET2 mutations are enriched within more advanced disease phenotypes such as myelofibrosis and leukemic transformation and often co-occur with the JAK2V617F mutation, which is present in the majority of MPN patients. We have developed and characterized a Jak2V617F conditional knockin mouse (Jak2VF/+), the phenotype of which closely recapitulates the features of human MPN. To determine the impact of Tet2 loss on Jak2V617F-mediated MPN, we crossed Tet2 conditional knockout mice with Jak2VF/+ knockin and Vav-Cre transgenic mice and backcrossed the compound mutant animals. We then characterized the effects of heterozygous and homozygous loss of Tet2 on the phenotype of Jak2VF/+ mice. We assessed peripheral blood counts, histopathology, hematopoietic differentiation using flow cytometry, colony formation and re-plating capacity. We also evaluated the effects of Tet2 loss on the transcriptome of the HSC compartment using gene expression microarrays and on HSC function using competitive bone marrow transplantation assays. Similar to Jak2VF/+/VavCre+ mice, Tet2+/-/Jak2VF/+/VavCre+ and Tet2-/-/Jak2VF/+/VavCre+ mice develop leukocytosis, elevated hematocrits (HCT) and thrombocytosis. Tet2-/-/Jak2VF/+/VavCre+ mice demonstrate enhanced leukocytosis and splenomegaly compared to the other groups. All groups demonstrate myeloid expansion, erythroid hyperplasia and megakaryocytic abnormalities consistent with MPN in the bone marrow and spleen, while more prominent myeloid expansion and megakaryocytic morphological abnormalities are observed in Tet2-/-/Jak2VF/+/VavCre+ mice as compared to the other groups. Notably, we do not see the development of acute myelogenous leukemia (AML) in Tet2-/-/Jak2VF/+/VavCre+ mice at 6 months. We see enhanced expansion of lineagelowSca1+cKithigh (LSK) cells (enriched for HSC) most prominently in the spleens of Tet2+/-/Jak2VF/+/VavCre+ and Tet2-/-/Jak2VF/+/VavCre+ mice as compared to Jak2VF/+/VavCre+ mice. In colony forming assays, we find that Tet2-/-/Jak2VF/+/VavCre+ LSK cells have enhanced re-plating activity compared to Jak2VF/+/VavCre+ LSK cells and that Tet2-/-/Jak2VF/+/VavCre+ LSK cells form more colonies that Tet2-/-/Jak2+/+/VavCre+ cells. Gene expression analysis demonstrates enrichment of a HSC self-renewal signature inTet2-/-/Jak2VF/+/VavCre+ LSK cells. Concordant with this, we find that Tet2-/-/Jak2VF/+/VavCre+ LSK cells have enhanced competitive repopulation at 16 weeks as compared to Jak2VF/+/VavCre+ and Tet2+/-/Jak2VF/+/VavCre+ LSK cells. In aggregate these findings demonstrate that Tet2 loss promotes disease progression in MPN but is insufficient to drive full leukemic transformation. Disclosures: No relevant conflicts of interest to declare.

Combined Assessment of WT1 and BAALC Expression Levels Improves Risk Stratification in Myelodysplastic Syndromes

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5603-5603
Author(s):  
Paola Minetto ◽  
Fabio Guolo ◽  
Marino Clavio ◽  
Laura Mitscheunig ◽  
Raffaella Grasso ◽  
...  
Keyword(s):  
High Risk ◽  
Copy Number ◽  
Who Classification ◽  
Univariate Analysis ◽  
Risk Groups ◽  
Molecular Profile ◽  
Free Survival ◽  
Expression Levels ◽  
Molecular Expression

Abstract BACKGROUND AND AIMS In patients with myelodysplastic syndromes (MDS) several validated prognostic scores, such as IPSS and R-IPSS, are available to assess the risk of AML progression and predict overall survival (OS) as well as leukemia-free survival (LFS). A number of molecular aberrations can be identified in MDS. However, differently from AML, none of the current prognostic indexes takes into account molecular profile at diagnosis. WT1 expression has often been evaluated in acute leukemias and MDS. High WT1 expression levels on bone marrow at diagnosis have been reported to identify MDS patients who are at high risk of progression to AML. BAALC (Brain And Acute Leukemia Cytoplasmic) hyper-expression has been associated with a poor prognosis in AML patients, whereas its prognostic value in MDS is not yet clearly defined. The aim of our study was to determine if combined assessment of WT1 and BAALC expression levels at diagnosis could be predictive of leukemic evolution. MATERIALS AND METHODS We selected 86 patients with available WT1 and BAALC expression levels on BM samples at diagnosis. According to IPSS score, 22 patient were considered low-risk, 27 intermediate-1 and 28 intermediate-2 or high risk. Patients underwent different treatment schedules including supportive care, erythropoietin, hypomethylating and immunomodulating agents, according to their risk group. Median follow-up was 36 months (range 4 -121 months). Leukemia-free survival (LFS) was calculated from the diagnosis until last follow-up or documented leukemic progression as defined in literature. LFS was estimated using the Kaplan–Meier method. All Real-Time PCR were performed on DNA Engine 2 (Opticon®, MJ Research®). WT1 copy number/Abl copy number 1000x104 was used as cut-off value for high WT1 expression, a level of 1000x104 BAALC copy number/Abl copy number was set as cut-off for BAALC hyper-expression. RESULTS After a median time of 32 months, 43 patients died. The main cause of death was leukemic evolution (accounting for 31/43 deaths, 72%), other causes were cardiovascular events and infections (data not shown). The risk of death by any cause was significantly affected by leukemic evolution, diagnosis according to WHO classification and molecular expression profile at diagnosis. Multivariate analysis showed that leukemic evolution was an independent predictor of death (p <0.001). Twenty-nine leukemic evolutions were observed. Median LFS was 34 months. The probability of leukemic evolution was significantly affected by karyotype, IPSS and R-IPSS scores, diagnosis according to WHO classification, and molecular profile at diagnosis. According to our data WT1 and BAALC combined expression levels further enhanced prognostic stratification. In IPSS Int-1, Int-2/high and in R-IPSS high risk groups, low levels of expression resulted in significantly lower probability of leukemic progression, whereas high levels predicted poor outcome. Furthermore, in patients assigned to IPSS unfavorable prognostic groups, low levels of WT1 and BAALC seemed to predict a significantly longer LFS. In the univariate analysis LFS duration was significantly affected by WT1 and BAALC expression levels (fig. 1), IPSS and R-IPSS scores, karyotype and WHO classification at diagnosis. A multivariate Cox Regression model showed that LFS duration was significantly influenced only by molecular profile at diagnosis and R-IPSS risk group (p <0.001 and p <0.01, respectively). Median OS was 32 months. In univariate analysis OS was significantly influenced by diagnosis according to WHO classification, karyotype, R-IPSS score, leukemic evolution and molecular profile expression at diagnosis. The multivariate model disclosed molecular expression profile, R-IPSS score and leukemic evolution as independent predictor of OS (p <0.02, <0.03 and <0.01, respectively). CONCLUSIONS In MDS patients combined WT1 and BAALC expression levels on bone marrow samples at diagnosis is a reliable predictor of risk of AML progression, LFS and OS. This can improve risk stratification especially in intermediate and high risk groups and may lead to a risk tailored therapy. Figure 1: LFS according to molecular profile Figure 1:. LFS according to molecular profile Disclosures No relevant conflicts of interest to declare.

Ph-Negative Chronic Myeloproliferative Neoplasms – Population Analysis, a Single Center 10-years’ Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5556-5556
Author(s):  
Vasily Shuvaev ◽  
Irina Martynkevich ◽  
Alla Abdulkadyrova ◽  
Vera Udaleva ◽  
Tatyana Zamotina ◽  
...  
Keyword(s):  
Overall Survival ◽  
Risk Stratification ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Myeloproliferative Neoplasms ◽  
Population Analysis ◽  
Myelogenous Leukemia ◽  
Rank Test ◽  
Chronic Myeloproliferative Neoplasms

Abstract Objectives and background. Nowadays chronic myeloproliferative neoplasms (MPN) other than chronic myelogenous leukemia undergo renaissance of interest. It results from advances in decryption of molecular mechanisms of pathogenesis and invention of target drugs. Epidemiological information is needed to assess potential effect and additional costs of new diagnostic and therapeutic techniques. The objective of our study was to review experience of MPN diagnostic and treatment in our center for past ten years. Methods. Our institution serves as primary hematological outpatient department for a half of Saint-Petersburg city with about 2 million inhabitants. We reviewed patients' charts to obtain information about incidence, symptoms, diagnostic test results, treatment options and relationship to prognostic factors. Statistical methods included descriptive statistics, nonparametric ANOVA for frequencies comparisons and Kaplan-Meyer method with log-rank test for survival comparisons in Statistica 7.0 package. Results. Since 2004 to 2013 there were 570 newly diagnosed MPN patients (pts) in our center. This group consisted of primary myelofibrosis (PMF) (203 pts; 126 female, 77 male; median age 63 years, range 16-83 years), essential thrombocythemia (ET) (201 pts; 146 female, 55 male; median age 58 years, range 23-78 years), polycythemia vera (PV) (166 pts; 96 female, 70 male; median age 57 years, range 20-85 years). The incidence rates were stable during study period: PMF incidence varied from 0.65 to 1.35 with mean of 1.01 new patient per 100 000 inhabitants per year; ET had incidence from 0.60 to 2.1 with mean of 1.00 and PV had incidence from 0.5 to 1.15 with mean of 0.83. The most prevalent symptoms of disease were: splenomegaly (65.5%), constitutional symptoms (fever, night sweats, weight loss) (31.0%), anemia (36.3%) thrombosis (24.1%) for PMF; fatigue (33.2%), headache and dizziness (25.6%), arthralgia (21.8%), erythromelalgia (15.8%) for ET; plethora (82.5%), headache and dizziness (52.4%), fatigue (31.3%) for PV. JAK2V617F was detected in 49.7% of PMF pts, 57.8% of ET pts and in 97.7% of PV pts. Thrombosis rates according WHO IPSET-thrombosis system risks` groups of ET and PV pts were: low-risk group 3.33% (3/90), intermediate-risk group 11.1% (13/117) and 39.4% (63/160) in high-risk group with highly significant (p<0.0001) differences between risks' groups. There were 169 lethal outcomes in the analysed group (102 PMF; 31 ET; 36 PV). Ten-years overall survival rates were 49.8% in PMF pts, 84.6% in ET pts and 78.3% in PV pts. (fig.1). Overall survival in PMF was significantly influenced by risk stratification as IPSS, DIPSS and DIPSS+. Survival curves according DIPSS+ groups are presented in fig.1. Conclusions. Patients with MPN are presented in substantial number; therefore need much finance for novel therapy introduction. Risk stratification systems has high predictive value. Innovative drugs treatment results should be evaluated in comparison with historical control. Figure1 Overall survival in PMF patients according to DIPPS+ stratification groups. Figure1. Overall survival in PMF patients according to DIPPS+ stratification groups. Disclosures No relevant conflicts of interest to declare.

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