Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3312-3312

Abstract: Introduction. The outlook for myeloma patients who relapse after or become refractory to bortezomib and IMiDs is poor, with limited therapeutic options and a median survival (OS) of 9 months. In the phase 3 MM-003 study, pomalidomide plus low-dose dexamethasone resulted in a significant PFS (median 4 vs 1.9 months) and OS (median 13.1 vs 8.1 months) benefit, compared to high-dose dexamethasone. Information on real-world outcomes of pomalidomide therapy is limited. We carried out a retrospective analysis of patients receiving pomalidomide in the UK, to compare outcomes and tolerability with published clinical trial data, and focus on high risk subgroups. Methods. All patients treated with pomalidomide at 5 major UK centres between August 2013 and March 2016 were identified from chemotherapy records, and clinical data including toxicity and survival from patient records. Disease response and adverse FISH were defined as per IMWG. Survival was estimated using Kaplan-Meier, and correlations made using log-rank methods. Key subgroups: eGFR 〈 45ml/min, adverse genetics, and older age were assessed. Results. A total of 85 patients were identified. Of these, 70 (82%) had measurable disease (IMWG criteria) and received ≥1 cycle so were included in response analyses. Baseline patient characteristics are reported in Table 1. 96.5% of patients were refractory to one or more IMiDs, and 72.9% were refractory to both IMiDs and bortezomib. 92.9% were refractory to their last treatment. The median dose of pomalidomide was 4mg (2-4). Grade 3-4 non-haematological toxicities occurred in 42.4%: pneumonia (16.5%), neutropenic sepsis (8.2%), and acute kidney injury (7.1%), were most common. Grade 3-4 neutropenia occurred in 38% and thrombocytopenia in 24%. Seven patients died on treatment, 6 during the first cycle (2 PD and sepsis, 2 neutropenic sepsis, 1 PD and AKI, 2 pneumonia). In the 70 patients assessable for response, ORR was 52.9% (5.7% VGPR, 47.1% PR, 38.6% SD). Median duration of response (DoR) was 4 months. With median follow-up of 13 months, median PFS was 5 months (95%CI 3.6-6.4), and median OS 13 months (95%CI 10.8-15.2). Patients with renal failure (eGFR 〈 45ml/min) had PFS and OS that were similar to those with eGFR ≥45ml/min ((HR=0.95, 95%CI 0.49-1.82, and HR=1.22, 0.59-2.53). Patients with adverse FISH (44%) had similar outcomes to those with standard FISH (ORR 45.8 vs 50%, median PFS 6 vs 5 months (HR=0.86, 95%CI 0.44-1.67, and median OS 10 vs 8 months, HR=1.223, 0.55-2.68). Patients aged 〉 65yrs had similar outcomes to younger patients,(ORR 54.1 vs 51.5%, median PFS and OS comparable between groups). Rates of toxicity were also not influenced by renal impairment, adverse genetics, or older age. The most important predictors of PFS and OS were depth and durability of response. PFS was 6 months for patients achieving PR, 4 months for SD and 1 month for PD, while OS was 18 months in patients achieving PR, 13 months for SD and 3 months for PD. For patients with DoR 〉 4 months, PFS was 11 months and OS 23 months. In contrast, in patients whose DoR was 〈 4 months or who did not respond, OS was 9 months. Conclusions. Our real-world data on the characteristics and outcomes of patients receiving pomalidomide for relapsed/refractory myeloma in the UK reflect results of published clinical trials. The ORR of 52.9% in our cohort is higher than in MM-003 and MM-010, but PFS (5 months) and OS (13 months) were remarkably similar. Rates of haematological toxicity and infections are low, confirming the good tolerability of pomalidomide in this patient group. Depth and sustainability of response were important predictors of survival: achievement of PR was associated with improved PFS and OS, while patients who achieved SD still derived a survival benefit. Patients who maintained a response for at least 4 months had an estimated survival of nearly 2 years. No difference in response, survival or tolerability was seen in key subgroups, including those with moderate renal impairment, adverse cytogenetics and older age. Our findings confirm the efficacy of pomalidomide in these heavily pre-treated patients and add to the evidence for the benefit of pomalidomide in high risk patient groups. Table Patient characteristics and comparison with MM003 trial Table. Patient characteristics and comparison with MM003 trial Figure 1 PFS and OS for the edited group of 70 patients Figure 1. PFS and OS for the edited group of 70 patients Disclosures Maciocia: Autolus: Equity Ownership, Patents & Royalties: TRBC1 and 2 Targeting for the Diagnosis and Treatment of T-cell Malignancies. Ramasamy:Celgene: Honoraria, Research Funding. Jenner:Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding. Schey:Celgene, Takeda: Honoraria; Celgene, Johnson & Johnson: Speakers Bureau; Celgene: Consultancy. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3312.3312

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: British Journal of Haematology, Wiley, Vol. 162, No. 1 ( 2013-07), p. 107-111

Type of Medium: Online Resource

ISSN: 0007-1048

URL: Issue

URL: Article

DOI: 10.1111/bjh.2013.162.issue-1

DOI: 10.1111/bjh.12345

Language: English

Publisher: Wiley

Publication Date: 2013

detail.hit.zdb_id: 1475751-5

In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 7 ( 2020-07), p. 1840-1852

Abstract: Current guidelines for smoldering multiple myeloma (SMM) recommend active monitoring until the onset of multiple myeloma (MM) before initiating treatment or enrollment in a clinical trial. Earlier intervention may delay progression to MM. In CENTAURUS, 123 patients with intermediate-risk or high-risk SMM were randomly assigned to daratumumab 16 mg/kg intravenously on extended intense (intense), extended intermediate (intermediate), or short dosing schedules. At the prespecified primary analysis (15.8-month median follow-up), the complete response (CR) rates (co-primary endpoint) were 2.4%, 4.9%, and 0% for intense, intermediate, and short dosing, respectively; the co-primary endpoint of CR rate  〉 15% was not met. Progressive disease (PD)/death rates (number of patients who progressed or died divided by total duration of progression-free survival [PFS] in patient-years; co-primary endpoint) for intense, intermediate, and short dosing were 0.055 (80% confidence interval [CI] , 0.014–0.096), 0.102 (80% CI, 0.044–0.160), and 0.206 (80% CI, 0.118–0.295), respectively, translating to a median PFS ≥24 months in all arms ( P   〈  0.0001, 〈 0.0001, and =0.0213, respectively). With longer follow-up (median follow-up, 25.9 months), CR rates were 4.9%, 9.8%, and 0% for intense, intermediate, and short dosing, respectively. PD/death rates for intense, intermediate, and short dosing were 0.059 (80% CI, 0.025–0.092), 0.107 (80% CI, 0.058–0.155), and 0.150 (80% CI, 0.089–0.211), respectively, again translating to a median PFS ≥ 24 months in all arms ( P   〈  0.0001 for all arms). Twenty-four–month PFS rates were 89.9% (90% CI, 78.5–95.4%), 82.0% (90% CI, 69.0–89.9%), and 75.3% (90% CI, 61.1–85.0%) for intense, intermediate, and short dosing, respectively. Pharmacokinetic analyses indicated that intense dosing maintained target-saturating trough concentrations in most patients throughout weekly, every-2-week, and every-4-week dosing periods. No new safety signals were observed. These data provide the basis for an ongoing phase 3 study of daratumumab in SMM.

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0718-z

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 25 ( 2022-09-01), p. 2889-2900

Abstract: Minimal residual disease (MRD) can predict outcomes in patients with multiple myeloma, but limited data are available on the prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy after autologous stem-cell transplant (ASCT) and the interaction between MRD and molecular risk. METHODS Data from a large phase III trial (Myeloma XI) were examined to determine the relationship between MRD status, progression-free survival (PFS), and overall survival (OS) in post-ASCT patients randomly assigned to lenalidomide maintenance or no maintenance at 3 months after ASCT. MRD status was assessed by flow cytometry (median sensitivity 0.004%) before maintenance random assignment (ASCT + 3) and 6 months later (ASCT + 9). RESULTS At ASCT + 3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. MRD-negative status was associated with improved PFS (hazard ratio [HR] = 0.47; 95% CI, 0.37 to 0.58 P 〈 .001) and OS (HR = 0.59; 95% CI, 0.40 to 0.85; P = .0046). At ASCT + 9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was associated with improved PFS (HR = 0.20; 95% CI, 0.13 to 0.31; P 〈 .0001) and OS (HR = 0.33; 95% CI, 0.15 to 0.75; P = .0077). The findings were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT + 3 to ASCT + 9 or the conversion to MRD negativity by ASCT + 9 was associated with the longest PFS/OS. Patients randomly assigned to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance random assignment to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. On multivariable analysis of MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT + 3 and ASCT + 9. CONCLUSION In patients with multiple myeloma, MRD status at both ASCT + 3 and ASCT + 9 is a powerful predictor of PFS and OS.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.21.02228

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2022

detail.hit.zdb_id: 2005181-5

In: The Lancet Haematology, Elsevier BV, Vol. 6, No. 12 ( 2019-12), p. e616-e629

Type of Medium: Online Resource

ISSN: 2352-3026

URL: Article

DOI: 10.1016/S2352-3026(19)30167-X

Language: English

Publisher: Elsevier BV

Publication Date: 2019

In: Leukemia, Springer Science and Business Media LLC, Vol. 34, No. 11 ( 2020-11), p. 3091-3096

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0750-z

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2020

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 110-110

Abstract: Abnormalities of 16q are important recurrent events in multiple myeloma (MM). We performed FISH on CD138 selected plasma cells from 701 newly diagnosed MM patients from the LRF UKMF cytogenetics database. Gene mapping, including paired normal controls, and gene expression analysis was performed on 55 cases using the Affymetrix Human Mapping 500K Array Set and U133 Plus 2.0 Arrays respectively. 16q deletion (del16q) was identified by FISH using probes for cMAF (Abbott Diagnostics) in 131/701 cases (18.7%) and was significantly associated with deletion 17p (16.5% vs. 8.9%, p=0.006), deletion 13 (60.8% vs. 48.5%, p=0.009), deletion of IgH (22.1% vs. 11.1%, p=0.0003) and non-hyperdiploid status (58.3% vs. 42.7%, p=0.006). Del16q showed a trend to poor overall survival, mean survival 43 vs. 61 months (p=0.09), and was associated with significantly worse survival in combination with t(4;14) compared with either t(4;14) or del16q alone, mean survival 15 vs. 26 vs. 45 months respectively (p=0.006). t(14;16) was identified by FISH in 31/701 cases (4.4%) and was associated with poor prognosis, mean survival 29 vs. 54 months (p=0.005). Mapping arrays revealed loss of heterozygosity (LOH) involving all or part of 16q in 20 of 55 cases (36%) in 3 distinct patterns: uniparental disomy (UPD) of chromosome 16 or 16q in 4/55 cases (7%); deletion of chromosome 16 or the whole of 16q in 11/55 cases (20%); and interstitial deletion of small regions of 16q in 5/55 cases (10%), focused on 16q12, the location of CYLD, and 16q23, the location of WWOX. 16q LOH was distributed across translocation groups but was identified in all 4 mapping cases containing 17p deletion, supporting the association identified by FISH. As WWOX is the site of the common fragile site FRA16D and deletions at common fragile sites have been associated with DNA instability in human cancers, we assessed this using gene mapping in these 55 MM cases. Although deletions spanning other common fragile sites were identified, they were not restricted to those with 16q LOH. However, in 2 t(14;16) cases, hemizygous deletions of approximately 100kb could be identified within WWOX at the presumed translocation breakpoint. One of the t(14;16) cases had a similar hemizygous deletion within FHIT, another tumor suppressor gene located within common fragile site FRA3B, consistent with findings in other cancer types. Cases with 16q LOH or t(14;16) all had significantly reduced WWOX expression relative to cases without 16q abnormalities, confirming gene inactivation by either LOH or translocation. Cases with 16q LOH also had significantly reduced expression of two other potential tumor suppressor genes located on 16q, CYLD and RBL2. In summary, our data confirms the adverse prognosis associated with 16q translocation or deletion. Array data reveals 16q LOH occurs due to deletion or UPD with two regions involved, one defined by CYLD and the other by WWOX. WWOX is also inactivated by translocation and is associated with interstitial deletions at this and other common fragile sites. WWOX is a likely candidate gene in MM pathogenesis because of its interaction with TP53 and CYLD via its effects on NF-κB.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.110.110

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 40-43

Abstract: Background The most common cause of severe renal impairment in myeloma (MM) is the direct effect of a high concentration of nephrotoxic monoclonal free light chains (LC) leading to MM cast nephropathy. Decreasing LC and therefore improving renal function is important for long term outcome. In the UK NCRI Myeloma XI trial the addition of the second generation PI carfilzomib (K) to the immunomodulatory agent (IMiD) lenalidomide, cyclophosphamide and dexamethasone (Rdc) improved progression-free survival (PFS) in newly diagnosed MM patients (NDMM) eligible for autologous stem cell transplant (ASCT) (median PFS KRdc not reached (NR) v Rdc 36 months HR 0.66 (95% CI 0.52, 0.83, P=0.0004). This exploratory subgroup analysis compares PFS and renal recovery between patients receiving KRdc and Rdc within renal function subgroups. Methods Myeloma XI is a phase III, randomized controlled trial with an adaptive design for symptomatic NDMM patients of all ages. This renal analysis is of the transplant eligible (TE) pathway and compares induction treatment with the quadruplet KRdc to triplet Rdc. Patients were randomized contemporaneously 2:1. All patients were randomized to post-ASCT R maintenance or observation. For further exploratory analysis patients randomized earlier in the study to Rdc were also included. Relevant exclusion criteria were acute renal failure non-responsive to 72 hours rehydration (creatinine & gt;500umol/L, urine output & lt;400ml/day or dialysis). The Modification of Diet in Renal Disease formula was used to calculate the baseline estimated glomerular filtration rate (eGFR). Renal function was normal, eGFR & gt;=60 ml/min/1.73m2, moderately impaired 30-59 or severely impaired & lt;30. Potentially nephrotoxic LC were considered those with a difference of & gt;=500mg/L between the involved and uninvolved (dFLC). Renal recovery was defined as an improvement in eGFR of ≥25% at the end of induction therapy. Results 1547 patients were randomized to KRdc n=526 or Rdc n=1021 (265 contemporaneous, 756 not). In the contemporaneous group baseline renal function was normal in 609/791 (77.0%), moderately impaired in 141/791 (17.8%) and severely impaired in 40/791 (5.1%) (data n/a in 1 patient). Patients with moderately or severely impaired renal function had shorter PFS compared to those with normal renal function. Subgroup analysis showed consistent outcomes for KRdc compared to Rdc across all renal subgroups with no evidence of significant heterogeneity (Figure 1, Phet=0.9354). Further exploratory analysis combined patients with moderate or severe renal impairment into one group. Difference in PFS and renal recovery between patients with normal or impaired renal function and high ( & gt;=500) or low ( & lt;500) dFLC were examined. Consistent with the findings in the contemporaneous group, KRdc was associated with a significant improvement in PFS compared to Rdc in both the normal and renal function impaired groups. Within the group of patients with normal renal function at baseline those with high dFLC had shorter PFS than those with low dFLC. KRdc was associated with improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 39, NR) v Rdc 34 months (30, 39) and low dFLC KRdc NR (44, NR) v Rdc 41 (37, 47). In the group of patients with renal impairment at baseline KRdc was also associated with an improved PFS irrespective of LC level: high dFLC KRdc median PFS NR (95% CI 29, NR) v Rdc 32 months (28, 42) and low dFLC KRdc 37 (25, NR) v Rdc 27 (24, 33). In contrast to those with normal renal function, however, patients with renal impairment and high dFLC had a longer PFS than those with low dFLC. This observation was apparent whether patients received KRdc or Rdc and suggests that patients with high dFLC may have had reversible renal impairment, improving their ultimate outcomes. Supporting this hypothesis, measurable renal recovery in the renal impaired group at the end of induction was more common in patients with high dFLC (dFLC & gt;=500 68.6% v dFLC & lt;500 53.2%). Interestingly the rate of renal recovery was similar between KRdc and Rdc in the high dFLC group (KRdc 71.1% v Rdc 67.5%) suggesting the improved PFS seen with KRdc in the group with renal impairment is not due to an increased rate of renal recovery. Conclusions KRdc was associated with improved PFS compared to Rdc in NDMM patients across all renal subgroups. Irrespective of treatment, renal function is more likely to improve if attributable to nephrotoxic LC. Disclosures Pawlyn: Janssen: Honoraria, Other: Travel expenses; Celgene: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Other: Travel expenses; Takeda: Consultancy, Other: Travel expenses. Menzies:Celgene, Amgen, Merck: Research Funding. Davies:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cook:Celgene, Janssen, Takeda: Research Funding; Amgen, Bristol-Myers Squibb, Celgene, Janssen, Takeda, Roche, Sanofi: Honoraria; Karyopharm: Honoraria. Gregory:Celgene, Amgen, Merck: Research Funding; Janssen: Honoraria; Celgene: Consultancy. Jenner:Amgen, Janssen, Celgene, Takeda, Novartis, Sanofi, GSK: Consultancy; Janssen, Takeda, Amgen, Celgene, Novartis: Honoraria; Janssen, Celgene: Research Funding; Janssen, Takeda, Amgen: Other: Travel expenses. Jones:Celgene: Honoraria, Research Funding. Kaiser:Bristol-Myers Squibb/Celgene, Janssen, Karyopharm: Research Funding; Bristol-Myers Squibb, Chugai, Janssen, Amgen, Takeda, Celgene, AbbVie, Karyopharm, GlaxoSmithKline: Consultancy; Janssen, Amgen, Celgene, Bristol-Myers Squibb, Takeda: Honoraria; Bristol-Myers Squibb, Takeda: Other: Travel expenses. Owen:Takeda: Honoraria, Other: Travel expenses; Janssen: Consultancy, Other: Travel expenses; Celgene: Consultancy, Honoraria, Research Funding. Morgan:Karyopharm: Consultancy, Honoraria; Janssen: Research Funding; GSK: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Jackson:Takeda: Honoraria, Research Funding, Speakers Bureau; Gsk: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Cairns:Celgene, Amgen, Merck: Research Funding; Celgene: Other: Travel Support. OffLabel Disclosure: Carfilzomib, lenalidomide, dexamethasone and cyclophosphamide combination induction therapy for newly diagnosed myeloma

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-139238

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1371-1372

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-165376

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 395-395

Abstract: We have previously shown that integration of gene expression and SNP based mapping arrays can identify genes dysregulated as a result of copy number loss and gain in multiple myeloma. Using FISH, it has been possible to identify that gain and loss frequently occurs in association with primary IgH translocations, such as loss of FGFR3 and gain of CCND1 in a proportion of t(4;14) and t(11;14) cases. The aim of this study was to determine the frequency and size of such copy number change associated with IgH translocations and to identify the genes dysregulated as a consequence of these. FISH was performed on CD138 selected plasma cells from 80 newly diagnosed myeloma cases to identify cases with primary IgH translocations. Affymetrix 500K mapping arrays were used to determine copy number change using paired tumor and constitutional DNA and Affymetrix U133 plus 2.0 expression arrays were used to determine global gene expression. Samples were analyzed in dChip and CNAG. Thirty eight of 80 cases (47.5%) had primary IgH translocations: 7 t(4;14), 1 t(6;14), 16 t(11;14), 3 t(14;16), 2 t(14;20) and 9 with an unknown translocation partner. Of 29 cases with a known translocation partner, 11 had gain or loss of all or part of the derivative chromosome. Three of 7 t(4;14) cases had loss of FGFR3 by FISH, confirmed by mapping array as being due to deletion of the derivative 14, with loss of 4p16.3-pter and the remainder of chromosome 14 excluding IgH. The region on 4p commenced at FGFR3 and extended to the telomere. Gene expression analysis showed that there was underexpression of FGFR3 and 4 other genes in the deleted region in the 4p16 deleted cases. In 6 of 16 t(11;14) cases, the translocation was associated with an additional copy of CCND1 by FISH. Mapping arrays revealed in all cases the gain commenced at the presumed translocation breakpoint: in 4 cases there was gain of 11q13.3-qter and in 2 there was gain of a small region of 11q13 only. In most cases there was isolated gain of a variable sized region of 14q32 suggesting a sequence whereby translocation was followed by gain then by deletion of a portion of the derivative chromosome. Gene expression analysis identified 4 genes overexpressed on 11q in t(11;14) cases with 11q gain. In a single t(6;14) case there was a complex rearrangement involving gain of 6p21.1-pter and IgH with loss of the derivative 6, again suggesting translocation followed by gain then loss. In one t(14;16) case there was UPD of 16q except for 16q23-qter with associated gain of IgH alone. This complex pattern suggests a sequence whereby deletion is followed by IgH translocation then by duplication of the untranslocated 16q. This study has shown that loss and gain of translocated regions is a frequent occurrence, present in 11/29 cases with known IgH translocations. Using mapping arrays it is possible to demonstrate that in the majority of cases, the translocation is the initial event, followed by subsequent gain or loss as a later event. We have shown the variable size of these regions and have identified genes dysregulated as a result of the deletions of 4p in t(4;14) cases and gains of 11q in t(11;14) cases. These findings provide evidence of collaborating mechanisms that may be responsible for disease progression in these cases.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V110.11.395.395

Language: English

Publisher: American Society of Hematology

Publication Date: 2007

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detail.hit.zdb_id: 80069-7