scholarly journals Fluorescence in-Situ Hybridization (FISH) Analysis in Untreated AL Amyloidosis Has an Independent Prognostic Impact By Abnormality Type and Treatment Category

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3269-3269
Author(s):  
Eli Muchtar ◽  
Angela Dispenzieri ◽  
Shaji Kumar ◽  
Rhett P. Ketterling ◽  
David Dingli ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Board Of Directors ◽  
Research Funding ◽  
Independent Effect ◽  
Al Amyloidosis ◽  
Fish Analysis ◽  
Prognostic Impact ◽  
Advisory Committees

Abstract The impact of fluorescence in-situ hybridization (FISH) on outcome in AL amyloidosis remains uncertain. We analyzed the response and overall survival (OS) of 692 AL amyloidosis patients with available FISH testing at diagnosis. First line treatment was categorized as autologous stem cell transplant or three non-transplant regimens (melphalan-based; bortezomib-based, and immunomodulatory drug (IMiD)-based). Forty-nine percent of patients had t(11;14), 37% del 13q/monosomy 13 and 19% had trisomy/tetrasomy. Analysis by abnormality type was restricted to t(11;14) and trisomy/tetrasomy sub-groups as chromosome 13 abnormalities were commonly associated with the other abnormalities. Patients with t(11;14) had lower rate of very good partial response or better (≥VGPR) compared to those lacking t(11;14) (56% vs 70%, P=0.001). By regimen stratification, this difference was maintained for bortezomib-based (52% vs 77%; P=0.004) and IMiD-based therapy (13% vs 54%; P=0.04) (Figure 1). Patients with trisomy/tetrasomy had no difference in the rate of ≥VGPR compared to those who did not (66% vs 63%, P=0.62), with no difference within regimen types. OS was similar between t(11;14)-positive and negative patients (median 43 vs 57 months; P=0.58). However, sub-analysis by regimen type showed a significantly inferior OS among t(11;14)-positive bortezomib-treated patients (median 15 vs 27 months; P=0.05) and t(11;14)-positive IMiD-treated patients (median 12 vs 32 months; P=0.05) (Figure 2). Among t(11;14)-positive bortezomib-treated patients, the OS difference was maintained among favorable-prognosis patients, but was absent for poor-prognosis sub-groups (Table). Trisomy/tetrasomy was associated with inferior OS (median 29 vs 69 months; P=0.001), a difference that was maintained for melphalan (median 15 vs 32 months; P=0.01) and borderline significance for bortezomib (median 14 vs 38 months; P=0.09). Multivariate analysis confirmed an independent effect on OS for trisomy/tetrasomy in the study cohort and for t(11;14) among bortezomib-treated patients. FISH analysis is essential in newly diagnosed AL amyloidosis, as it provides prognostic information among treatment groups and may influence the selection of induction treatment. Patients with t(11;14) should be considered for ASCT at diagnosis. Disclosures Dispenzieri: Celgene: Research Funding; Alnylam: Research Funding; pfizer: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen: Research Funding. Kumar:Glycomimetics: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Kapoor:Amgen: Research Funding; Takeda: Research Funding; Celgene: Research Funding.

scholarly journals Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1884-1884 ◽  
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
David Iberri ◽  
Erik Eckhert ◽  
...  
Keyword(s):  
Disease Progression ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Control Group ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Free Interval ◽  
Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

scholarly journals Long-Term Outcomes and Organ Responses with Daratumumab Therapy in Previously Treated Patients with AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1828-1828
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
Erik Eckhert ◽  
Stanley Schrier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Renal Response ◽  
Cardiac Responses ◽  
Previously Treated

Introduction: AL amyloidosis involves deposition of abnormally folded light chains into a wide range of tissues causing end-organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously relapsed/refractory disease. However, data on long-term outcomes to daratumumab, including organ responses, are lacking. Here we present the largest retrospective study to date on patients with previously treated AL amyloidosis treated with daratumumab. Methods: We conducted a retrospective analysis of relapsed/refractory AL amyloidosis patients treated at Stanford University from January 2016 to January 2019. Patients treated with daratumumab, either as monotherapy with dexamethasone (DMT) or in combination with other plasma-cell directed therapies (DCT) were included. Hematologic and organ responses were assessed by consensus guidelines. Hematologic responses were based on the maximal change in the difference between involved and uninvolved free light chains (dFLC). For cardiac response, a >30% and >300 pg/mL decrease in NT-proBNP for patients with initial baseline NT-proBNP ≥650 pg/mL was considered a response. A graded cardiac response metric was also explored with partial response (PR) representing 30-59% reduction, very good partial response (VGPR) ≥60% reduction, and complete response (CR) NT-proBNP <450 pg/mL as previously reported. For renal response, a >30% decrease (by at least 0.5 g/day) in 24-hour urine protein without worsening in creatinine or creatinine clearance by more than 25% in patients with at least 0.5 g/day pretreatment was considered a response. A graded renal response metric was also explored with PR representing 30-59% reduction in proteinuria, VGPR ≥60%, and CR ≤ 200 mg per 24-hour period. Survival data was analyzed using the Kaplan-Meier method. All time-to-event outcomes, including survival and organ responses, were determined from initiation of daratumumab. Results: Eighty-four patients were identified with baseline characteristics at start of daratumumab shown in Table 1. Median duration of follow-up was 16 months. Two-year overall survival (OS) was 83% and median OS was not reached. Median time-to-next-treatment or death was 31 months. Sixty-seven out of 80 evaluable patients (84%) achieved a hematologic response, with 47 patients (59%) achieving a VGPR or better (Figure 1). Sixty-eight patients (81%) had cardiac involvement, and among the 34 evaluable patients, 18 (53%) of evaluable patients achieved a cardiac response with a median response time of 2 months among responders. In terms of a graded cardiac response, 6 patients (18%) were able to achieve cardiac CR, 5 patients (15%) cardiac VGPR, and 7 patients (21%) PR (Figure 2). The median NT-proBNP percent reduction was 64.5% (IQR: 48.3 - 81.1%) and the median absolute reduction was 2395 pg/mL (IQR 1279.5 - 4089.5 pg/mL). Cardiac responses were associated with an improvement in OS (p<0.001, Figure 3), with landmark analysis for cardiac responses at 6-month trending towards statistical significance (100% vs. 51% at 30 months, p=0.052). Fifty-three patients (63%) had renal involvement, and among the 26 evaluable patients, 12 patients (46%) achieved a renal response with a median initial response time of 6 months among responders. Using graded response, 1 patient (4%) achieved renal CR, 7 patients (27%) renal VGPR, 4 patients (15%) renal PR, and 14 patients had no response, worsening creatinine, or were subsequently started on hemodialysis (54%) (Figure 4). The median percent reduction in proteinuria was 74.1% (IQR: 49.2 - 83.1%) and the median absolute reduction in proteinuria was 3.1 g/24 hours (IQR 2.1 - 4.9 g) among responders. There were no significant differences in OS between renal responders and non-responders. Conclusion: Daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve durable hematologic responses as well as improvements in organ function. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. OffLabel Disclosure: Daratumumab in AL amyloidosis

scholarly journals The Broad Spectrum of TP53 Variants in CLL: NGS Analysis of 573 Pathogenic TP53 Variants

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3021-3021
Author(s):  
Gregory Lazarian ◽  
Floriane Theves ◽  
Myriam Hormi ◽  
Virginie Eclache ◽  
Stéphanie Poulain ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Snp Analysis ◽  
Advisory Committees ◽  
Exon 2 ◽  
Tp53 Mutations ◽  
Mutational Status

TP53 aberrations, including somatic mutations of TP53 gene or 17p deletion leading to the loss of the TP53 locus, are a major predictive factor of resistance to fludarabin based chemotherapy in chronic lymphocytic leukemia (CLL) and remain an adverse prognostic factor in the chemofree era. Therefore, detection of TP53 alteration before each new line of treatment is required for theranostic stratification. In order to better characterize the distribution and combination of the TP53 variants in CLL, we collected the TP53 sequencing data of 343 patients harboring TP53 mutations from centers of the French Innovative Leukemia Organization-CLL (FILO) and established a large data base of 573 TP53 mutations. Mutations were identified through NGS sequencing (covering exon 2 to 11) allowing the detection of low frequency variants down to 1% VAF. Several distinct low VAF mutations were orthogonally confirmed by digital PCR. TP53 variants were analyzed through UMD_TP53 data gathering 90 000 TP53 mutations from all type of cancers. IGHV mutational status and FISH analysis were available for 224 and 176 patients respectively. Using ACMG criteria from the UMD_TP53 database, we confirmed that 523 could be classified as pathogenic, 42 were likely pathogenic and 8 were VUS (Variants of Unknown Significance). As expected, the mutation distribution along the p53 protein exhibited a clustering of variants in the DNA binding domain of the protein. We also confirmed the presence of a specific hotspot at codon 234 (6%) which is noticeable in other CLL cohorts but absent in solid tumors. 431 TP53 variants led to the expression of a mutant protein whereas the remaining 142 led a TP53 null phenotype. For 8 patients without 17p deletion and a mutation VAF larger than 50%, SNP analysis indicate that these tumors had a copy number neutral loss of heterozygosis at 17p with a duplication of the mutant allele leading to homozygous mutations of TP53. When focusing on the allele burden of TP53 mutations, 264/573 (46%) variants had an allele frequency <10%. Even if they were predominantly found in polymutated cases, presence of only low VAF (<10%) mutations was evidenced in 74 (21%) patients (50 patients with a single TP53 mutation and 24 patients with more than one). All these cases would have been missed by conventional sequencing. Among the 343 patients, 113 (33%) were poly-mutated and harbored more than one pathogenic TP53 variants (2 to 11 variants per patient): 57 (16,7 %) had 2 variants, 32 (9,3%) had 3, 10 had 4 (3%) and 14 patients (4%) had 5 to 11 variants. Using both long range sequencing and in silico analysis, we could show that all these variants were distributed in different alleles supporting an important intratumoral heterogeneity and a strong selection for TP53 loss of function during tumor progression in these patients. Null variants were rarely found as single alteration: only 46 patients (13,4%) patients harbored a single null mutation. Null mutations were predominantly found in patients with multiclonal mutations (87% with 4 or more). Median size of variants significantly decreased with the number of mutations and most of low VAF (less than 10%) variants were found in multiclonal combinations. Multiclonal mutations were predominantly found in previously treated patients (41% treated versus 10 % untreated) but whether all these variants preceded treatment and were further selected is currently unknown. We observed that 71,5 % of patients were IGHV unmutated and multiclonal mutations were surprisingly more frequent in mutated IGHV cases than in unmutated ones. Only 50% of cases carried a 17p deletion, highlighting again the importance of testing for TP53 mutations in addition to FISH analysis. Presence or absence of 17p deletion was unrelated to the number of TP53 mutations. Taken together these observations suggest that the TP53 mutational landscape in CLL is very complex and can involve multiple mechanisms, converging to a total loss of TP53 function and tumor progression. NGS provides a powerful tool for detecting all these alterations including variants with low VAF and should become a standard for CLL screening prior to each line of treatment. Disclosures Leblond: Amgen: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Letestu:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Cymbalista:Abbvie: Honoraria; Roche: Research Funding; Sunesis: Research Funding; Gilead: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

scholarly journals Characterizing Atypical BCL6 Signal Patterns Detected by Digital Fluorescence In Situ Hybridization (FISH) Analysis

2018 ◽  
Vol 38 (6) ◽  
pp. 619-622
Author(s):  
Michael Liew ◽  
Leslie R. Rowe ◽  
Phillipe Szankasi ◽  
Christian N. Paxton ◽  
Todd Kelley ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Fish Analysis

scholarly journals Fluorescence In Situ Hybridization (FISH) Analysis of the Locations of the Oligonucleotides 5S rDNA, (AGGGTTT)3, and (TTG)6 in Three Genera of Oleaceae and Their Phylogenetic Framework

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 375 ◽  
Author(s):  
Xiaomei Luo ◽  
Juncheng Liu
Keyword(s):  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
5S Rdna ◽  
Fish Analysis ◽  
Cytogenetic Map ◽  
Ligustrum Lucidum ◽  
Starting Point ◽  
Central Regions ◽  
Almost All

We report the cytogenetic map for a collection of species in the Oleaceae, and test similarities among the karyotypes relative to their known species phylogeny. The oligonucleotides 5S ribosomal DNA (rDNA), (AGGGTTT)3, and (TTG)6 were used as fluorescence in situ hybridization (FISH) probes to locate the corresponding chromosomes in three Oleaceae genera: Fraxinus pennsylvanica, Syringa oblata, Ligustrum lucidum, and Ligustrum × vicaryi. Forty-six small chromosomes were identified in four species. (AGGGTTT)3 signals were observed on almost all chromosome ends of four species, but (AGGGTTT)3 played no role in distinguishing the chromosomes but displayed intact chromosomes and could thus be used as a guide for finding chromosome counts. (TTG)6 and 5S rDNA signals discerned several chromosomes located at subterminal or central regions. Based on the similarity of the signal pattern (mainly in number and location and less in intensity) of the four species, the variations in the 5S rDNA and (TTG)6 distribution can be ordered as L. lucidum < L. × vicaryi < F. pennsylvanica < S. oblata. Variations have observed in the three genera. The molecular cytogenetic data presented here might serve as a starting point for further larger-scale elucidation of the structure of the Oleaceae genome, and comparison with the known phylogeny of Oleaceae family.

scholarly journals Comparative Performance of Breast Cancer Human Epidermal Growth Factor Receptor 2 Fluorescence In Situ Hybridization and Brightfield In Situ Hybridization on College of American Pathologists Proficiency Tests

2018 ◽  
Vol 142 (10) ◽  
pp. 1254-1259 ◽  
Author(s):  
Katherine B. Geiersbach ◽  
Julia A. Bridge ◽  
Michelle Dolan ◽  
Lawrence J. Jennings ◽  
Diane L. Persons ◽  
...  
Keyword(s):  
Breast Cancer ◽  
In Situ Hybridization ◽  
Fluorescence In Situ Hybridization ◽  
Proficiency Testing ◽  
Copy Number ◽  
Fish Analysis ◽  
Proficiency Tests ◽  
Comparative Performance ◽  
Significant Difference

Context.— Fluorescence in situ hybridization (FISH) and brightfield in situ hybridization (ISH) are 2 clinically approved laboratory methods for detecting ERBB2 (HER2) amplification in breast cancer. Objective.— To compare the performance of FISH and brightfield ISH on proficiency testing administered by the College of American Pathologists Laboratory Accreditation Program. Design.— Retrospective review was performed on 70 tissue core samples in 7 separate proficiency testing surveys conducted between 2009 and 2013. Results.— The samples included 13 consensus-amplified tissue cores, 53 consensus-nonamplified cores, and 4 cores that did not reach consensus for FISH and/or brightfield ISH. There were 2552 individual responses for FISH and 1871 individual responses for brightfield ISH. Consensus response rates were comparable for FISH (2474 of 2524; 98.0%) and brightfield ISH (2135 of 2189; 97.5%). The FISH analysis yielded an average HER2 copy number per cell that was significantly higher (by 2.86; P = .02) compared with brightfield ISH for amplified cores. For nonamplified cores, FISH yielded slightly, but not significantly, higher (by 0.17; P = .10) HER2 copy numbers per cell. There was no significant difference in the average HER2 to control ratio for either consensus-amplified or consensus-nonamplified cores. Participants reported “unable to analyze” more frequently for brightfield ISH (244 of 2453; 9.9%) than they did for FISH (160 of 2684; 6.0%). Conclusions.— Our study indicates a high concordance rate in proficiency testing surveys, with some significant differences noted in the technical performance of these assays. In borderline cases, updated American Society of Clinical Oncology/College of American Pathologists cutoff thresholds that place greater emphasis on HER2 copy number per cell could accentuate those differences between FISH and brightfield ISH.

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.

Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL-Amyloidosis with Tolerable Neurotoxicity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 746-746 ◽  
Author(s):  
Jeffrey A Zonder ◽  
Vaishali Sanchorawala ◽  
Rachel M. Snyder ◽  
Jeffrey Matous ◽  
Howard Terebelo ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Adjustment ◽  
Response Rate ◽  
Al Amyloidosis ◽  
Two Stage ◽  
Advisory Committees ◽  
Subsequent Dose ◽  
Stage 1

Abstract Abstract 746 Introduction: Primary systemic amyloidosis (AL) is a monoclonal plasma cell disorder associated with progressive organ dysfunction and short survival. Standard therapy for patients (pts) not eligible for autologous stem cell transplant (ASCT) is melphalan (Mel; M) + dexamethasone (Dex; D). With non-ASCT therapy, the median overall survival (OS) of high-risk AL pts remains < 1 yr. After the VISTA study showed the addition of bortezomib (Bz) to Mel + Prednisone improved response rate, complete response rate, response duration, and OS in pts with myeloma, we designed this study to determine if adding Bz to MD improves outcomes in AL. Key eligibility criteria: ECOG PS ≤ 3, Cr ≤ 5 mg/dL, T.Bili ≤ 2.5 x IULN, ALT/AST ≤ 3 x IULN, ANC ≥ 1.0 K/mm3, PLT ≥ 80 K/mm3, peripheral neuropathy (PN) ≤ Gr 2 (≤ 1 if painful), no lower limit for LVEF. Study design: Two-stage Phase II study. Stage I: 16 pts with biopsy-proven AL or light chain deposition disease (LCDD). 1° endpoint: complete hematologic responses (cHR). If ≥5 cHRs observed, then 2nd stage with 17 more pts to be opened. The study has a 90% power to detect a true cHR rate of 50%. 2° endpoints include overall HR (cHR + Partial Responses (PR)), organ response (OrR), and OS. Treatment: M (9 mg/m2 PO days 1-4; 6 mg/m2 if Cr > 2.5 mg/dL), Bz (1.3 mg/m2 IV days 1, 8, 15, 22; 1.0 mg/m2 if pt has PN at baseline) and D (40 mg PO/IV days of & days after Bz; 20 mg if ≥ 70 yrs, peripheral edema, or CHF) in 4-6 wk cycles, max of 20 cycles. PN was assessed serially with the FACT/GOG-Ntx survey. Results: To date, 23 pts have been enrolled: 21 with AL; 2 with LCDD. Med age 64 (range: 47-76). Med # prior Rx: 1 (range: 0-2; 7 with ≥1 prior ASCT). Med # organs involved: 4 (range 1-6; 8 pts with ≥ 3). PS 0-1/2-3: 18/1. Response data for the 16 pts comprising stage 1 of this two-stage study are reported here; accrual of all 33 pts is expected to be complete by ASH, and results will be updated. One pt who was not response-evaluable (RE) for HR is included in toxicity data (n=17). Med # cycles MD-Bz: 4+ (range: 2-12+; 9 pts still on treatment). 15 of 16 pts had heme responses: 6 cHRs & 9 PRs. Ten RE pts had OrR (2 cardiac, 3 renal, 6 nerve, 1 lung; total >10 because some pts improved in > 1 organ). Nerve symptom improvement occurred exclusively in pts with cHR. Two pts had progressive disease (PD). Two pts died (4.5 and 9 mos from enrollment, from pneumonia and PD, respectively). Despite baseline dose adjustment for co-morbidities, 12 pts needed subsequent dose-reduction of ≥ 1 of the study meds during therapy (10 Bz, for thrombocytopenia and/or PN in almost all cases). Five pts developed neutropenia (Gr 3-4: 1), 15 pts developed thrombocytopenia (Gr 3-4: 11). Nine pts developed peripheral neuropathy (Gr 3: 2). Other grade 3-4 non-hematologic AEs seen in ≥ 2 pts included edema (5), syncope (3), SVT (2), dehydration (2), fatigue (2), and renal failure (2). One pt developed reversible cardiomyopathy (cycle 8) attributed to Bz. Calculated sensory/dysfunction (S/D) composite scores based on patient responses from the FACT/GOG-Ntx survey improved in 7 of 14 pts between cycles 1 and 4, were stable in 4 pts and worsened in only 3. On average, the S/D score accounted for 43% of each pt's total Ntx score at baseline, whereas it only accounted for 39% of the score after 4 cycles, and 45% after 8 cycles, indicating progressive disability from Bz-related PN was uncommon. As results of nerve conduction studies did not correlate well with reported symptoms or FACT/GOG-Ntx scores in stage 1 of the study, mandatory EMGs were discontinued in stage 2. Conclusions: MD-Bz shows promising activity in the treatment of AL, with 94% of pts in the first stage of this trial achieving HR (38% cHR) and evidence of OrR observed in 63%. Toxicity is manageable, but meds often require baseline or subsequent dose adjustment. A randomized study of MD +/- Bz in AL is planned. Disclosures: Zonder: Cephalon: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Millennium: Consultancy, Research Funding, Speaking CME Only, No PromotionalTalks; Celgene: Speaking CME only; no Promotional Talks. Off Label Use: Bortezomib is being used in the treatment of AL amyloidosis in this trial; it is currently approved for use as treatment of multiple myeloma.. Matous:Celgene: Honoraria, Speakers Bureau; Cephalon: Speakers Bureau. Janakiraman:Millennium: Honoraria, Research Funding. Mapara:Resolyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Membership on an entity's Board of Directors or advisory committees, My Wife: Suzanne Lentzsch, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, My wife: Suzanne Lentzsch, Research Funding; Sentium: Stocks. Gasparetto:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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