scholarly journals Significance of Modified Risk Stratification Msmart 3.0 and Autologous Stem Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5593-5593
Author(s):  
Andrey Garifullin ◽  
Sergei Voloshin ◽  
Vasily Shuvaev ◽  
Irina Martynkevich ◽  
Elizaveta Kleina ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Risk Stratification ◽  
Risk Group ◽  
High Risk Group ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Genetic Abnormalities ◽  
Standard Risk

Background The risk-stratification systems are repeatedly updated in accordance with the emergence of new information about the prognostic impact of anomalies and other factors. The most extensive and modern system in this time is mSMART risk stratification involving many parameters such as genetic anomalies, albumin, beta-2-microglobulin, LDH, Plasma Cell S-phase and GEP levels. It is possible to use risk-adapted treatment programs with or without ASCT. Nevertheless, the role of complex karyotype, combination of genetic abnormalities and ASCT remains unclear. Aims To estimate the genetic abnormalities in patients with newly diagnosed multiple myeloma and define the role of risk-stratification and ASCT in prognosis of disease. Methods The study included 159 patients (median age 63 years, range 28 - 83; male: female ratio - 1:1.37) with NDMM. Metaphase cytogenetics on bone marrow samples was done by standard GTG-method. FISH analyses were performed according to the manufacturer's protocol for detection primary IgH translocations, 13q (13q14/13q34) deletion, 1p32/1q21 amplification/deletion, P53/cen 17 deletion (MetaSystems DNA probes). We additional searched the t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20) in patients with IgH translocation. All patient was treated by bortezomib-based programs (VD, CVD, VMP, PAD). ASCT was performed at 42% patients. Results The frequency of genetic abnormalities in NDMM patients was 49% (78/159). IgH translocation was detected in 26.4% (42/159) patients: t(11;14) - 16.3% (26/159), t(4;14) - 5.0% (8/159); TP53/del17p - 5.6% (9/159); 1p32/1q21 amp/del - 12% (19/159); hypodiploidy - 3.1% (5/159); hyperdiploidy - 1.25% (2/159); del5q - 0,6% (1/159); other - not found. Combination two aberrations was discovered in 11.9% (19/159) patients, complex abnormalities (>3 aberrations) - in 4.4% (7/159) patients. The median OS in "two aberration" and "complex abnormalities" groups were lower than in standard-risk mSMART 3.0 (normal, t(11;14), hypodiploidy, hyperdiploidy and other): 49 months, 26 months and was not reached, respectively (p=.00015). The median PFS for these groups was 12 months, 11 months and 30 months, respectively (p=.011). Differences between "two aberration" and "complex abnormalities" groups were not find (p> .05). We modified high-risk (gain 1q, p53 mutation, del 17p deletion, t(4;14), t(14;16), t(14;20), R-ISS stage III, double and triple hit myeloma) mSMART 3.0 by adding "two aberration" and "complex abnormalities" groups on based the OS and PFS results. The final analysis was based on the results of the complex examination of 87 patients: 53 patients in standard-risk group and 34 patients in high-risk group. The median OS in standard-risk mSMART 3.0 was not reached, in high-risk mSMART 3.0mod - 48 months; 5-years OS was 62% and 38%, respectively (p=0.0073). The median PFS was 43 and 29 months, respectively (p=.09). The best results of OS and PFS were reach in both groups of patient who performed ASCT. The median OS in standard-risk mSMART 3.0 with ASCT (n=37) was not reached, in high-risk mSMART 3.0mod with ASCT - 48 months (n=20); standard-risk mSMART 3.0 without ASCT - 40 months (n=16); in high-risk mSMART 3.0mod without ASCT - 22 months (n=14); 5-years OS was 81%, 60%, 33% and 28%, respectively (p=0.0015). The median PFS was not reached, 46, 22 and 19 months, respectively (p=.017). Conclusions The combination of two aberrations and complex abnormalities is unfavorable prognostic markers. The median OS and PFS was higher in standard-risk than high-risk group according mSMART 3.0mod. The ASCT can improve treatment's outcomes and life expectancy especially in patients with high-risk. It can be useful for update risk stratification in a future. Disclosures Shuvaev: Novartis: Consultancy; Pfize: Honoraria; Fusion Pharma: Consultancy; BMS: Consultancy.

The Profile of Endothelial Function in Children with ALL Is Associated with the Risk Stratification Determining the Outcome – a Pilot Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4230-4230
Author(s):  
Ewa Niedzielska ◽  
Adrian Doroszko ◽  
Alicja Chybicka ◽  
Andrzej Szuba
Keyword(s):  
Lipid Peroxidation ◽  
High Risk ◽  
Risk Stratification ◽  
Endothelial Function ◽  
Risk Group ◽  
High Risk Group ◽  
No Bioavailability ◽  
Anti Inflammatory ◽  
Standard Risk ◽  
Pai 1

Abstract Abstract 4230 Background: Endothelial dysfunction (ED) is characterized by impaired balance between pro- and anti-aggregatory, pro- and anti-inflammatory factors as well as vasodilative and vasoconstrictive action of numerous metabolic and signaling pathways. ED is an important factor worsening the outcome in severe diseases. The aim of this study was to assess if the profile of endothelial function during the treatment of ALL might be associated with the risk stratification and with the outcome. Material and Methods: N=18 children at age of 4–18 years with ALL, treated with the ALLIC- BFM 2002 protocol were investigated. Plasma levels of the NO pathway metabolites (L-Arginine, ADMA – an endogenous competive eNOS inhibitor), markers of endothelial inflammatory and aggregatory function (VCAM-1, ICAM-1, E-selectin, P-selectin and PAI-1), lipid peroxidation (MDA – malonyldialdehyde) were analyzed at baseline, then during the 33rd and 78th day of treatment. Results were compared between three subgroups: standard risk, intermediate risk and high risk. Results: Subjects in the high risk groups were characterized by increased baseline lipid peroxidation, as assessed by the MDA levels in comparison to those in the standard risk group (8.56±2.14U/ml vs. 3.57±0.81U/ml, respectively, p<0.05). In the high risk group low E-selectin levels at baseline (32.1±6.1ng/ml vs. 101.3±11.8ng/ml in the standard risk group, respectively, p<0.05), as well as high NO production at the beginning of the M protocol, assessed by the L-Arg/ADMA ratio (88.6±11.6ng/ml vs. 41.7±6.4ng/ml, respectively, p<0.05) were observed. Moreover, increase in the PAI-1 level during the therapy was associated with smaller risk for poor outcome. Conclusions: Increased lipid peroxidation, low E-selectin at baseline, as well as increased NO bioavailability, decreased PAI-1 levels at the beginning of the M protocol are common feature in children classified to the high risk group. Low NO bioavailability at baseline and high at the beginning of the M protocol as well as decreased anti-inflammatory and antiaggregatory function of endothelium at the beginning of the M protocol are associated with higher risk for poor prognosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Circulating Plasma Cells as a Biomarker to Predict Newly Diagnosed Multiple Myeloma Prognosis: Developing Nomogram Prognostic Models

2021 ◽  
Vol 11 ◽  
Author(s):  
Qianwen Cheng ◽  
Li Cai ◽  
Yuyang Zhang ◽  
Lei Chen ◽  
Yu Hu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Plasma Cells ◽  
Validation Cohort ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Newly Diagnosed ◽  
Training Cohort ◽  
Entire Cohort

Background: To investigate the prognostic value of circulating plasma cells (CPC) and establish novel nomograms to predict individual progression-free survival (PFS) as well as overall survival (OS) of patients with newly diagnosed multiple myeloma (NDMM).Methods: One hundred ninetyone NDMM patients in Wuhan Union Hospital from 2017.10 to 2020.8 were included in the study. The entire cohort was randomly divided into a training (n = 130) and a validation cohort (n = 61). Univariate and multivariate analyses were performed on the training cohort to establish nomograms for the prediction of survival outcomes, and the nomograms were validated by calibration curves.Results: When the cut-off value was 0.038%, CPC could well distinguish patients with higher tumor burden and lower response rates (P &lt; 0.05), and could be used as an independent predictor of PFS and OS. Nomograms predicting PFS and OS were developed according to CPC, lactate dehydrogenase (LDH) and creatinine. The C-index and the area under receiver operating characteristic curves (AUC) of the nomograms showed excellent individually predictive effects in training cohort, validation cohort or entire cohort. Patients with total points of the nomograms ≤ 60.7 for PFS and 75.8 for OS could be defined as low-risk group and the remaining as high-risk group. The 2-year PFS and OS rates of patients in low-risk group was significantly higher than those in high-risk group (p &lt; 0.001).Conclusions: CPC is an independent prognostic factor for NDMM patients. The proposed nomograms could provide individualized PFS and OS prediction and risk stratification.

scholarly journals Targeting UCHL1 Induces Cell Cycle Arrest in High-Risk Multiple Myeloma with t(4;14)

2021 ◽  
Vol 27 ◽  
Author(s):  
Parin Kamseng ◽  
Teerapong Siriboonpiputtana ◽  
Teeraya Puavilai ◽  
Suporn Chuncharunee ◽  
Karan Paisooksantivatana ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
High Risk ◽  
Molecular Mechanism ◽  
Risk Group ◽  
Enrichment Analysis ◽  
High Risk Group ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Newly Diagnosed

Multiple myeloma (MM) patients considered to be at high cytogenetic risk commonly fail to respond to standard treatment. A thorough understanding of the molecular mechanism of MM development is, therefore, needed. We endeavored to explore the transcriptional signature among different subgroups of newly diagnosed MM using gene chip-based expression microarray. Bone marrow samples of 15 newly diagnosed Thai MM patients were included. The chromosomal translocation t(4;14) was the most frequently identified genetic alteration in the high-risk subgroup. Cluster analysis from expression profiling demonstrated that high-risk MM have a distinctly different expression pattern compared to standard-risk patients. The most significant differentially expressed gene was UCHL1. Functional enrichment analysis by Gene Set Enrichment Analysis, FUNRICH, and Gene Ontology Panther pathway revealed the gene sets involved in cell cycle control to be enriched in the t(4;14) high-risk group. Interestingly, among the well-established downstream targets of UCHL1, only CCND2 was significantly expressed in the t(4;14) high-risk group. Suppression of UCHL1 protein level by LDN-5744 inhibitor could arrest the cell cycle in G1 phase in cell lines. These findings shed light on the molecular mechanism of UCHL1 in t(4;14) high-risk MM and support the evidence that alteration of the UCHL1 pathway may play a role in the pathogenesis of high-risk MM.

Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3171-3179 ◽  
Author(s):  
Francesco Lo-Coco ◽  
Giuseppe Avvisati ◽  
Marco Vignetti ◽  
Massimo Breccia ◽  
Eugenio Gallo ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Promyelocytic Leukemia ◽  
Risk Group ◽  
High Risk Group ◽  
Promyelocytic Leukemia ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
All Trans Retinoic Acid ◽  
Risk Patients

AbstractAfter the identification of discrete relapse-risk categories in patients with acute promyelocytic leukemia (APL) receiving all-trans retinoic and idarubicin (AIDA)–like therapies, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) designed a protocol for newly diagnosed APL (AIDA-2000) in which postremission treatment was risk-adapted. Patients with low/intermediate risk received remission at 3 anthracycline-based consolidation courses, whereas high-risk patients received the same schedule as in the previous, non–risk-adapted AIDA-0493 trial including cytarabine. In addition, all patients in the AIDA-2000 received all-trans retinoic acid (ATRA) for 15 days during each consolidation. After induction, 600 of 636 (94.3%) and 420 of 445 (94.4%) patients achieved complete remission in the AIDA-0493 and AIDA-2000, respectively. The 6-year overall survival and cumulative incidence of relapse (CIR) rates were 78.1% versus 87.4% (P = .001) and 27.7% versus 10.7% (P < .0001). Significantly lower CIR rates for patients in the AIDA-2000 were most evident in the high-risk group (49.7% vs 9.3%, respectively, P < .0001). Our data confirm that anthracycline-based consolidation is at least equally effective as cytarabine-containing regimens for low-/intermediate-risk patients and suggest that a risk-adapted strategy including ATRA for consolidation improves outcome in newly diagnosed APL. Furthermore, our results highlight the role of cytarabine coupled to anthracyclines and ATRA during consolidation in the high-risk group. This trial was registered at www.clinicaltrials.gov as #NCT 001064570.

Transplantation From 8/8-Matched or 7/8-Matched Unrelated Donors Compared with HLA-Matched Siblings in Acute Myeloid Leukemia in First Complete Remission

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2040-2040
Author(s):  
Byung-Sik Cho ◽  
Jae-Ho Yoon ◽  
Seung-Hwan Shin ◽  
Seung-Ah Yahng ◽  
Sung-Eun Lee ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Autologous Transplantation ◽  
High Risk Group ◽  
Hla Typing ◽  
Standard Risk ◽  
First Complete Remission ◽  
Acute Myeloid

Abstract Abstract 2040 Comparable survival after 8/8-matched unrelated donor (URD) transplantation with HLA-matched siblings (MSD) has been reported in AML from a few multicenter studies. However, the role of 8/8-matched URD in acute myeloid leukemia (AML) with first complete remission (CR1) is uncertain because they applied various methods for HLA typing, such as low or intermediate resolution or partly high resolution (HR) typing, and/or included various disease status at transplantation. Additionally, there have been few studies comparing the clinical outcomes of 7/8-matched URD with current standard donors, such as MSD or 8/8-matched URD, particularly in AML, as a single disease. According to the risk-adapted treatment strategy, AML CR1 with intermediate or adverse cytogenetics received allogenetic transplantation as a post-remission treatment, if MSD or 8/8-matched URD was available. Patients with no available donor received 7/8-matched URD or autologous transplantation (only intermediate cytogenetics). Among 567 consecutive adult patients with AML who underwent transplantation between January 2002 and December 2009, in order to investigate the role of URD type in AML CR1, we assessed the transplantation outcomes of 8/8-matched URD (n=59) or 7/8-matched URD (n=36) classified by HR HLA typing, compared to MSD (n=165). Only intermediate or adverse cytogenetics was included, and we defined high-risk group as having one of the poor risk features, including adverse cytogenetics, hyperleukocytosis at diagnosis (over 100×109/L), older age over 60 years, or AML with myelodysplasia-related changes. In all, multivariate analyses showed that 8/8-matched URD had comparable 5-year disease-free survival (DFS; HR, 0.94; P=0.803), relapse (HR, 1.03; P=0.935), and non-relapse mortality (NRM; HR, 0.62; P=0.294) to MSD, while 7/8-matched URD had higher relapse (HR, 1.95; P=0.034) and a lower trend for DFS (HR, 1.47; P=0.154) than MSD without the difference in NRM (HR, 0.61; P=0.390). The equivalent outcomes of 8/8-matched URD were consistent irrespective of risk groups (high or standard). Particularly, only in standard-risk group, 7/8-matched URD (n=18) failed to show any benefit compared to concurrently performed autologous transplantation (n=67), contrasting to the superior survival of 8/8-matched URD (n=32) as well as MSD (n=108). In conclusion, the equivalent outcomes between MSD and 8/8-matched URD, irrespective of risk-group in AML CR1, suggest that 8/8-matched URD is useful for standard-risk as well as high-risk group of AML CR1, when lacking of MSD. On the other hand, the inferior outcome of 7/8-matched URD raise the necessity of trials comparing with other alternative graft sources, such as umbilical cord bloods or haploidentical family donors, particularly in AML with high-risk group. Disclosures: No relevant conflicts of interest to declare.

The Impact of Genetic Abnormalities (GA) and Other Factors on Survival in Patients after 65 Years with Multiple Myeloma (MM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5314-5314
Author(s):  
Andrei Garifullin ◽  
Irina Martynkevich ◽  
Sergei Voloshin ◽  
Alexei Kuvshinov ◽  
Ludmila Martynenko ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
High Risk ◽  
Risk Group ◽  
Fish Analysis ◽  
Intermediate Risk ◽  
Old Patients ◽  
Genetic Abnormalities ◽  
The Impact ◽  
Standard Risk

Abstract Background. The increase of life expectancy in patients after 65 years with MM is the main aim of treatment. Lack of carrying out aggressive anti-multiple myeloma therapy increase influence of different factors on OS. Aims. To compare influence GA and other different factors on overall survival in 65 and more years old patients with MM. Methods. We retrospectively analyzed 40 patients 65 and more years (median age 71 years, range 65-86; male/female - 1:1.35). The incidences of genetic abnormalities were determined in all cases. Cytogenetic analysis was performed on bone marrow samples using standard GTG-method. Metaphase FISH analysis was performed according to the manufacturer's protocol using DNA probes: LSI 13(RB1)13q14, IGH/CCND1, IGH/FGFR3, LSI TP53 (17q13.1). Stratification of patients was carried in groups of risk according to the modified molecular classification mSMARTmod 1.0 and mSMARTmod 2.0. Patients with 2 and more chromosomal aberrations were additionally entered in high-risk group of both systems. Results. GA in multiple myeloma after 65 years old patients were detected in 22.8% (9/40). The occurrence frequency of t(11;14) was 26.0% (6/23), del(13q) - 20.8% (5/24), t(4;14) - 4.3% (n=1/23), del(17p) - 0% (n=0/11). 33/40 (82.5%) patients entered into standard risk group, 4/40 (10%) - into intermediate risk, 3/40 (7,5%) - into high-risk. Median OS (MOS) according to mSMARTmod 1.0 in standard risk group (33/40) was 78 months, in high-risk (7/40) - 54 months. Median OS according to mSMARTmod 2.0 in standard risk group (33/40) was 78 months, in intermediate-risk (4/40) - 56 months, in high-risk (3/40) - 49 months. In patients groups without renal failure (35/40) MOS was 78 vs. 46 months with renal failure (5/40). MOS isn't reached in patients with ISS I (4/27), but MOS in patients with ISS II (13/27) and ISS III (10/27) were 50 and 54 months, respectively. MOS in patients group (10/40), who have both (bortezomib and lenolidomide) anti-myeloma agents was 110 months vs. 57 months in group (30/40) only with bortezomib-based regimen of treatment. Conclusions. Many factors influence on OS in 65 and more years old patients with MM. However, patients, who had treatment with bortezomib and lenelidomide had the best results of OS. Disclosures No relevant conflicts of interest to declare.

Bortezomib-Based Induction Treatments Improve Outcomes of Newly Diagnosed Multiple Myeloma Patients with High-Risk Cytogenetic Abnormalities

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 781-781 ◽  
Author(s):  
Michele Cavo ◽  
Sara Bringhen ◽  
Carolina Terragna ◽  
Paola Omedè ◽  
Giulia Marzocchi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Plasma Cells ◽  
Risk Group ◽  
High Risk Group ◽  
Newly Diagnosed ◽  
Negative Group ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities

Abstract Abstract 781 Aim of the present study was to evaluate the impact of bortezomib-based induction treatments on clinical outcomes of newly diagnosed multiple myeloma (MM) patients with unfavorable cytogenetic abnormalities. For this purpose, we analyzed 590 bortezomib-treated patients who were screened at diagnosis for the presence of del(13q), t(4;14) and del(17p) by fluorescence in situ hybridization (FISH) on highly purified bone marrow plasma cells. Patients were stratified into the following 3 groups based on 1) the absence of any cytogenetic abnormality (n=261, or 44%) or 2) the presence of del(13q) alone (n=175, or 30%) or 3) positivity for t(4;14) and/or del(17p) (n=154, or 26%). In the great majority of the patients, loss of 17p was detected in more than 70% of bone marrow plasma cells, a finding which precluded a comparison with patients carrying del(17p) in a lower percentage of plasma cells. After diagnosis, 218 patients received induction therapy with bortezomib-thalidomide-dexamethasone (VTD), while the remaining 372 patients were treated with bortezomib-melphalan-prednisone (VMP) (n=181) or VMP plus thalidomide (VMPT) (n=191). The median number of bortezomib infusions (1.3 mg/m2) actually received was 24. Baseline characteristics of the 3 groups of patients were comparable, with the exception of a higher frequency of ISS stage 3 among patients with t(4;14) and/or del(17p) as compared with the cytogenetic-negative group (29% vs 17%, respectively; p=0.003). The rates of absence or presence of del (13q), t(4;14) and/or del(17p) were comparable among patients receiving VTD or VMP or VMPT treatments. Best CR to overall treatment protocols was 39% for the cytogenetic-negative group and 44% for high-risk patients carrying t(4;14) and/or del(17p). With a median follow-up of 27.5 months, median PFS was 40.5 months for patients without cytogenetic abnormalities as compared with 34 months for the high-risk group (p=0.7), while it was not reached after 38 months in the group with del(13q) alone (p not statistically significant for comparison with the other two groups). Overall, the frequency of events was 31% for patients without cytogenetic abnormalities or with del(13q) alone in comparison with 38% for those with high-risk cytogenetic profiles (p=0.15). Median OS was not reached in any of the 3 groups. Forty-month projected OS rates were 89% for the cytogenetic-negative group, 81% for the group with del(13q) alone (p=0.6) and 77% for the high-risk group (p=0.003 for comparison between this latter and the cytogenetic-negative group). Patients with t(4;14) and/or del(17p) had a shorter OS after relapse in comparison with the cytogenetic-negative group (20-month projected rates: 60% vs 76%, respectively; p=0.01). To more carefully evaluate the prognostic relevance of high-risk cytogenetic abnormalities, we stratified patients in the high-risk group into the following 3 subgroups: 1) t(4;14)-positive but del(17p)-negative (84 patients); 2) del(17p)-positive in the absence of t(4;14) (54 patients); t(4;14)-positive and del(17p)-positive (16 patients). Median PFS was not reached after 40 months for patients with t(4;14) alone, while it was 33 months for patients with del(17p) alone (p=0.1) and was 18.5 months for those who carried both these abnormalities (p=0.0008 for comparison between these latter patients and t(4;14)-positive patients). Overall, the frequency of events was 30% and 41% for patients carrying either t(4;14) or del(17p), respectively (p=0.13), while it was as high as 69% for patients with both these abnormalities. The 40-month projected OS rates for these 3 subgroups were 79%, 82% and 64%, respectively (p not significant). In conclusion, the present analysis of a large series of newly diagnosed MM patients receiving bortezomib-based induction treatments showed that: 1) del(13q) alone had no adverse effect on both PFS and OS; 2) the presence of t(4;14) and/or del(17p) did not adversely influence PFS, but was associated with a shorter OS, due at least in part to a worse outcome after relapse; 3) in comparison with t(4;14), del(17p) alone did not predicted for shorter PFS and OS, possibly as a result of the relatively long-term exposure to bortezomib); 4) the presence of both del(17p) and t(4;14) was likely to confer a particularly dismal clinical outlook, a finding which needs to be confirmed in larger series of patients. Disclosures: Cavo: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Use of bortezomib-based treatment for newly diagnosed multiple myeloma. Petrucci:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:NOVARTIS: Honoraria; CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Palumbo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, no.

scholarly journals Improved Treatment of Childhood ALL in Malaysia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5828-5828
Author(s):  
Hamidah Alias ◽  
Sie Chong Doris Lau ◽  
C-Khai Loh ◽  
Christine J. Harrison ◽  
Jeyanthy Eswaran
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
High Risk Group ◽  
Cure Rate ◽  
Childhood All ◽  
Low Middle Income Countries ◽  
Treatment Abandonment ◽  
Standard Risk

The survival rate of childhood acute lymphoblastic leukemia (ALL) has reached >80-90% in developed countries, which is a triumph of modern medicine. This success is due to implementation of contemporary treatment protocols, optimal application of risk stratification, risk-directed multi-agent chemotherapy regimens, and improved supportive care. Unfortunately, such improvements have not translated to Low Middle Income Countries (LMICs), where 90% of the world's children live. The estimated 5 year survival rates in Asia range widely between 44.3% and 80%. The Intercontinental-BFM2002 study, conducted in 15 upper-middle and high-income countries reported a 5 year event-free survival (EFS) and overall survival (OS) rates of 74% and 82%, respectively. Factors that may contribute to the lower survival in LMICs are highly complex, including delays in presentation, diagnostic inaccuracy, restricted budget for risk-stratification and appropriate treatment, treatment abandonment and socio economic status. In Malaysia, different protocols are used by different leukemia treatment centers for treating children with ALL. In UKM Medical Centre (UKMMC), the UKALL protocols (modified UK X, XI, XII, 97(99) and 2003) have been used in the Pediatric Hemato-Oncology Unit since the 1990s. Herein, we report the adopted protocol, the stratification profile and outcome of children with ALL, treated with modified UKALL 97(99) and UKALL 2003 in our institution from 2006 to 2014. Clinical data from children with ALL, who received these modified therapies, were retrospectively reviewed. Prednisolone was used in modified UKALL97(99) and Dexamethasone in modified UKALL 2003, while 6-mercaptopurine was used in both modified protocols. Otherwise, chemotherapy and duration of treatment were identical to the original protocols of Regimens A, B and C. ALL was diagnosed based on standard morphology and immunophenotyping criteria. At diagnosis, patients were stratified according to the National Cancer Institute (NCI) risk criteria and using FISH for detection of cytogenetic abnormalities. EFS and OS were determined using the Kaplan-Meier methods. Newly diagnosed ALL in 156 children were included in the study; 103 (66.0%) were standard risk, 49 (31.4%) were high risk and 4 (2.5%) were infants. There were 2 children with Down syndrome. The success rate of FISH was 76.4% (94/123). Patients were stratified as standard risk, based on ETV6-RUNX1, and high risk based on unfavorable cytogenetics, BCR-ABL and MLL rearrangements. Half of the patients with unfavorable cytogenetics were classified in the NCI high risk group, with WCC >100x109/L. A total of 151 patients were treated as per risk stratification, 2 patients transferred care, while 3 patients refused treatment. Mortality from sepsis during treatment was approximately 10%, including 2 deaths during induction remission and induction at relapse. The majority of disease progression was relapse-related, however, treatment abandonment also contributed to relapse. Approximately 5% of patients abandoned their treatment (3 patients abandoned and 3 patients refused treatment). The 5-year OS for the standard risk group was 86.6%, with 3-year and 5-year EFS of 88.1% and 83.4%, respectively. The 5-year OS for the high risk group was 65.7%, while 3-year and 5-year EFS were 64.7% and 58.2%, respectively (Figure 1). The MRC UKALL97 stratification by NCI risk reported a 5-year EFS of 83.1% for the standard risk group and 66.9% for the high risk group, while the UKALL2003 interim analysis reported a 5-year EFS of 87.7%. The MRC UKALL97/99 reported a 5-year OS of 88%. The cure rate of children with standard risk ALL at UKMMC, using modified UKALL 97(99) and UKALL 2003 protocols, was comparable to MRC UKALL97. However, the cure rate for high risk ALL was comparatively lower. This single center study from UKMMC has highlighted some critical factors that improved the outcome of children with ALL and suggests further improvements that are necessary to reduce the relapse rate, especially in the high risk ALL patients. Disclosures No relevant conflicts of interest to declare.

Generation of An Automated Tool for the Identification of Genetics Markers and Signatures in Multiple Myeloma Risk-Stratification

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2881-2881
Author(s):  
Esteban Braggio ◽  
Jonathan J Keats ◽  
Shaji Kumar ◽  
Gregory Ahmann ◽  
Jeremy Mantei ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
High Risk ◽  
Risk Stratification ◽  
Research Funding ◽  
Plasma Cells ◽  
Risk Group ◽  
High Risk Group ◽  
Proliferation Index ◽  
Gene Index

Abstract Abstract 2881 Multiple myeloma (MM) is characterized by a remarkable heterogeneity in outcome following standard and high-dose therapies. Significant efforts have been made to identify genetic changes and signatures that can predict clinical outcome and include them in the routine clinical care. Gene expression profiling (GEP) studies have achieved a central role in the study of multiple myeloma (MM), as they become a critical component in the risk-based stratification of the disease. To molecularly stratify disease-risk groups, we performed GEP on purified plasma cells (obtained from the immunobead selection of CD138+ cells) from 489 MM samples in different stages of the disease using the Affymetrix U133Plus2.0 array. A total of 162 probes were analyzed using an in house automated script to generate a GEP report with the most used risk stratification indices and signatures, including the UAMS 70-gene, UAMS class, TC classification, proliferation and centrosome signature, and NFKB activation indices. In a subset of 57 samples, IgH translocations were analyzed using FISH and results were correlated with GEP data. A macrophage index was calculated and used as a surrogate measurement of non-plasma cell contamination. A total of 49 samples (10%) were excluded from subsequent analysis as the macrophage index indicated a significant contamination with no plasma cells, hence potentially compromising the results. The percent of high-risk disease patients identified from different signatures ranged from 26.4% by using high proliferation index to 28.8% with high centrosome signature and 31.3% with high 70-gene index. This percent of high-risk cases based on the 70-gene index is similar to what was found in Total therapy 2 (TT2) and TT3 cohorts. A third of patients (33.2%) were classified as D1 in the TC class, followed by 11q13 (19.3%), D2 (16.4%), 4p16 (13.8%), MAF (6.1%), None (4.7%), D1+D2 (4.5%) and 6p21 (1.8%). The NF-kB pathway was likely activated in 45.5% to 59.5% of cases, depending on the index used for its calculation. High proliferation index and high centrosome signature significantly correlates with 70-gene high-risk group (p<0.0001). Conversely, the activation of NF-kB pathway was not significantly different between high- and low- risk subgroups. TC subgroups D1 (p<0.0001) and 11q13 (p=0.01) were significantly more common in the 70-gene low-risk group. Similarly, TC subgroups 4p16 (p=0.0004), Maf (p=0.02) and D2 (p=0.05) were enriched in the high-risk group. Translocations t(4;14)(p16;q32), t(11;14)(q13;q32) and t(14;16)(q32;q23) were precisely predicted by the TC classification (100% correspondence). Cases with IgH translocations with unknown partner were classified in subgroups D1 (33%), D2 (25%), 6p21 (25%) and Maf (16%). Here we summarized the associations between the most significant gene expression indices and signatures relevant to MM risk-stratification. The multiple variables simultaneously analyzed in an automated way, provide a powerful and fast tool for risk-stratification, helping in the therapeutic decision-making. Disclosures: Stewart: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding. Fonseca:Consulting :Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.

Cohort Analysis of FISH Testing of CD138+ Cells in Relapsed Multiple Myeloma: Implications for Prognosis and Choice of Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3399-3399
Author(s):  
Dean Smith ◽  
Clemency Stephenson ◽  
Anna Lach ◽  
Steve Chatters ◽  
Helena Kempski ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Cohort Analysis ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Interphase Fish ◽  
Line Of Therapy ◽  
Standard Risk

Abstract Introduction: Interphase FISH on CD138-selected bone marrow cells enables genetic risk stratification in newly diagnosed multiple myeloma (MM), however as MM remains incurable, most centres still treat newly diagnosed MM uniformly, utilising the most active regimens available. At relapse an increasing choice of regimens, coupled with co-morbidities and treatment-emergent toxicities, means no uniform approach is possible. Instead, therapy is tailored to disease and patient related risk factors. In this setting, FISH testing may be particularly useful if not done at diagnosis and to identify progression events that may alter prognosis. Aim: To evaluate the outcome of FISH analysis in consecutive patients with relapsed MM undertaken at our centre: success rate, frequency of abnormalities, incidence of progression events and correlation of FISH abnormalities with treatment outcomes. Methods: FISH analysis was performed on 192 samples from 154 relapsed patients (2012-13). Plasma cells were selected using magnetic CD138 MicroBeads and interphase FISH carried out using probes as recommended by the EMN (Ross et al, 2012). If patients had no prior results, a full FISH MM panel was performed, using probes for t(4;14), t(14;16), t(11;14), deletion 17p (17p-), Chr 1 abnormalities (1p-/1q+) and deletion 13q (13q-). If patients had been previously tested for an IgH translocation (Tx), a progression event panel was used: 1p-/1q+, 17p- and 13q-. Patients underwent FISH testing prior to starting the next line of therapy. Results: 79% of samples were successfully analysed, with analysis limited in 16% and failed in 5%. Common reasons for failure were poor quality/aged slides, insufficient material and poor hybridisation. 17% of patients had no cytogenetic abnormality. The most common abnormality was 13q- (43.1%), followed by 1q+ (41.4%), t(11;14) (18.3%), t(4;14) (12.4%), 17p- (12.0%) 1p- (8.9%), and t(14;16) (5.6%) Progression events were more common in t(14;16) and t(4;14) groups. All patients with t(14;16) and 82% with t(4;14) had an additional genetic lesion. Only 21% of patients with t(11;14) and 54% with no IgH Tx had an additional event. 80 patients (51.3%) had prior FISH results and 13 (16.3%) had developed a new abnormality on the later test. In 9 cases the progression event was 17p-, in 2 it was 1q+ and 2 cases developed 17p- and 1q+. The patients developing 1q+ were previously standard risk, so repeat testing altered risk group. Acquisition of 17p- indicates especially poor outcome, thus in all 13 cases repeat FISH analysis altered risk. Among patients with progression events none harboured t(11;14), 8 (64%) had no IgH Tx, 3 had t(14;16) and 2 had t(4;14). FISH results were correlated with clinical outcome. Patients were stratified as having high risk genetics [t(4;14), t(14,16), 17p- in ≥50% cells, 1p-/1q+] or standard risk [t(11;14), normal cytogenetics]. 63 (41%) patients were high risk, 83 (54%) standard risk, with no information available for 8 (5%). Both groups had received a median of 2 prior lines of therapy. Response rates (≥PR) to the next line of therapy were similar (60.4% standard risk vs 56.0% high risk). PFS from time of FISH was significantly longer in the standard risk group (9.8 months vs 5.9, p<0.01) as was OS (not reached vs 17.1 months, p<0.01, Fig. 1). In the high risk group, PFS was significantly longer in patients receiving a proteasome inhibitor (PI) as the next line of treatment versus those receiving other therapies (9.6 months vs 4.6, p=0.01) as was OS (not reached vs 9.7 months, p<0.01, Fig. 2). In the standard risk group, PFS was similar if patients received PI or not (9.5 months PI vs 9.8 other) as was OS (not reached both groups, Fig. 2). Conclusions: FISH analysis on MM patients at relapse was achievable. 74/154 patients had no prior results and a further 13 developed new poor prognostic markers, thus FISH at relapse provided new information in 56% of patients. Progression events were more common in patients harbouring t(4;14) or t(14;16). FISH at relapse was prognostic with high risk abnormalities associated with significantly shorter PFS and OS. The use of PI appeared to abrogate this poor prognosis, suggesting FISH at relapse could be a predictive and prognostic marker. Given the availability of second generation PI and the option of bortezomib re-treatment, results of FISH testing at relapse could directly influence clinical practice. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document