EUTOS Score Is Also Valid in CML Patients Not Involved in Clinical Studies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3759-3759 ◽  
Author(s):  
Verena S Hoffmann ◽  
Jiri Mayer ◽  
Anna G. Turkina ◽  
Andrzej Hellmann ◽  
Karel Indrak ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Progression Free Survival ◽  
Study Data ◽  
Observation Time ◽  
High Risk Group ◽  
Advisory Committees ◽  
Free Survival ◽  
Risk Patients ◽  
Eutos Score

Abstract Abstract 3759 Data of 2060 patients from the in-study registry of the European Outcome and Treatment Study (EUTOS) for CML were used to develop and validate the EUTOS score [1]. All these patients were included in prospective controlled clinical trials. The EUTOS score aims to support clinical decision making within the first 18 months after initiation of treatment with imatinib. Patients who did not achieve complete cytogenetic remission (CCyR) within 18 months had a lower probability of achieving CCyR in the further course of therapy and were more likely to suffer from progressive disease. The EUTOS score is calculated by multiplying the percentage of basophiles by seven and the spleen size measured in centimeters below costal margin by four and adding both values. Both parameters have to be assessed before any therapy is started. If the resulting value is higher than 87 the patient is at high risk of not being in CCyR after 18 months of therapy, otherwise he is a low risk patient. In the In-study data the EUTOS score showed a sensitivity of 21%, a specificity of 92% and a positive predictive value of 34%. So every third patient in the high risk group eventually did not achieve CCyR. As the development and validation of the EUTOS score used patient data from prospective clinical studies we now wanted to assess the score's performance on CML-patients in routine health care. The EUTOS Out-Study registry provides data of 1547 patients from Spain, Poland, Czech Republic, Romania, Slovakia, and Russia. Information on the EUTOS score and the status of CCyR at 18 months (+/− 3 months) was available for 316 patients. The patients in the In-study registry were slightly older than in the Out-study registry (median (range): 52 years (18–83) vs 48 years (18–85)) and more men were involved (61% vs 52%). The Out-study data support the timeline of 18 months as patients without CCyR at 18 months progress more often than patients with CCyR (progression free survival after 36 months 99.2% vs 90.8%, p<0.0001). As 316 of 1547 datasets might lead to a selection bias we compared the characteristics of both groups but medians of age, spleen size, platelets, percentage of blast cells, percentage of eosinophils, white blood cell count, hemoglobin and percentage of basophils were almost equal. So no selection bias is evident. In the Out-study data the EUTOS score reached a sensitivity of 16%, a specificity of 90%, and a positive predictive value of 41%. These results were similar to the results of the In-study data and confirmed that the score defines a small high risk group with a high probability of not reaching CCyR. The cumulative incidence curve showed that high risk patients achieve CCyR significantly later and less often than low risk patients (Median 34.0 months vs 20.4 months, 32.6% vs 43.4% after 18 months of therapy, p<0.0001). In addition high risk patients have a significantly higher risk of progression (progression free survival after 5 years: 88.8% vs 80.7%, p=0.0235, median observation time 66 months) and death (overall survival after five years 89.9% vs 82.0%, p=0.0103, median observation time 66 months). The results show that the EUTOS score is also valid in Out-study patients and is able to identify patients with a significantly higher risk of not achieving CCyR and of progression, after 18 months of therapy. As the score is easy to calculate with only two variables needed that are routinely measured it is a simple way to alert physicians to the need for closer monitoring of the patient. Disclosures: Hoffmann: Novartis Pharma: Research Funding. Turkina:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Baccarani:Bristol Myers Squibb: Honoraria; Novartis Pharma: Research Funding.

EUTOS Score Identifies Cases with Poor Outcome in Patients with Early Chronic Phase Chronic Myeloid Leukemia, Though Not Predictive for Optimal Response to Imatinib

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3778-3778 ◽  
Author(s):  
Mario Tiribelli ◽  
Massimiliano Bonifacio ◽  
Elisabetta Calistri ◽  
Gianni Binotto ◽  
Elena Maino ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Group ◽  
Progression Free Survival ◽  
High Risk Group ◽  
Low Risk ◽  
Molecular Response ◽  
Free Survival ◽  
Optimal Response ◽  
Risk Patients ◽  
Eutos Score

Abstract Abstract 3778 Introduction. The EUTOS score has recently been developed by the European Leukemia-Net (ELN) to predict the achievement of an 18-month complete cytogenetic response (CCyR) and progression-free survival in imatinib-treated early chronic phase (ECP) chronic myeloid leukemia (CML) patients. The score uses the percentage of basophils and spleen size to divide patients in 2 groups of low- and high-risk. Since its publication in 2011, however, there have been conflicting reports about the efficacy of EUTOS score. Moreover, scanty data are available on the power of this scoring system to foresee optimal response to imatinib, as defined by ELN recommendations. Aims and Methods. To test the power of EUTOS score in predicting achievement of optimal response to imatinib, as defined by ELN, time to imatinib failure (TTF) and progression-free survival (PFS), we evaluated 265 ECP CML patients treated with front-line standard dose imatinib (400 mg daily) at 5 major hematology centres in the north-eastern area of Italy. Partial cytogenetic response (PCyR) and CCyR were defined as 1–35% and 0% Ph+ metaphases, respectively; major molecular response (MMR) was defined as BCR-ABL <0.1%IS. TTF was measured from the start of imatinib to the date of any of the following events: progression to accelerated or blastic phase, death for any cause at any time, imatinib dose increase (≥ 600 mg/day) for primary or secondary hematologic or cytogenetic resistance. PFS was measured from the start of imatinib to the date of progression to accelerated or blastic phase or death for any cause at any time. Survival probabilities were estimated by the Kaplan-Meier method and compared by log rank test; differences among variables were evaluated by the Fisher's exact test or by Student's t-distribution. Results. A total of 265 consecutive patients with ECP CML were included in this study. The median age was 55 years (range 19–84), with 149 males and 116 females. The median follow-up was 61 months (range 6–136). The median time from diagnosis to imatinib therapy was 0.7 months (range 0 – 7.6). The distribution according to the EUTOS score was: 248 patients (93.6%) in the low risk group and 17 patients (6.4%) in the high risk group. The “optimal response” endpoints to imatinib (i.e. PCyR at 6th months, CCyR at 12th months and MMR at 18th months) were higher in low-risk patients, but did not achieve statistical significance. Specifically, the values were as following: PCyR 86% vs 67% (p=0.055), CCyR 80% vs 63% (p=0.117) and MMR 61% vs 36% (p=0.126). Cumulative incidence of CCyR was comparable in the two groups (88%% in low-risk and 80% in high risk), but time to CCyR was shorter in low-risk patients (6 months) compared to the one in high-risk patients (9 months) (p=0.048) [figure 1]. More importantly, EUTOS score was able to predict long term response to therapy. Indeed, 59% of patients in the high-risk group experienced imatinib failure, compared to 30% in the low-risk group (p=0.027). Moreover also TTF was significant shorter in the high-risk group [figure 2]. Fifty-three patients in the low-risk group (21%) were switched to 2nd-generation TKIs (29 dasatinib, 22 nilotinib, 1 bosutinib, 1 ponatinib), compared to six (35%) in the high-risk group (4 dasatinib, 2 nilotinib). Also PFS rate was significantly worse in patients with high EUTOS score, with 11/248 events (4%) in the low-risk group and 4/17 (23%) in the high-risk cases (p=0.01) [figure 3]. Conclusions. In our study group, the EUTOS score was predictive for long-term outcome of imatinib therapy, both in terms of treatment failure and of progression-free survival. Taking into consideration the ELN definitions of optimal response, there was a trend toward better cytogenetic and molecular response in low-risk patients; the lack of statistical significance could be due to the relatively small number of high-risk cases. Disclosures: No relevant conflicts of interest to declare.

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1565-1565 ◽  
Author(s):  
Patrizia Mondello ◽  
Irene Dogliotti ◽  
Jan-Paul Bohn ◽  
Federica Cavallo ◽  
Simone Ferrero ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advanced Stage ◽  
Advisory Committees ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with &gt;90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= &lt;0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS &lt;3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, 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, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score

Blood ◽  
2011 ◽  
Vol 118 (3) ◽  
pp. 686-692 ◽  
Author(s):  
Joerg Hasford ◽  
Michele Baccarani ◽  
Verena Hoffmann ◽  
Joelle Guilhot ◽  
Susanne Saussele ◽  
...  
Keyword(s):  
High Risk ◽  
Kinase Inhibitors ◽  
Prognostic Score ◽  
Progression Free Survival ◽  
Risk Groups ◽  
High Risk Group ◽  
Prognostic Scores ◽  
Imatinib Treatment ◽  
Free Survival ◽  
Eutos Score

AbstractThe outcome of chronic myeloid leukemia (CML) has been profoundly changed by the introduction of tyrosine kinase inhibitors into therapy, but the prognosis of patients with CML is still evaluated using prognostic scores developed in the chemotherapy and interferon era. The present work describes a new prognostic score that is superior to the Sokal and Euro scores both in its prognostic ability and in its simplicity. The predictive power of the score was developed and tested on a group of patients selected from a registry of 2060 patients enrolled in studies of first-line treatment with imatinib-based regimes. The EUTOS score using the percentage of basophils and spleen size best discriminated between high-risk and low-risk groups of patients, with a positive predictive value of not reaching a CCgR of 34%. Five-year progression-free survival was significantly better in the low- than in the high-risk group (90% vs 82%, P = .006). These results were confirmed in the validation sample. The score can be used to identify CML patients with significantly lower probabilities of responding to therapy and survival, thus alerting physicians to those patients who require closer observation and early intervention.

High Risk Diffuse Large B Cell Lymphoma: A Comparison of Aggressive Subtypes Treated with Dose Adjusted Chemotherapy-the University of Texas MD Anderson Experience

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 106-106 ◽  
Author(s):  
Vishwanath Sathyanarayanan ◽  
Yasuhiro Oki ◽  
Amir K Issa ◽  
Mohamed Amin Ahmed ◽  
Mansoor Noorani ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Time To Event ◽  
Advisory Committees ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
Md Anderson

Abstract Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of non Hodgkin lymphoma (NHL).Nearly 50% of high-risk DLBCL patients are not cured with standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP). High risk DLBCL may be defined as double hit lymphoma (DHL, translocation of MYC and BCL2 or BCL6), double expressor lymphoma (DEL, over expression of MYC and BCL2), high risk international prognostic index (IPI) of 3-5, high Ki-67, and non-germinal center subtype (non-GCB). The majority of DHL cases occur in the GCB subtype, as opposed to the majority of DEL cases which occur in non-GCB. Hence we sought to compare different high risk subsets treated with dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and rituximab (DA) EPOCH-R. In single arm phase II clinical trials, dose adjusted (DA) EPOCH-R has shown promising results, with potential greater efficacy in the GCB subtype in subset analyses (Wilson et al, Hematologica 2012). A randomized phase III study comparing RCHOP with (DA) EPOCH-R in newly diagnosed DLBCL has completed accrual, with highly anticipated results due in late 2016. Methods: We conducted a retrospective reviewof all consecutive, newly diagnosed DLBCL patients treated with (DA) EPOCH-R at MD Anderson Cancer Center from 2010 to 2014. Eligible patients were 18 years or greater, had high-risk DLBCL as determined by the treating physician, and had available data of treatment and response. The cell of origin subtype was determined by immunohistochemistry using Hans algorithm, and MYC and BCL2 positivity were defined as BCL2 positive in at least 70% and MYC positive in at least 40% of cells. DHL was defined as rearrangement of MYC and BCL2 or BCL6 by fluorescent in situ hybridization. The objectives were to analyze demographic, prognostic, and treatment variables in comparison with clinical response and survival outcomes in three sub groups which included 1. DHL (GCB) 2. DLBCL without MYC and BCL2 expression (GCB), and 3. DEL (GCB and non GCB). Complete response (CR), overall survival (OS) and progression free survival (PFS) were calculated using standard methods. Statistical analysis was done using Fishers exact test or Chi-square test / Kruskal-Wallis test. Kaplan-Meier method was used for time-to-event analysis including overall survival and progression free survival. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Results: We identified 233 high risk DLBCL patients treated with (DA) EPOCH-R. After filtering the data to identify patients which were included in our three groups, we identified 22 patients with DHL (GCB), 46 patients with non DEL (GCB), and 16 with DEL. The demographic features and outcomes are mentioned in the table 1 below. The DHL group had more frequent bone marrow (BM) involvement, and the DHL and DEL groups were more frequently age >60 years and high IPI in comparison to the non DEL GCB group. The CR rate, OS and PFS at 1 year were not significantly different between these three groups. Figure 1 highlights the OS (A) and PFS (B) results of each group. Conclusions: (DA) EPOCH-R is highly effective in patients with subsets of patients with high-risk DLBCL and may be able to overcome prognostic factors which have been shown to be adverse with RCHOP therapy. The results of this retrospective study suggest that OS in DHL, DEL and non DEL (GCB) are not statistically different. Hence, intensive chemotherapy with (DA) EPOCH-R could be considered as a frontline treatment option for patients with high risk DLBCL, pending further confirmation in randomized trials. Disclosures Oki: Novartis: Research Funding. Fowler:Infinity: Consultancy, Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Gilead: Research Funding. Wang:Pharmacyclics: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; BeiGene: Research Funding; Kite Pharma: Research Funding; Onyx: Research Funding; Asana BioSciences: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fayad:Seattle Genetics: Consultancy, Research Funding. Westin:ProNAi: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Novel Prognostic Scoring System for Autologous Hematopoietic Cell Transplantation (AHCT) in Multiple Myeloma (MM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 783-783 ◽  
Author(s):  
Binod Dhakal ◽  
Raphael Fraser ◽  
Zhubin Gahvari ◽  
Aric C. Hall ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Scoring System ◽  
Research Funding ◽  
Validation Cohort ◽  
Progression Free Survival ◽  
Low Risk ◽  
Advisory Committees ◽  
Final Model ◽  
Free Survival

Background: Novel agent induction and AHCT remains the preferred initial therapeutic strategy for transplant-eligible MM patients. Current prognostic tools in MM focus solely on disease-specific factors at diagnosis to determine patient prognosis-International Staging System (ISS) and revised-ISS (R-ISS). A major limitation to both, the ISS and R-ISS, is that they are not specific for HCT-eligible patients and do not take into account other patient factors that may enter into a decision to pursue AHCT. The data used to generate these staging systems were from broad populations with varying upfront treatment strategies and included patients who were ineligible for intensive therapy. Additionally, there is considerable interest in identifying the population that relapses early despite modern induction/AHCT approaches who are candidates for novel approaches for maintenance/consolidation. To address these problems, we used data from the Center for Blood and Marrow Transplant Research (CIBMTR) registry to identify disease-, patient-, and transplantation-specific variables that are associated with progression-free survival (PFS) in patients undergoing upfront AHCT (within 12 months of diagnosis). Methods: We used the outcomes of 2528 MM patients undergoing upfront AHCT from 2008-2017 reported to the CIBMTR. Patients were divided into training and validation sets with a 50% random split. High risk cytogenetics was defined as the presence of one or more of the following: t(4;14), t (14;16), t (14;20), del 13q, del 17p, 1q gain, or 1p deletion. We used a Cox multivariable model to identify factors prognostic of progression free survival (PFS) in a training subset. The regression coefficients of the final model was transformed into a risk score with an appropriate transformation. A weighted score using these factors was assigned to the training cohort (n = 917) and validation cohort (n=897) using subset that had all values that entered the final model. Kaplan-Meier estimates of the individual scores were used to classify patients into risk groups for both cohorts. Results: Baseline characteristics of these patients are shown in Table 1. No cytogenetic abnormality, VRD induction, pre-AHCT bone marrow plasma cells (BMPCs) &lt;10% and 1 line of induction chemotherapy were assigned 0 points. Pre-AHCT BMPCs ≥10% (hazard ratio HR, 1.47; 95% CI, 1.19-1.83), use of ≥2 lines of induction chemotherapy prior to AHCT (HR 1.32; 95% CI 1.06-1.64), standard cytogenetic risk vs. no abnormality (HR 1.41; 95% CI 1.13-1.77) and induction regimens (non-VRD regimens vs. VRD) (HR 1.4, 95% CI 1.17-1.74) were associated with increased hazard of progression and assigned 1 point in the scoring system. Presence of high-risk cytogenetics vs. no abnormality (HR 1.87; 95% CI 1.45-2.42) was assigned 2 points, and the use of thalidomide and dexamethasone (TD) as an induction regimen (HR 2.19; 95% CI 1.48-3.2) was assigned 3 points. A two-category system was created based on the scoring: low risk (0-3) and high risk (4-6). The scoring system was prognostic for PFS when applied to both cohorts. High-risk group was found to have significantly higher risk of progression and/or death compared to low risk in training (HR 2.2; 95% CI 1.74-2.86; p&lt;0.0001) and validation cohort (HR 1.7, 95% CI 1.30-2.22; p=0.0001) respectively (Table 2). The 3-year PFS in the training cohort was 60% (95% CI 56%-64%) in low risk and 27% (95% CI 17%- 36%) in high risk while in the validation cohort was 51% (95% CI 47%-55%) in low risk and 28% (95% CI 16%- 39%) in high risk (Figure 1A and 1B). Conclusions: We describe a prognostic model specifically for patients undergoing upfront AHCT in MM which can identify patients at very high risk for early relapse/progression. These patients should be ideal candidates for studies of immunotherapy or other interventions after AHCT aimed at reducing relapse. Disclosures Dhakal: Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Shah:Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees; University of California, San Francisco: Employment; Poseida: Research Funding; Indapta Therapeutics: Equity Ownership; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy; Genzyme: Other: Speaker. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.

scholarly journals Outcomes of Tandem Hematopoietic Stem Cell Autologous Transplant in High-Risk Myeloma Patients: A Single-Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4901-4901
Author(s):  
Shona Philip ◽  
Selay Lam ◽  
Chai Wye Phua ◽  
Martha L Louzada ◽  
Anargyros Xenocostas ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Partial Response ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Progression Free Survival ◽  
Single Center ◽  
Advisory Committees ◽  
Free Survival ◽  
Risk Patients

Abstract Introduction: Studies have demonstrated that multiple myeloma (MM) is a clinically, genetically complex and heterogeneous disease. Cytogenetic alterations identify high-risk patients in MM and are associated with a poor prognosis. They include at least one of the following at diagnosis: t(4;14), t(14;16), t(14;20), del(17p), 1q amp and 1q amp + del(1p). Autologous stem cell transplantation (ASCT) and the development of novel agents have considerably increased the median survival of MM patients. Patients with high-risk cytogenetics are associated with worse survival, and studies have shown improvement in progression-free survival with tandem ASCT when compared to single ASCT. Methods: This is a retrospective single-center study evaluating MM patients with high-risk cytogenetics at our center who have undergone a tandem autologous transplant from January 1, 2017, to December 31, 2020. Primary objective was overall response rates (ORR) and relapse rates. Secondary objectives looked at progression-free survival (PFS), overall survival (OS) using the Kaplan-Meier method. Results: From January 1, 2017, to December 31, 2020, 25 high-risk patients underwent tandem ASCT. Key patient characteristics are shown in table 1. Translocation (4:14) was seen in 8/25 (32%) patients; t(14:16) in 5/25 (20%) patients; del17p in 7/25 (28%), 1q amp in 8/25 (32%) patients, del1p + 1q amp in 5/25 (20%) patients. In terms of double hit and triple hit disease, 9/25 (36%) patients had two high risk changes and 3/25 (12%) with had three high risk changes. ISS staging wise, 5/25 (20%) patients were ISS stage I, 5/25 (20%) patients ISS stage 2 and 9/25 (36%) patients were ISS stage 3. The most common induction regimen consisted of cyclophosphamide, bortezomib, and dexamethasone (CyBorD). One patient each transitioned to daratumumab, lenalidomide and dexamethasone and PAD/CVD due to poor response. Maintenance therapy was given to 21/25 (84%) tandem ASCT patients with 5 (20%) patients receiving lenalidomide, 4 (16%) patients receiving proteasome inhibitor and 12 (48%) patients received dual maintenance. In terms of response, we recorded CR (complete response) vs VGPR (very good partial response) vs PR (partial response) after induction, 2-3 months after ASCT #1, 2-3 months after ASCT #2, 12 months after ASCT #2, and 12 months after maintenance. Following induction, 16 patients had achieved VGPR, and 9 of patients had achieved PR. After ASCT #1, 5 (55.5%) PR patients deepened their response to a VGPR. 1-3 months post ASCT #2, 3 (33.3%) PR patients deepened to a VGPR, and 2 (12.5%) VGPR patients achieved CR. 12 months after ASCT #2, 2 of the previous VGPR patients (12.5%) achieved CR, and 1 PR (11.1%) patient achieved VGPR. At the median follow-up time of 60 months, 44% of patients had relapsed. 1 patient relapsed within 1-3 months post ASCT#1. Nine other patients relapsed post ASCT #2 and maintenance except one patient who relapsed at time of ASCT #2. Univariable analysis identified hemoglobin as a statistically significant association with risk of progression or death. All patients who received any maintenance after tandem transplant were progression-free at 60 months (p&lt;0.001). Conclusion: In our retrospective study, results suggest that tandem ASCT allows for deepening of responses. Together with maintenance therapy, this contributes to the durability of further PFS prolongation in high-risk MM patients. Figure 1 Figure 1. Disclosures Lam: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Amgen: Honoraria. Louzada: Amgen: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

scholarly journals Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 154-154 ◽  
Author(s):  
Chia-jen Liu ◽  
Irene M. Ghobrial ◽  
Mark Bustoros ◽  
Kaitlen Reyes ◽  
Kalvis Hornburg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Therapeutic Intervention ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Genomic Studies ◽  
Equity Ownership

Abstract Background This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, Lenalidomide, and Dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). ClinicalTrials.gov Identifier: NCT02279394. Aims The overarching objective of this trial is to determine progression free survival to symptomatic multiple myeloma (MM). Furthermore, the study examined whether genomic studies can help in determining patients who would benefit the most from this early therapeutic intervention. Methods Patients enrolled in this study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. For cycles 3-8, patients were administered elotuzumab infusions on days 1, 8, and 15. dexamethasone (40mg) was given on days 1, 8 and 15 to 40 of the 50 enrolled patients. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28-day cycle. Bone marrow (BM) samples of 32 patients were obtained before starting therapy for baseline assessment and whole exome sequencing (WES) of plasma cells. Results In total, 50 patients were enrolled on this study from January 2015 and completed accrual in December 2016, with the participation of eight sites. The median age of enrolled patients was 62 years (range, 29-79) with 18 males (36%) and 32 females (64%). Interphase fluorescence in situ hybridization (iFISH) detected high-risk cytogenetics (defined by the presence of 17p deletion, t(4;14), and 1q gain) in 20 patients. The median time to response was 2.8 months (range, 1.8-4.6). The most common toxicities were fatigue (92%), followed by diarrhea (72%), and hyperglycemia (62%). The most common grade 3 or more adverse events were hypophosphatemia (34%), neutropenia (26%), and lymphocyte count decreased (22%). Three patients (6%) had grade 4 hypophosphatemia during treatment. Additionally, grade 4 cholecystitis, cataract, lymphocyte count increase, hyperglycemia, neutropenia, and thrombocytopenia occurred in one patient (2%). Diabetic Ketoacidosis and sepsis led to death in a patient (2%). Stem cell collection was successful in all mobilized patients to date. As of this abstract date, the overall response rate is 84% (41/49). There were 3 complete responses (6%), 18 very good partial responses (37%), 20 partial responses (41%), 5 minimal responses (10%), 3 stable disease (6%), and 2 unevaluable patients. All the study participants except for three have finished treatment and are currently under follow up. None of the patients showed progression to overt MM to date. We continue to collect data for progression free survival. WES was performed on 32 samples at the time of initiation of therapy. Recurrent mutations in the MAPK pathway (KRAS, NRAS) and tumor suppressor gene, TP53, were detected in 40% of the cases (16% and 24%, respectively), while mutations in the NF-KB and plasma cell differentiation pathways were present in 13% of patients. Somatic copy number alterations (SCNAs) were called based on WES: 1q duplication, 13q, 17p, and 1p deletions were identified in 25, 31, 12, and 7% of cases, respectively. Interestingly, in 6 patients, high-risk SCNAs (1q gain and 17p deletion) were not reported in iFISH but were detected by WES. The analysis of these 32 samples showed that patients who are harboring mutations in the DNA repair pathway genes, had modest response to treatment. Finally, we are analyzing the transcriptomic profile of CD138 negative cells, which represent the BM microenvironment cells (immune and stromal cells) to characterize the BM microenvironment at baseline and end of treatment, and thus, elucidate the role of these cells in the differential response to therapy. Conclusion The combination of elotuzumab, lenalidomide, and dexamethasone is well tolerated and demonstrates a high response rate with no progression to overt MM to date. Correlation with genomic studies can help define patients who benefit the most from this early therapeutic intervention. Disclosures Ghobrial: Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy; Celgene: Consultancy. Bustoros:Dava Oncology: Honoraria. Badros:GSK: Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Research Funding. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Rosenblatt:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:Karyopharm: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding. Zonder:Celgene: Consultancy, Honoraria; Pharmacyclics: Other: DSMC; Janssen: Honoraria; Takeda: Honoraria; Alnylam: Honoraria; Coelum: Honoraria; BMS: Research Funding. Munshi:OncoPep: Other: Board of director. Anderson:Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; OncoPep: Equity Ownership, Other: Scientific founder; Millennium Takeda: Consultancy; Celgene: Consultancy. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: 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; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Integrative Network Analysis of Newly Diagnosed Multiple Myeloma Identifies a Novel RNA-Seq Based High Riskgene Signature

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3285-3285
Author(s):  
Alessandro Lagana ◽  
Deepak Perumal ◽  
David Melnekoff ◽  
Ben Readhead ◽  
Brian Kidd ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
Kaplan Meier ◽  
Risk Patients ◽  
Equity Ownership

Abstract High-risk Multiple Myeloma (MM) is characterized by unresponsiveness to multiple therapies, rapid disease progression and short overall survival, and may be significantly different from relapsed MM, where aggressiveness is usually a result of drug-resistance associated to clonal selection. Several gene expression-based signatures have been proposed in the past years, however the identification of high-risk patients at diagnosis still represents a challenge. Next generation high-throughput sequencing technologies have enabled a deeper insight into cancer genomes and transcriptomes at an unprecedented level of detail. MMRF CoMMpass is a longitudinal, prospective observational study, started in 2011, that aims to collect and analyze sequencing and clinical data from >1,000 MM patients at initial diagnosis and at relapse. CoMMpass is a real world observational study and, as such, reflects the therapeutic heterogeneity seen across patient populations and provides a unique opportunity to correlate molecular profiles, genomic alterations and clinical characteristics of MM with treatment outcome. Here we present a network approach to identify high-risk myeloma patients developed using next generation sequencing data from 450 patients in the IA7 release of CoMMpass. We generated MMNet, an integrated network model of newly diagnosed myeloma based on RNA-seq, Whole-Exome (WXS) and Whole-Genome (WGS) data correlated with clinical outcomes. MMNet consisted of 37 modules of coexpressed genes, that were further characterized by functional enrichment analysis and correlation with clinical traits and genomic alterations, i.e. somatic mutations and copy number alterations inferred from WGS and WXS data. A total of 89 progression/death events have been reported for the cohort within the second year since the beginning of the study. Cox regression analysis identified a module of co-expressed genes whose over-expression was significantly correlated with early relapse (<2yr) (HR 1.75, 95%CI = 1.169-2.614, p=0.005). The module was also associated to stage III R-ISS, high clonality (>4 clones) and high mutational burden, as well as higher percentage of plasma cells in both bone marrow and peripheral blood, which are traits associated with high-risk disease. Module expression was also up regulated in patients with mutations in TP53 and MAX, 13q deletion and 1q amplification. We further narrowed down the signature to 286 genes (the MMNet-286 signature) strongly correlated with time to Event Free Survival (EFS) (r = -0.81, p = 0). This gene-set was significantly enriched for several pathways including Cell Cycle, DNA repair and Homologous Recombination (q < 0.01). Cox regression analysis showed that the two clusters induced by MMNet-286 discriminated between lower and higher risk patients with respect to EFS (HR = 2.22, 95% CI = 1.505-3.295, p = 4.007e-5) (Fig. 1). The prognostic value of MMNet-286 was confirmed on two independent datasets: Broyl-2010 (HR = 1.76, 95% CI = 1.182-2.642, p = 0.005) and Shaughnessy-2006 (HR = 2.65, 95% CI = 1.746-4.031, p = 2.03e-6) (Fig. 2 and 3). The Broyl-2010 dataset consisted of 275 samples from newly diagnosed myeloma patients included in the HOVON65/GMMG-HD4 trial (GSE19784). The Shaughnessy-2006 dataset consisted of 559 samples from newly diagnosed patients pre-TT2 and -TT3 treatments (GSE2658). Comparison of MMNet-286 with previous high risk signatures and disease classes revealed an overlap of five genes with the UAMS-70 signature, twelve genes with the EMC-92 signature and fifteen genes with the set of up-regulated genes in the UAMS PR class, for which the coexpression module was enriched. In Conclusion, our results demonstrate the advantages of employing integrated network models to identify prognostic features based on next generation sequencing data from large cohort of patients. Applications of the MMNet-286 signature include the generation of a prognostic assay (i.e. NanoString) for the identification of high-risk patients. Future work will aim at validation of the signature in larger cohorts from CoMMpass and other studies. Figure 1 Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 1. Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 2 Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 2. Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 3 Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Figure 3. Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Disclosures Chari: Novartis: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen Inc.: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus, Inc.: Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding. Barlogie:Signal Genetics: Patents & Royalties. Dudley:GlaxoSmithKline: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Ayasdi, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership; Ontomics, Inc.: Equity Ownership; AstraZeneca: Speakers Bureau; NuMedii, Inc.: Patents & Royalties; Personalis: Patents & Royalties.

scholarly journals Evomela® Significantly Increases the Risk of Engraftment Syndrome in Patients with Multiple Myeloma Treated with Autologous Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3316-3316 ◽  
Author(s):  
Marshall McKenna ◽  
Phyllis McKiernan ◽  
David S. Siegel ◽  
Scott D. Rowley ◽  
Noa Biran ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Progression Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Engraftment Syndrome ◽  
Equity Ownership

Background: Evomela, a Melphalan bioequivalent, was approved by the FDA in 2016 for high-dose conditioning treatment prior to hematopoietic stem cell transplantation for multiple myeloma (MM). Evomela has increased solubility and stability compared to traditional Melphalan which requires propylene glycol, a stabilizing agent. A retrospective review (Miller et al. 2019) showed that there was no difference in outcomes or short term morbidity in autologous stem cell transplant (ASCT) recipients conditioned with either Melphalan or Evomela. There was, however, an increased incidence of C. difficile-negative diarrhea in the Evomela group. Engraftment syndrome (ES) is a well characterized, although poorly understood, conglomerate of symptoms occurring in the autologous peri-engraftment period. We have previously demonstrated (McKiernan et al. 2017) that patients with ES have an adverse overall outcome. This study aims to evaluate the effect of Evomela conditioning on patients with MM receiving ASCT. Methods: Our study cohort included 644 patients with MM who received ASCT between January 2008 and December 2018. Evomela conditioning was administered to all patients treated on or after September 4, 2016, defining the Melphalan and Evomela cohorts. ES was defined as diarrhea, rash, non-infectious fever, hepatic dysfunction, pulmonary infiltrates, or encephalopathy not attributed to other causes from 3 days prior to 15 days post engraftment. High-risk disease (HRD) was defined as del 17p, 1q gain, t(4;14), t(14;16), t(14;20) by FISH, monosomy 13, del 13q or hypodiploidy by standard cytogenetics, or high-risk gene expression profiling. Response criteria from the International Myeloma Working Group was used to determine response. Progression free survival (PFS) and overall survival (OS) probabilities were estimated using log rank or Wilcoxon tests. Cox hazard regression model was examined for factors influencing ES. Results: Of the 644 patients, 78 were conditioned with Evomela and 554 were conditioned with Melphalan. Thirty five percent of the total patient population had HRD, 234 (36%) were age 65 or older, and 369 (57%) were males. A total of 197 (30%) patients developed ES with 171 (87%) receiving treatment with corticosteroids. Conditioning with Evomela was associated with a significantly higher incidence of ES 15 days post ASCT compared to Melphalan (40.3% vs 24.8%, p=0.0006). Multivariate analysis showed that patients conditioned with Evomela were 60% more likely (HR-1.597, 95% CI, 1.116-2.285, p=0.0105) to develop ES than traditional Melphalan. Across both cohorts, higher median CD34+ stem cell doses (5.22 vs 5.85 x 10e6/kg, p=0.0026) were protective against ES. Age greater than 65 was associated with increased 15 day post ASCT incidence of ES (HR-1.903, 95% CI, 1.435-2.523, p=<0.0001). There was no PFS (p=0.2996) or OS (p=0.2778) difference between the Evomela group and the Melphalan group. There was a trend towards decreased OS (p=0.0914) among patients with ES, but it was not statistically significant. There was no statistically significant progression difference between ES and non-ES groups (p=0.9739). Conclusion: Patients conditioned with Evomela are significantly more likely to develop ES than patients conditioned with traditional Melphalan. We were not able to show any survival or progression-free survival advantage for patients treated with Evomela. We would caution the use of Evomela in patients with other risk factors for ES. More studies are needed to further understand the differences between Melphalan and Evomela. Disclosures Siegel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Goldberg:Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership. Goy:Hackensack University Medical Center, RCCA: Employment; Takeda: Other: Grants outside of the submitted work; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding.

scholarly journals Five Gene Probes Carry Most Of The Discriminatory Power Of The 70-Gene Risk Model In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 125-125
Author(s):  
Christoph Heuck ◽  
Pingping Qu ◽  
Frits van Rhee ◽  
Sarah Waheed ◽  
Saad Z Usmani ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Risk Model ◽  
Progression Free Survival ◽  
Dna Probes ◽  
Low Risk ◽  
Free Survival ◽  
The Us ◽  
Risk Patients ◽  
Total Therapy

Abstract Gene expression profiling (GEP) reliably predicts overall and progression free survival in multiple myeloma. Driven by the concept that therapy will reveal biology, we applied the GEP70 risk model to 56 patients enrolled in Total Therapy 6 (TT6), a phase 2 trial for previously treated patients. One year survival estimates were 62% vs.97%, p<0.0001, Figure 1A). To investigate whether fewer than the 70 genes could predict this difference in outcomes, the probe sets of the GEP70 risk model were ranked by p-values, based on univariate Cox regression analysis for OS. The five probe sets with the smallest P values (corresponding to genes ENO1, FABP5, TRIP13, TAGLN2, and RFC4) were combined to create a continuous score (Figure1B). Association of several of these genes with different cancers has previously been reported by others. We re-trained this 5 gene model (GEP5) on a dataset of 275 uniformly treated patients on Total Therapy 3A (TT3A) and identified a new optimal cutoff of 10.68. We validated this new cutoff with patients enrolled in Total Therapy 2 (TT2) (n=351) and Total Therapy 3B (TT3B) (n=166). For TT2 patients, the dataset from which the GEP70 model was developed, clinical outcomes of the GEP5defined low risk patients were very similar to the GEP70 defined low risk patients. Survival estimates were higher for GEP5-defined high risk than for GEP70 high risk patients (5-year estimated OS: 40%, GEP5; 28%, GEP70; 5-year estimated PFS: 26%, GEP5; 15%, GEP70) (Figure 2A and 2B). This was also seen in both TT2 treatment arms. For the second validation cohort (TT3B), GEP5 and GEP70 risk distinction were similar to the TT3A discovery cohort (Figures 2C and 2D). On multivariate analysis, the GEP5-defined high-risk designation was the most adverse variable for PFS, with an estimated hazard ratio of 3.44 (95% CI: 2.02-5.86), whereas the GEP70 model was selected first for OS. (Table 1).Table 1.Multivariate stepwise Cox regression analysis performed on the TT3B validation setOverall survivalProgression-free survivalVariablen/N (%)HR (95% CI)P-valueHR (95% CI)P-valueMultivariateGEP70 high-risk36/159 (23%)4.45 (2.47, 8.02)<.001B2M > 5.5 mg/L49/159 (31%)1.73 (1.01, 2.95)0.045GEP5 high-risk42/159 (26%)3.44 (2.02, 5.86)<.001 Applied to the publicly available dataset from the HOVON group, GEP5 identified a high risk group with a 3-year estimate OS survival of 52% compared to 75% for the low risk group (p<0.001). TT4 and TT5 are phase 2 trials for previously untreated GEP70 defined low-risk and high-risk patients, respectively. GEP5 identified in TT4 a subset (17/303) of high risk patients with significantly worse 3-year estimated OS (69% vs. 86%, p=0.03), and in TT5 GEP5 identifies a low-risk subset (22/57) of patients with significantly better 3-year estimate OS (94% vs. 59%, p=0.01). Recently a large-scale proteomics experiment involving 85 patients with MM identified ENO1, FABP5, and TAGLN2 among a set of 24 proteins that are associated with short OS. It was further shown that gene expression levels correlated closely with protein abundance. In summary, we have identified 5 genes that have the greatest influence on GEP defined risk. The GEP5 score maintains prognostic power even in patients who have been risk stratified using other risk models. The correlation of expression at both mRNA and protein levels indicate that the genes identified in GEP5 are not simply an artifact of the microarray methodology, but rather supports their biologic relevance. This simplified risk model with a reduced number of genes has the potential to open molecular risk testing to a larger audience. Figure 1. Figure 1. Overall Survival in TT6 according to A) GEP70 risk score and B) GEP5 risk score Figure 2. Figure 2. Overall survival (left panels) and progression-free survival (right panels) according to GEP5 risk score in A) TT3A training set set, B) TT2 test set and C) a second test set TT3B Figure 3. Figure 3. Overall survival (left panels) and progression-free survival (right panels) according to GEP5 in A) the publicly available HOVON dataset B) TT4, for previously untreated GEP70 defined low-risk myeloma and C) TT5, for previously untreated GEP70 defined high-risk myeloma Disclosures: van Rhee: Jansen & Jansen: Research Funding. Usmani:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Epstein:University of Arkansas for Medical Sciences: Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations, Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations Patents & Royalties. Zhang:University of Arkansas for Medical Sciences: Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations, Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; Myeloma Health, LLC: Patents & Royalties.

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