Risk Factors Associated with Survival Outcome in Patients with Chronic Myeloid Leukaemia in Accelerated Phase Treated with Tyrosine Kinase Inhibitors

Abstract Chronic Myeloid Leukaemia (CML) is a triphasic disease which typically presents in chronic phase with risk of progression to more aggressive phases in a certain proportion of patients. Accelerated Phase (AP), as described in the pre-Tyrosine Kinase Inhibitor (TKI) era by Kantarjian et al in 1988, is an intermediate stage with a poor median overall survival (OS) of ≤18 months without haematopoietic stem cell transplantation (HSCT). Since TKI therapy has revolutionized CML treatment, a significantly improved OS has been seen in most CML patients, including those in AP. Not all CML-AP patients require HSCT upfront nowadays and many are able to achieve major molecular remission (MMR) and favourable OS on TKI therapy. However, updated classifications of CML-AP by the World Health Organization (WHO) and European LeukemiaNet (ELN) do not reflect these significant advances in the TKI era. There is a need to re-evaluate the CML-AP classification that will have an impact on treatment decisions for CML-AP patients. In this study, we explored the association between various haematological parameters at diagnosis and the probabilities of OS and progression-free survival (PFS) of CML-AP patients on TKI therapy. Overall Survival (OS) and Progression-Free Survival (PFS) trends of 75 newly diagnosed CML-AP patients treated with frontline TKIs between 2000 to 2013 from Singapore General Hospital and Seoul St. Mary's Hospital in South Korea were retrospectively analysed with regards to demographic and haematological parameters, such as cell counts from serum and bone marrow at diagnosis, using cox proportional hazards analysis. Survival was also compared using log-rank test with Bonferroni corrections between CML-AP patients and 227 CML Chronic Phase (CML-CP) high-risk Sokal and 34 Blast Crisis (CML-BC) patients on TKI-based therapy. OS was defined as duration from diagnosis of CML-AP to death from any reason. PFS was defined as duration from disease diagnosis to the first occurrence of progression or death due to CML. As a whole, CML-AP patients treated with frontline TKI had survival that paralleled CML-CP high-risk Sokal patients (p-value = 0.694 for OS, p-value = 0.258 for PFS). Most of the death and progression occurred less than 3 years of starting TKI therapy (69.2% for OS, 84.6% for PFS). Multivariable analysis in CML-AP patients showed that male gender, bone marrow (BM) blasts ≥10% and clonal chromosomal abnormalities (CCAs) at diagnosis were associated with poor OS (Hazard Ratio (HR) 18.53, p-value = 0.013; HR 1.16, p-value = 0.010; HR 5.05, p-value = 0.044, respectively) and poor PFS (HR 12.96, p-value = 0.021; HR 1.17, p-value = 0.007; HR 8.84.05, p-value = 0.008, respectively). CML-AP patients with all 3 of these risk factors experienced the worst OS compared to those with 1 or zero risk factors (p-value <0.001). Patients with all 3 risk factors also had the poorest PFS compared to those with 2, 1 and zero risk factors (p-value = 0.022, <0.001, <0.001 respectively; figure 1). CML-AP Patients with 2 risk factors or less, had OS and PFS probabilities comparable to CML-CP patients with high-risk Sokal score (p-value = 0.082 for OS, p-value= 0.813 for PFS, figure 2 and 3 respectively). However, CML-AP patients with all 3 risk factors showed inferior OS and PFS probabilities similar to CML-BC patients (p-value = 0.799 for OS, p-value = 0.624 for PFS; figure 2 and 3 respectively). Our findings suggested that CML-AP was a heterogeneous group with varying survival probabilities on TKI therapy. Male gender, BM blasts ≥10% and CCAs at diagnosis were risk factors shown to be predictive of survival probabilities, and identified a high-risk sub-group among CML-AP patients with inferior OS and PFS rates similar to CML-BC patients. Aggressive chemotherapeutic strategies including HSCT should be warranted in these patients. However, TKI therapy alone with close molecular surveillance may be a reasonable option for optimally responding low-risk CML-AP patients who are not eligible for HSCT. Figure 1. Kaplan-Meier survival curves for PFS according to stratification of the number of risk factors present in CML-AP patients. Figure 1. Kaplan-Meier survival curves for PFS according to stratification of the number of risk factors present in CML-AP patients. Figure 2. Kaplan-Meier survival curves for OS according to phases of CML with AP patients separated by number of risk factors present. Figure 2. Kaplan-Meier survival curves for OS according to phases of CML with AP patients separated by number of risk factors present. Figure 3. Kaplan-Meier survival curves for PFS according to phases of CML with AP patients separated by number of risk factors present. Figure 3. Kaplan-Meier survival curves for PFS according to phases of CML with AP patients separated by number of risk factors present. Disclosures Kim: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Goh:BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Honoraria; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Connect MM®—the Multiple Myeloma (MM) Disease Registry: Interim Analysis of Overall Survival and Outcomes in Patients with High-Risk Disease

Blood ◽

10.1182/blood.v124.21.2106.2106 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2106-2106 ◽

Cited By ~ 1

Author(s):

Jatin J. Shah ◽

Rafat Abonour ◽

Brian G M Durie ◽

Jayesh Mehta ◽

Mohit Narang ◽

...

Keyword(s):

Risk Factors ◽

Overall Survival ◽

African American ◽

High Risk ◽

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Advisory Committees ◽

Kaplan Meier ◽

High Risk Disease

Abstract Background: MM treatment (Tx) advances have greatly improved clinical outcomes for patients (pts). A recent study demonstrated improved survival in MM through the past decade attributable to the impact of initial therapy with lenalidomide, bortezomib, and thalidomide. The greatest impact was observed in older pts (Kumar, et al. Leukemia, 2014). Connect MM, the first and largest prospective, observational, US-based, multicenter registry was designed to characterize pts, Tx patterns, and outcomes in newly diagnosed MM (NDMM). Methods: This ongoing registry was initiated in September 2009. Eligible pts with NDMM (diagnosis must have occurred within 2 mos of study entry) were enrolled at 234 US sites. Data were collected at baseline and each subsequent quarter using an electronic case report form. The initial enrollment includes all pts who had provided informed consent as of November 1, 2012 (N = 1493). The data cutoff for this analysis was Dec 10, 2013. A total of 1444 pts were treated and were included in overall survival (OS) analyses. Survival was examined for all treated pts adjusting for pt and Tx characteristics including age, autologous stem cell transplant (ASCT) status, gender, race, disease risk factors (International Myeloma Working Group [IMWG] high risk vs. non-high risk), and therapy received (triplet vs. non-triplet) among others. Triplet therapy was defined as any combination of 3 or more drugs during the first Tx regimen. OS was estimated using Kaplan-Meier methods and comparisons across groups were assessed used the log-rank test. Results: At the time of data cutoff, 1493 pts were enrolled with 1444 having received Tx. Of the treated pts 253 pts (18%) had IMWG high-risk disease and 108 pts (7%) had del(17p) at baseline. Median age was 67 y (range, 24-94 y), 57.2% were male, and 81.9% were white. Median follow-up was 29 mos (0-49.4 mos). The median OS for all treated pts was 44.4 mos. When assessed by age group, OS was significantly different (log-rank P < .0001) with a median of 47.6 mos for pts aged < 65 y (n = 632), 45.0 mos for those aged 65 to < 75 y (n = 443), and 33.7 mos for those aged ≥ 75 y (n = 369). OS was significantly longer for pts with ASCT vs. no ASCT (P < .0001), but not different by gender (P = .962) or race (Caucasian vs. African American vs. other; P = .250). Three-year OS probabilities by subgroup are listed in Table 1. When considering risk factors, IMWG risk was borderline significant (high vs. non-high; P = .106), and presence of del(17p) by cytogenetics and FISH was associated with significantly shortened OS (P = .005; Figure 1A). Interestingly, use of triplet therapy vs. non-triplet therapy was associated with significantly prolonged OS regardless of IMWG risk (non-high: P < .0001; high: P = .003; Figure 1B). However, no improvement was noted for triplet vs. non-triplet therapy in pts with del(17p). By multivariate analysis, the significant (P < .05) factors impacting OS were age (in 10-yr increments), International Staging System (ISS) disease stage, ECOG performance status, history of diabetes, anemia, renal function, and platelet count. Conclusions: This interim analysis based on initially treated pts demonstrated that age, ISS stage, and co-morbidities impact OS irrespective of IMWG cytogenetic risk. Triplet Tx was associated with significantly longer OS in pts regardless of IMWG risk status. This is the largest prospective pt cohort with high-risk disease including del(17p). Pts with high-risk disease did not have significantly lower OS vs. pts without high-risk features. Pts with del(17p) (p53 deletion) continue to have shorter OS approaching 3 y and increased survival with use of triplet therapy. Table 1. Kaplan-Meier Estimated 3-Y OS Probability Patients 3-y OS Probability (%) (95% CI) All (N = 1444) 62.6 (59.5-65.8) < 65 y (n = 632) 69.8 (65.2-74.3) 65 to < 75 y (n = 443) 65.0 (59.4-70.6) ≥ 75 y (n = 369) 47.2 (40.7-53.8) Gender Male (n = 831) 62.1 (57.9-66.3) Female (n = 613) 63.4 (58.7-68.2) Race Caucasian (n = 1191) 61.8 (58.3-65.3) African American (n = 183) 64.4 (55.4-73.5) Other (n = 27) 77.6 (57.3-98.0) ASCT Yes (n = 494) 77.1 (72.5-81.7) No (n = 950) 54.2 (50.0-58.3) Triplet therapy Yes (n = 778) 69.3 (65.3-73.3) No (n = 666) 54.8 (49.9-59.6) IMWG risk High (n = 253) 59.0 (51.6-66.4) Standard (n = 566) 66.3 (61.4-71.2) Low (n = 86) 75.7 (63.6-87.8) del(17p) Present (n = 108) 52.7 (41.8-63.6) Absent (n = 1336) 63.4 (60.1-66.7) Figure 1 Figure 1. Disclosures Shah: Celgene Corp: Consultancy, Research Funding. Abonour:Celgene Corp: Honoraria, Speakers Bureau. Durie:Celgene Corp: Export Board Committee Other, Membership on an entity's Board of Directors or advisory committees; IRC Onyx: Membership on an entity's Board of Directors or advisory committees; DMC Millennium: Membership on an entity's Board of Directors or advisory committees; IRC J&J: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene Corp: Consultancy, Speakers Bureau. Narang:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Consultancy, Honoraria; Millenium: Honoraria. Thomas:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene Corp: Membership on an entity's Board of Directors or advisory committees. Hardin:Celgene Corp: Research Funding. Srinivasan:Celgene Corp: Employment, Equity Ownership. Ricafort:Celgene Corp: Employment. Nagarwala:Celgene Corp: Employment. Rifkin:Celgene Corp: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Takeda: Consultancy; Amgen: Consultancy.

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Identifying Ultra-High Risk Smoldering Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-109709 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3192-3192 ◽

Cited By ~ 1

Author(s):

Theresia Akhlaghi ◽

Even H Rustad ◽

Venkata D Yellapantula ◽

Neha Korde ◽

Sham Mailankody ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Ultra High Risk ◽

Risk Of Progression ◽

Equity Ownership ◽

M Spike ◽

Risk Biomarkers

Abstract Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage to active multiple myeloma (MM), comprised by a heterogenous group of patients with varying rates of progression. While the overall yearly progression rate is 10% the first 5 years, some patients progress at a considerably higher rate. A study from the Mayo Clinic showed that in a subset of 21 patients defined by ≥60% monoclonal bone marrow plasma cells (BMPC), 95% progressed within 2 years. It was subsequently concluded by the International Myeloma Working Group (IMWG) that patients with biomarkers predictive of a 2-year progression rate at 80%, and a median time to progression at 12 months were at ultra-high risk of progression and should be considered to have MM requiring treatment despite being asymptomatic. In 2014, ultra-high risk biomarkers were incorporated in the definition of MM, including BMPC ≥60%, free light chain (FLC) ratio ≥100 and ≥2 focal lesions on magnetic resonance imaging (MRI). While the updated myeloma definition changed the diagnosis of some patients with ultra-high risk SMM to MM, there remain patients classified as SMM progressing at a very high rate. In the present study, we aimed at further identifying ultra-high risk biomarkers predictive of a high rate of progression to active MM. Methods Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2017 were identified and included in the study. Diagnosis of SMM and progression to MM requiring therapy was defined according to the IMWG criteria at the time of diagnosis. Baseline patient and disease characteristics were collected at date of diagnosis with SMM, including pathology reports, laboratory results and imaging data. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Optimal cut-off values for continuous variables were assessed with receiver operating characteristics (ROC) curve. Patients who had not progressed by the end of study or were lost to follow up were censored at the date of last visit. Univariate Cox regression was used to estimate risk factors for TTP with hazard ratios (HR) and 95% confidence intervals (CI). Significant univariate risk factors were selected for multivariate Cox regression. Results A total of 444 patients were included in the study. Median follow-up time was 78 months. During the study period, 215 (48%) patients progressed to active MM, with a median TTP of 72 months. Cut-off points for BMPC, M-spike, and FLC ratio were determined with ROC curves to be 20%, 2 g/dL, and 18, respectively, for predicting high risk of progression. The following factors were associated with significantly increased risk of progression to active MM: BMPC >20%, M-spike >2g/dL, FLC ratio >18, immunoparesis with depression of 1 and 2 uninvolved immunoglobulins respectively, elevated lactate dehydrogenase, elevated beta-2-microglobulin, and low albumin (Table 1). In the multivariate model, BMPC >20% (HR 2.5, 95% CI 1.6-3.9), M-spike >2g/dL (HR 3.2, CI 1.9-5.5), FLC ratio >18 (HR 1.8, CI 1.1-3.0), albumin <3.5 g/dL (HR 3.9, CI 1.5-10.0), and immunoparesis with 2 uninvolved immunoglobulins (HR 2.3, CI 1.2-4.3), predicted a decreased TTP (Table 1). A total of 12 patients had 4 or 5 of the risk factors from the multivariate model, 8 of these did not meet the 2014 IMWG criteria for MM. These patients had a significantly shorter TTP than patients with less than 4 risk factors (median TTP 11 vs 74 months, p<0.0001, Figure 1). At 16 months, 82% of these patients had progressed, and within 2 years, 91% of the patients progressed. Only one patient remained progression free after 2 years, progressing at 31 months. Of patients with less than 4 risk factors, 19% progressed within the first 2 years. Conclusion In addition to baseline BMPC >20%, M-spike >2g/dL, FLC-ratio >18, we found that albumin <3.5g/dL and immunoparesis of both uninvolved immunoglobulins at the time of diagnosis with SMM were highly predictive of a decreased TTP to MM requiring therapy. These biomarkers are readily available and routinely assessed in clinic. Patients with 4 or 5 of these risk factors represent a new ultra-high risk group that progress to active disease within 2 years, further expanding on the definition of ultra-high risk SMM. In accordance with the rationale on ultra-high risk biomarkers as criteria established by the IMWG in 2014, such patients should be considered to have MM requiring therapy. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Lesokhin:Squibb: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Mezzi:Amgen: Employment, Equity Ownership. Khurana:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Werther:Amgen: Employment, Equity Ownership. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding.

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Estimated Glomerular Filtration Rate Is an Independent Predictor of Outcome in High-Risk Myelodysplastic Syndrome (MDS) and Low Blast Count Acute Myeloid Leukaemia (AML) Patients Treated with Azacytidine (AZA). a Retrospective Study from the MDS Registry of the Hellenic MDS Study Group

Blood ◽

10.1182/blood-2019-125806 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5423-5423

Author(s):

Sotirios Papageorgiou ◽

Vasileios Papadopoulos ◽

Papoutselis Menelaos ◽

Anthi Bouhla ◽

Argiris Symeonidis ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Performance Status ◽

Univariate Analysis ◽

Advisory Committees ◽

Landmark Analysis ◽

Kaplan Meier ◽

Blast Count

Introduction. Myelodysplastic Syndrome (MDS) is a disease of the elderly. Apart from IPSS, IPSS-R and WPSS, several indexes incorporating patient comorbidities (such as the MDS CI index- Della Porta et al Haematologica 2011, the HCT-CI index - Sorror et al Blood 2005) and performance status (the GFM index- Itzykson et al Blood 2011) have been used to predict outcome in MDS patients treated with azacytidine (AZA). We sought to investigate the effect of comorbidities on the outcome after AZA in a large group of patients from the MDS registry of the Hellenic MDS Study Group. Methods. The present study has been conducted as a retrospective observational cohort one. It included high-risk MDS and low blast count AML patients treated with AZA from 26 centers in Greece from 2007 to 2018. T-test and ANOVA were used to compare scale variables between two or more groups respectively. Univariate analysis of nominal and scale survival data was performed using Kaplan-Meier survival curves and Cox regression respectively. All variables achieving p<0.05 at univariate analysis were considered eligible for multivariate analysis; the latter was based on Cox regression method. Results. We analyzed 536 consecutive patients. Patient characteristics are depicted in Table 1. The median follow-up period was 27.5±4.8 months. 371 patients received at least four cycles of AZA and 165 patients received less than 4 cycles of AZA. Patients who received ≥4 cycles of AZA did not differ from those who received <4 cycles regarding gender, age, estimated Glomerular Filtration Rate (eGFR), cardiovascular, renal, and tumor comorbidities. Significantly higher IPSS-R and GFM scores at baseline were found in the group of patients receiving < 4 cycles of AZA compared to patients who received ≥ 4 cycles of AZA (p=0.042 and 0.05 respectively), while transfusion dependence at baseline occurred more often in patients who received ≥ 4 cycles of AZA (p=0.039). To assess the prognostic significance of risk factors on leukemia free survival (LFS) and overall survival (OS), univariate and multivariate analysis for the whole population was performed, as well as a landmark analysis for patients who were treated with at least 4 cycles of AZA. ECOG performance status and the presence of peripheral blasts were independent prognostic factors for LFS and OS for the whole cohort analysis while response to AZA and the presence of peripheral blasts were independent prognosticators for LFS and OS in the landmark analysis. In addition, prior low dose cytarabine was an independent adverse prognostic factor for LFS in the landmark analysis. As regards comorbidities, neither of MDS-CI, HCT-CI and GFM systems independently predicted LFS or OS in either analysis, but eGFR with a cut-off of 45 ml/min was a strong and independent prognosticator for LFS and OS in both the standard and the landmark analysis. Kaplan-Meier survival curves regarding LFS and OS at AZA initiation and landmark analysis after 4th cycle of AZA in relation with eGFR are shown in Figure 1. Conclusion. This is the first study to demonstrate the importance of eGFR at baseline as a prognostic marker for LFS and OS in high-risk MDS and low-blast AML patients treated with AZA. The role of comorbidities and PS needs to be further evaluated in this patient group. Disclosures Symeonidis: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vassilakopoulos:Novartis: 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; WinMedica: 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; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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. Panayiotidis:Bayer: Other: Support of clinical trial. Pappa:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Gilead: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kotsianidis:Celgene: Research Funding.

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Venous Thromboembolism (VTE) Prevention with Semuloparin in Cancer Patients Initiating Chemotherapy: Benefit-Risk Assessment by VTE Risk in SAVE-ONCO

Blood ◽

10.1182/blood.v118.21.206.206 ◽

2011 ◽

Vol 118 (21) ◽

pp. 206-206 ◽

Cited By ~ 32

Author(s):

Daniel George ◽

Giancarlo Agnelli ◽

William Fisher ◽

Ajay Kakkar ◽

Michael R Lassen ◽

...

Keyword(s):

Risk Assessment ◽

High Risk ◽

Board Of Directors ◽

Cancer Patients ◽

Research Funding ◽

P Value ◽

Advisory Committees ◽

Benefit Risk Assessment ◽

Bayer Healthcare ◽

High Risk Cancer

Abstract Abstract 206 Background: Cancer patients receiving chemotherapy are at increased risk for VTE. Recent oncology guidelines emphasize the need for randomized studies with VTE risk assessment in these patients (Streiff MB, et al. JNCCN. 2011;9:714–777). Semuloparin is a new ultra-low-molecular-weight heparin with high anti-factor Xa and minimal anti-factor IIa activities. The SAVE-ONCO study investigated semuloparin vs placebo for VTE prevention in cancer patients receiving chemotherapy. Methods: Patients with metastatic or locally advanced cancer of lung, pancreas, stomach, colon-rectum, bladder or ovary initiating a chemotherapy course, were randomized to once-daily subcutaneous semuloparin 20 mg or placebo until change of chemotherapy. The primary efficacy outcome was a composite of symptomatic deep-vein thrombosis, any non-fatal pulmonary embolism, or VTE-related death. The main safety outcome was clinically relevant bleeding (major and non major). Baseline VTE risk was assessed by a score specifically developed and validated in chemotherapy-treated cancer patients (Khorana AA, et al. Blood. 2008;111:4902–7). According to this predictive model a score of 2 was assigned to very high-risk cancer sites (pancreatic or gastric), a score of 1 was assigned to high-risk cancer sites (lung, ovarian, or bladder cancer) and 1 is added to the score for each of the following parameters: platelet count ≥350 × 109/L, hemoglobin <10 g/dL and/or use of erythropoietin-stimulating agents, leukocyte count >11 × 109/L, and body mass index ≥35 kg/m2. Results: Among the 3212 patients randomized, the majority had lung (36.6%) or colorectal (28.9%) cancer and approximately two-thirds had metastatic cancer. In total, 550 (17.4%) of patients enrolled were at high risk of VTE, 1998 (63.2%) were at moderate risk, and 614 (19.4%) were at low risk (VTE risk score of ≥ 3, 1–2, or 0 points, respectively). All risk groups were well balanced between the treatment groups. Median treatment duration was approximately 3.5 months. Overall, semuloparin significantly reduced VTE or VTE-related death by 64% (p<0.0001; Table) vs placebo. The treatment effect was consistent across various levels of VTE risk (interaction p-value=0.6048; Table). Clinically relevant bleeding occurred in 2.8% and 2.0% of the patients in the semuloparin and placebo groups, respectively (Table). The incidence of major bleeding was similar: 1.2% and 1.1% patients in the semuloparin and placebo groups, respectively (hazard ratio [HR] 1.05; 95% confidence interval [CI] 0.55–1.99). No increased incidence of clinically relevant bleeding was observed with semuloparin vs placebo across various levels of VTE risk (interaction p-value=0.9409; Table). Conclusions: In cancer patients receiving chemotherapy, thromboprophylaxis with semuloparin was consistently associated with a favorable benefit-risk profile across various levels of VTE risk, but greatest in moderate to high risk patients. Antithrombotic prophylaxis should be considered in patients with cancer receiving chemotherapy, particularly in those who are at moderate to high risk of VTE. Disclosures: George: Viamet: Consultancy, Research Funding; Sanofi: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Medivation: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Ipsen: Consultancy, Research Funding; Genentech/Roche: Consultancy, Speakers Bureau; Dendreon: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy; Astellas: Consultancy; GSK: Research Funding, Speakers Bureau; BMS: Research Funding; Exelixis: Research Funding. Agnelli:GlaxoSmithKline: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; sanofi-aventis: Honoraria. Fisher:Boehringer Ingelheim: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; sanofi-aventis: Honoraria, Research Funding. Kakkar:Bayer HealthCare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; sanofi-aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARYx Therapeutics: Consultancy; Canyon: Consultancy; GlaxoSmithKline: Honoraria. Lassen:Astellas Pharma Europe: Consultancy; Bayer HealthCare AG: Consultancy; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; GlaxoSmithKline: Consultancy; Merck Serono: Consultancy; Pfizer: Consultancy; Protola Pharma: Consultancy; sanofi-aventis: Consultancy. Mismetti:sanofi-aventis: served as a member of Steering Committees. Mouret:Bayer HealthCare: Consultancy, Honoraria; sanofi-aventis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Lawson:Sanofi: Employment. Turpie:Astellas Pharma Europe: Consultancy; Bayer HealthCare AG: Consultancy; Portola Pharma: Consultancy; sanofi-aventis: Consultancy.

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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 ◽

10.1182/blood.v128.22.106.106 ◽

2016 ◽

Vol 128 (22) ◽

pp. 106-106 ◽

Cited By ~ 3

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.

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

Blood ◽

10.1182/blood-2019-126646 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 783-783 ◽

Cited By ~ 2

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) <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<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.

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The Role of Bortezomib-Containing Regimens in Improving Response in Patients with Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood.v118.21.2713.2713 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2713-2713

Author(s):

Ranjit Banwait ◽

Edie Weller ◽

Nitin Ropur ◽

Claudia E. Paba-Prada ◽

Lina Benajiba ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Staging System ◽

Initial Therapy ◽

Low Risk ◽

P Value ◽

Advisory Committees

Abstract Abstract 2713 INTRODUCTION: Waldenstrom Macroglobulinemia (WM) is a rare low-grade lymphoma characterized by the presence of lymphoplasmacytic cells in the bone marrow. Several clinical trials have shown that bortezomib has high activity in patients with WM. Bortezomib has also been indicated for patients with high-risk disease in multiple myeloma, a related plasma cell dyscrasia. We sought to investigate the role of bortezomib, a proteasome inhibitor, in overall response rate compared to other non-bortezomib containing regimens in patients with WM. In addition, we examined the role of the international staging system for WM (ISS-WM) at the time of initial therapy compared to the time of relapsed disease in this patient population. METHODS: A retrospective analysis was performed on 182 WM patients enrolled on various clinical trials at Dana-Farber Cancer Institute between November 2000 to October 2009. Patient were stratified as newly diagnosed/upfront (n=86) or relapsed (n=96) according to their disease status at the time of entry into clinical trial. Patient medical records were studied to gather information on demographics, initial diagnosis, disease staging by ISS-WM (at initial therapy and at the time of relapsed disease), prior medical history including prior lines of therapies, types of therapies, and best response on clinical trial (PR or better). RESULTS: Among the 182 patients, 112 (62%) were female and 86 (47%) patient were previously untreated, while 96 (53%) had at least one prior line of treatment; 44(24%) had 1 line, 29(16%) had 2 lines, and 23(13%) had 3 or more lines of therapy. Both the upfront and relapsed groups had a median age of 63 yrs (range, 42–86 and 43–81 respectively). Based on the Morel ISS-WM study, 49 (27%) patients were high risk, 71 (39%) were intermediate risk, and 62 (34%) were low risk. In the upfront setting, 75% (24/32) of patients on a bortezomib containing regimen responded with a PR or better, while 80% (43/54) of patients not receiving bortezomib containing regimen responded with a PR or better (p-value=0.79). When looking at ISS-WM staging and bortezomib-containing regimen in the upfront setting, patients who received bortezomib as their initial therapy and were low risk by ISS-WM staging had a response rate of 73% (8/11), while those who had non-bortezomib containing regimen as their initial therapy and were low risk by ISS-WM staging had a response rate of 82% (14/17). Similarly, patients who received bortezomib as their initial therapy and were intermediate/high risk by ISS-WM staging achieved a response rate of 76% (16/21), while those who had a non-bortezomib containing regimen achieved a response rate of 78% (29/37). We further explored the role of bortezomib in patients who received a bortezomib-containing regimen in the relapsed setting. Of the 96 relapsed patients, 55% (18/33) of patients on a bortezomib containing regiment responded with a PR or better, while only 33% (21/63) of patients not receiving bortezomib containing regimen responded with a PR or better (p=0.05). Furthermore, when assessing response rate by ISS-WM and regimen containing bortezomib in relapsed setting, low risk patients by ISS-WM who received bortezomib had a response rate of 60% (6/10), while those with non-bortezomib containing regimen and low risk by ISS-WM had a response rate of 42% (10/24, p-value=0.45). Similarly, patients with intermediate/high risk by ISS-WM staging who received bortezomib had a response rate of 52% (12/23), while those who received a non-bortezomib containing regimen had a response rare of 28% (11/39, p-value=0.10). CONCLUSION: The results of this analysis indicate that bortezomib can improve response rate (PR or better) in patients in the relapsed setting. In the upfront setting, bortezomib had a similar activity to other therapeutic agents, suggesting that a novel agent such as bortezomib can achieve similar response rate to standard therapies including cyclophosphamide and fludarabine. Moreover, patients in the relapsed setting who received bortezomib and were low or intermediate/high risk by ISS-WM staging showed a high response rate compared to those who did not receive bortezomib and were low or intermediate/high ISS staging system, though the numbers did not reach statistical difference. Based on this study, larger prospective studies to evaluate the role of bortezomib as a factor in overcoming poor prognostic features in the relapsed setting are warranted. Disclosures: Treon: Millennium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria. Ghobrial:Noxxon: Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Influence of Renal Impairment and Genetic Risk Factors on Response to Induction Therapy in the HD4 and MM5 Trials of the GMMG

Blood ◽

10.1182/blood.v124.21.4777.4777 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4777-4777

Author(s):

Christof Scheid ◽

Thomas Hielscher ◽

Uta Bertsch ◽

Christina Kunz ◽

Hans Salwender ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Renal Impairment ◽

Board Of Directors ◽

Genetic Risk ◽

Research Funding ◽

Response Rates ◽

Genetic Risk Factors ◽

Advisory Committees ◽

Prospective Trials

Abstract Background: In the HOVON65/GMMG HD4 trial in patients with newly diagnosed multiple myeloma we have previously shown that patients with renal impairment (RI) (creatinine > 2 mg/dl) have higher response rates and better survival when receiving bortezomib both in the induction and maintenance therapy before and after high-dose chemotherapy (HDT) (Scheid et al. Haematologica 2014). In addition patients with RI showed a higher prevalence of genetic high-risk features such as del17p or t(4;14). The aim of this analysis was to further elucidate the interaction between renal and genetic risk factors in well defined homogeneously treated myeloma patients. Methods: For this study we selected 2 cohorts of patients entered into 2 consecutive prospective trials with centralised FISH-assessement on CD138-selected bone marrow cells. The first cohort (1) comprises 395 patients from the HOVON65/GMMG HD4 trial having been treated in the German centers and the second cohort (2) consisted in the 601 patients (intention-to-treat population) from the recently closed GMMG MM5 trial. Patients lacking FISH results were excluded from the analysis, which was the case for 53 (13.4%) patients in cohort 1 and 43 (7.2%) patients in cohort 2. In cohort 1 induction treatment was vincristine or bortezomib + doxorubicin and dexamethason followed by tandem HDT followed by bortezomib or thalidomide maintenance. Cohort 2 received doxorubicin or cyclophosphamide + bortezomib and dexamethason as induction followed by 1- 2 HDT and consolidation and maintenance with lenalidomide. Results: In cohort 1 38 (10%) had RI and del 17p was found in 12/33 (36.4%) evaluable patients compared to 24/302 (7.9%) patients without RI (p<0.001). t(4;14) was present in 11/33 (33.3%) patients with RI and 38/304 (12.5%) without RI (p=0.005). Gain of 1q21 (> 2 copies) was present in 14/33 (42.4%) patients with RI and 92/298 (30.9%) without RI (n.s.). In cohort 2 68/601 (11.3%) had RI and 7/63 (11.1%) had del17p compared to 56/495 (11.3%) patients without RI (n.s.) while 29/63 (46%) patients with RI had t(4;14) versus 265/495 (53.5%) without RI (n.s.). Gain1q21 (>2 copies) was found in 36/63 (57.1%) with RI versus 209/495 (42.2%) without RI (p=0.025). In cohort 1 the response rate with at least VGPR after induction was low with and without RI in the VAD arm (15 vs 7.1 %) and reduced in patients with RI in the PAD arm compared to those without RI (22.2 vs 37.9%). This trend was not found in cohort 2: Patients with RI had VGPR or better in 42.4% in the PAD and 52.9% in the VCD arm, compared to 33.5% and 33.1% without RI respectively. Del17p and t(4;14) which were more frequent in patients with RI in cohort 1 did not have a negative impact on response rates after induction. Similarly gain1q was more frequent among patients in cohort 2 with RI but did not impact on response to induction. Conclusions: We analysed the effect of RI and genetic risk factors on the response to induction therapy in two different patient cohorts from two consecutive prospective trials. High-risk genetic features where found more frequently in patients with RI, but the pattern was entirely different between cohort 1 and 2 and they did not seem to influence response rates after induction. Our results confirm that bortezomib-based induction regimens achieve high response rates in myeloma patients with RI similar to those in patients without RI, independent of the presence of genetic risk factors. Disclosures Scheid: Janssen: Honoraria; Celgene: Honoraria. Salwender:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Binding site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Mai:Janssen: Travel support Other. Hose:Novartis: Research Funding. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

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Molecular Response at 3 Months Measured with Genexpert BCR-ABL (IS) Platform Predicts Further Outcome in Chronic Myeloid Patients but the Cutoff Differs from the 10% Commonly Used with BCR-ABL (IS) EUTOS Method

Blood ◽

10.1182/blood.v126.23.2776.2776 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2776-2776 ◽

Cited By ~ 1

Author(s):

Valentín García-Gutierrez ◽

Maria Teresa Gómez Casares ◽

Jimenez Velasco Antonio ◽

Alonso Juan Manuel ◽

Santiago Osorio ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Sensitivity And Specificity ◽

Research Funding ◽

Detection System ◽

Chronic Phase ◽

Molecular Response ◽

Advisory Committees ◽

Optimal Response ◽

Historical Series

Abstract INTRODUCTION: In chronic myeloid leukemia (CML) patients in chronic phase (CML-CP), BCR-ABL levels ≤10% at 3 months measured by RT-qPCR (IS) has been consistently correlated with probabilities to obtain an optimal response at 12 months. Monitoring molecular response with automated cartridge-based detection system GeneXpert BCR-ABL (Cepheid®) method has shown an optimal correlation with standardized BCR-ABL (IS) EUTOS method in patients with complete cytogenetic response (CCyR). However, is not known if both methods are also equivalent when measuring BCR-ABL levels above 1%, and therefore, the utility of GeneXpert in order to evaluate response at 3 months must be confirmed. AIMS: To validate the predictive value of molecular response at 3 months with GeneXpert method METHODS: We have studied 125 new consecutive CML-CP patients treated with tyrosine kinase inhibitors (TKIs) followed in 13 centers. Median age at diagnosed was 55 years. The percentage of low, intermediate and high risk Sokal groups were 42%, 40% and 18% . First line treatment was imatinib (IM), nilotinib (NI), dasatinib (DA) or bosutinib (BO) in 58%, 28%, 13% and 1% of the patients, respectively. BCR-ABL level was measured by GeneXpert platform, where all necessary steps to measure BCR-ABL levels are automatically performed. ABL was used as gene control. The study was approved by the Ethics Committee. RESULTS: Median follow up was 43 months. The proportion of patients that achieved CCyR by 12 months, analyzed by intention to treat, was 84% (108/123). Probabilities for each specific TKI were 78%, 93%, 100% and 100% for IM, NI, DA and BO respectively. 23% (96/125) of patients required treatment changed due to resistance or intolerance. Treatment discontinuation probabilities were 32%, 11%, 5% and 0% for IM, NI, DA and BO respectively. Only 4% (5/125) did not achieve an optimal response at 3 months (BCR-ABL ≤10%), which is significant lower compare to results obtain with historical series when using EUTOS IS method. 10% cut-off at 3 month was unable to identify patients that achieved an optimal response in further evaluations. By 12 months, this cutoff did not correlate with probabilities to obtain CCyR (50% vs 86% (p=0.1) or major molecular response (MMR) (60% vs 79% (p=0.21)). In order to find a cutoff that could correlate with optimal response at 12 months, we used a receiver operating characteristic curve to identify the optimal cutoff in transcript level that would allow us to classify the patients as high risk or low risk with maximal sensitivity and specificity for each individual outcome. At 3 months, patients with transcript levels ≤ 1.6% had significantly better probabilities to obtain an optimal response by 12 months, with 81% and 94% sensitivity and specificity for CCyR. With this new cutoff, probabilities for CCyR and MMR at 12 months were 98% vs 54% (p<0.001) and 88% vs 56% (p<0.001) respectively (OR:. Finally, this cutoff has also been correlated with probability for treatment changed at any time (46% vs 16% (p=0.005)) CONCLUSIONS: The results of our study seem to show that the 10% threshold, commonly used to evaluate response at 3 months when using BCR-ABL (IS) EUTOS method, is not associated with probabilities to achieve further optimal responses when using the GeneXpert platform. We have shown how a new cutoff of 1,6% % at 3 months when using GeneXpert could better identify patients with lower risk to achieve an optimal response at 12 months. Disclosures García-Gutierrez: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Steegmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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A 20 Gene Expression Signature That Predicts Early Molecular Response Failure in Chronic Phase CML Patients Treated with Frontline Imatinib

Blood ◽

10.1182/blood.v126.23.596.596 ◽

2015 ◽

Vol 126 (23) ◽

pp. 596-596 ◽

Cited By ~ 1

Author(s):

Chung Hoow Kok ◽

Tamara M Leclercq ◽

Dale Watkins ◽

David T Yeung ◽

Verity A Saunders ◽

...

Keyword(s):

Gene Expression ◽

High Risk ◽

Board Of Directors ◽

Clinical Outcomes ◽

Research Funding ◽

Chronic Phase ◽

Gene Expression Signature ◽

Gene Signature ◽

Molecular Response ◽

Advisory Committees

Abstract BACKGROUND: In chronic phase chronic myeloid leukemia (CP-CML) patients treated with frontline imatinib, failure to achieve early molecular response (EMR failure: BCR-ABL1 >10% at 3 months) predicts for subsequent inferior outcomes. Identifying patients at high-risk of EMR failure provides an opportunity to improve outcomes by personalising treatment at the time of diagnosis, as intervention after EMR failure may be less effective. AIM: To utilise a predictive gene signature to identify CP-CML patients at diagnosis, who are at high risk of EMR failure and inferior clinical outcomes. METHODS: Peripheral blood mononuclear cells collected from 119 patients enrolled in the TIDEL-II study were subjected to gene expression microarray profiling (GEP) Illumina HT12. Validations of the identified microarray genes were performed using Taqman qPCR. All patients commenced imatinib treatment, and switched to nilotinib with or without an antecedent trial of high dose imatinib if they failed to achieve time dependent molecular targets. Clinical outcomes included EMR and cumulative incidence of MMR and MR4.5 (BCR-ABL1 ≤0.1% and ≤0.0032% on the international scale, respectively), and comparisons were made using Fine and Gray test. Competing risks included permanent trial discontinuation for any reason (including death or progression). Event-free survival (EFS) and failure-free survival (FFS) were performed using Kaplan-Meier and comparisons were made using the log-rank test. RESULTS: Fourteen of the 119 patients demonstrated EMR failure (12%). Comparing the GEP of these patients with those that achieved EMR identified 4456 aberrantly expressed genes in the EMR failure group. This gene set was significantly enriched for stem cell phenotype/signalling (e.g. Myc, β-catenin, Hoxa9/Meis1), cell cycle, and reduced immune response pathways associated with adverse prognosis in other cancers. From these genes, 20 genes (IGFBP2, CD3E, RASGRP1, BNIP3L, ETS1, PDK1, METTL7A, HECA, COL8A2, PRSS57, TMEM167A, SPAST, FZD7, VPS41, CDKN1B, CPXM1, SEPT7, RPS28, SLX4IP, and SRSF11) validated by qPCR were selected by nearest shrunken centroid model as the high-risk gene expression signature (high-riskGES) to predict EMR failure. Patients who had a high-riskGES exhibited significantly higher rates of EMR failure compared to those with low-riskGES (training cohort: 73.3% vs 8.0%; p<0.0001; n=40, Hazard Ratio (HR): 4.1). This was validated on an independent patient cohort (validation cohort: 50.0% vs 14.8%; p=0.018; n=39; HR: 3.2). Overall, when both cohorts were combined, patients who had a high-riskGES exhibited significantly higher rates of EMR failure compared to those with low-riskGES (63.0% vs 11.5%; p<0.0001; n=79, HR: 3.3; Figure 1A). The overall prediction accuracy of the signature was 80% (82% specificity, 74% sensitivity). Additionally, patients with a high-riskGES demonstrated significantly worse clinical outcome than those with low-riskGES by 24 months (MMR: 41% vs 83%, p=0.0003; MR4.5: 4% vs 42%, p=0.0004; EFS: 52% vs 92%, p<0.0001; FFS: 44% vs 89%, p<0.0001) (Figure 1B-E). This high-riskGES was confirmed as an independent predictor for EMR failure, when Sokal, age and gender were added as covariates based on the Cox-proportional multivariate analysis (HR: 0.34, p=0.003). Patients who had a high-riskGES also had significant inferior outcomes even if they subsequently achieved EMR, compared to the low-riskGES patient group that subsequently achieved EMR (MR4.5: 10% vs 48%, p=0.034; EFS: 68% vs 96%, p=0.0099; FFS: 60% vs 91%, p=0.011). Furthermore, this 20-gene signature compared favourably to Sokal, EUTOS, Hasford, and OCT-1 Activity in predicting EMR failure based on assessing their respective overall performance F -score (harmonic mean of precision and sensitivity). EMR failure was observed in 15% (n=33) of low Sokal score patients overall and 12% of the low-riskGES group (n=49) but amongst patients who had both low-riskGES and a low Sokal score, 0/25 experienced EMR failure. SUMMARY: For the first time in the CML setting, we have identified and validated a 20-gene signature to predict, at the time of diagnosis, patients at high risk of EMR failure and subsequent inferior clinical outcomes. The ability to predict high risk patients at diagnosis may facilitate the assessment of novel therapeutic approaches designed to improve clinical outcomes for patients with aggressive disease. Disclosures Yeung: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. White:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Hughes:ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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