Prognostic Markers in Core-Binding Factor Acute Myeloid Leukaemia

Abstract Introduction While core-binding factor acute myeloid leukaemia (CBF AML) as defined by t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) has a favourable prognosis, 30-40% of patients still relapse after chemotherapy. Risk factors predictive for relapse include increasing age and white cell count (WCC), poor performance status and adverse-risk cytogenetics. Rising minimal residual disease (MRD) by molecular monitoring and receptor tyrosine kinase (RTK) mutations also predict higher risk of relapse (Yin et. al., Blood 2012; Jourdan et. al., Blood 2013). Aims 1. Identify prognostic markers for CBF AML 2. Determine significance of persistent molecular positivity in complete remission (CR) post-treatment Methods We undertook a retrospective audit from 2001-2012 at 4 tertiary-level hospitals. The inclusion criteria were adult patients >18 years with de novo CBF AML treated with at least intermediate dose cytarabine. Co-variates included in univariate analysis and then multivariate analysis if predictive of overall survival (OS) and relapse-free survival (RFS) included age, WCC, sex, cytogenetics, RTK mutations (KIT and FLT3) and MRD (RUNX1-RUNX1T1 or CBFB-MYH11 bone marrow (BM) qPCR post-induction (MRD1). Univariate analysis was also performed for BM MRD after each consolidation cycle 1-4 (MRD2-5 respectively). Results 70 patients were identified (Male=39, Female=31; inv(16)=30, t(8:21)=40). The median age at diagnosis was 43 years (range 17-73). There were 2 induction deaths and 68 achieved morphological CR. OS was 70.7% and RFS was 59.1% at a median follow-up of 31.4 months. There were 16 deaths (inv(16)=9, t(8;21)=7; median OS 14.8 months; 9 from relapsed AML, 4 treatment-related complications, 2 graft-versus-host disease (GVHD) and 1 unrelated). 24 relapses (22 morphological, 2 molecular) occurred with a median RFS of 9 months (inv(16)=17, t(8;21)=7). RFS was significantly worse for inv(16) vs t(8;21) (39% vs 75%; p=0.0004). The inv(16) cohort had significantly higher median WCC of 33x109/L vs 10.5x109/L t(8;21). Univariate analysis identified age (p=0.032) and WCC>40 (p=0.002) as significant for inferior OS and RFS respectively. The impact of KIT (n=34, Pos=14, p=0.158) and FLT3 (n=27, Pos=2, p=0.152) mutations on OS/RFS were non-significant independent of CBF AML subtype. However, there were systematic differences in KIT and FLT3 data availability in the relapse vs non-relapse cohorts (Absent data: KIT 17/24(71%) vs 19/46(41%); FLT3 17/24(71%) vs 26/46(57%)). MRD analysis by qPCR at the different timepoints (MRD1=37, MRD2=24, MRD3=28, MRD4=23, MRD5=12) by < or ≥3 log reduction in comparison to pre-treatment values was not predictive of OS/RFS. On multivariate analysis excluding RTK mutations, age was the only significant predictor for OS (p=0.032) and WCC>40 for relapse (p=0.025). Standard vs intermediate/high-dose cytarabine in induction had no impact on OS/RFS but ≥3 consolidation cycles of intermediate-dose cytarabine improved OS vs ≤2 cycles (p=0.035). There was no significant difference in the median age of the cohorts receiving consolidation chemotherapy (≤2: n=37, 47 years, ≥3: n=30, 35.5 years). Median BM qPCR values increased from 0 to 11% at relapse for inv(16) at a median duration of 4.3 months (range 1-8) and 0.05 to 178% for t(8;21) at 6 months (range 5-35) respectively. Of the 43 with durable CR, 28 maintained PB or BM qPCR values of 0-0.1% or <10 copy numbers throughout follow-up for 2 years post-completion of consolidation treatment. 6 had qPCR values >0.1% or >50 copy numbers; 5 were t(8;21) achieving PCR negativity at a range of 9-24 months post-completion of consolidation. Of the 24 who relapsed, 15 proceeded to stem cell transplant (13 allograft: inv(16)=8, t(8;21)=5; 2 autograft: inv(16)). There were 6 deaths in the allograft group (inv(16)=3, t(8;21)=3) and none in the autograft group. 3 deaths were related to relapsed disease post-allograft, 2 GVHD and 1 from non-GVHD complications. Conclusions Age is a significant predictor of OS in our CBF AML cohort while WCC is more predictive of relapse risk. The significance of RTK mutations and MRD is limited by data availability. ≥3 consolidation cycles of intermediate-dose cytarabine improved OS in comparison to fewer cycles. Stable low level MRD did not predict relapse. Regular monitoring of PB and BM qPCR values post-completion of treatment is necessary for prediction of subsequent relapse. Figure 1. Figure 1. Disclosures Grigg: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Szer:Alexion Pharmaceuticals Australasia Pty Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Australia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire Australia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽

10.1182/blood.v128.22.3180.3180 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3180-3180

Author(s):

Felix Lopez-Cadenas ◽

Blanca Xicoy ◽

Silvia Rojas P ◽

Kaivers Jennifer ◽

Ulrich Germing ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Research Funding ◽

Statistical Significance ◽

Univariate Analysis ◽

Rank Test ◽

Advisory Committees ◽

Disease Evolution ◽

Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

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Tracking Daratumumab Clearance Using Mass Spectrometric Approaches: Implications on M Protein Monitoring and Reusing Daratumumab

Blood ◽

10.1182/blood-2021-153209 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2707-2707

Author(s):

Nadine Abdallah ◽

David L Murray ◽

Angela Dispenzieri ◽

Prashant Kapoor ◽

Morie A. Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Univariate Analysis ◽

M Protein ◽

Urine Protein ◽

Advisory Committees ◽

Plasma Cell Disorders

Abstract Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein <0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR <60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs >2weeks) (RR: 1.0, P=0.97), treatment duration (<200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

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Rituximab Resistant Follicular Lymphoma: Predictors of Rituximab Resistance, Incidence of Transformation and Prognosis

Blood ◽

10.1182/blood.v118.21.4981.4981 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4981-4981 ◽

Cited By ~ 3

Author(s):

Lee Mozessohn ◽

Matthew Cheung ◽

Michael Crump ◽

Rena Buckstein ◽

Neil L Berinstein ◽

...

Keyword(s):

Partial Response ◽

Follicular Lymphoma ◽

Disease Progression ◽

Board Of Directors ◽

Cox Regression ◽

Univariate Analysis ◽

Previous Treatment ◽

Primary Therapy ◽

Advisory Committees

Abstract Abstract 4981 Follicular lymphoma (FL) is an indolent lymphoma characterized by slow growth, initial response to treatment with inevitable relapse. Recent trials have demonstrated improved progression free survival (PFS) with rituximab-containing induction, maintenance rituximab (MR) or both. However, a small subset of patients (pts) will show disease progression during the induction or maintenance phase. We evaluated rituximab resistance (RR) including incidence, predictors, rate of transformation and prognosis for pts demonstrating RR. We defined RR as disease progression during induction, maintenance or within 6 months of last dose of rituximab. We retrospectively identified pts who received rituximab for symptomatic FL from July 2006 to April 2010 at 2 regional cancer centres. Those with a diagnosis of FL grades 1, 2 or 3a with first exposure to rituximab (induction, maintenance or both) were included. Exclusion criteria included FL grade 3b and previous rituximab exposure. Progression was ascertained from clinical notes or radiological investigation as per IWG Criteria (1999). Transformation was defined by confirmatory biopsy and clinical suspicion of transformation was also recorded (nodal growth, rapid rise in LDH or new B symptoms). PFS and overall survival (OS) were measured from initiation of rituximab induction. Log-rank statistics were used to identify univariate predictors for RR and Cox regression for multivariate analysis with outcome as time to early progression (RR). Of the pts screened, 132 met inclusion criteria (112 pts receiving primary therapy, 20 for ≥ 2nd line therapy); 22 pts (16.7%) demonstrated RR. Incidence of RR was similar for pts receiving primary therapy (17.0%). Pt characteristics for rituximab sensitive (RS) and RR groups are shown in Table 1. From induction, median follow-up was 33 months (range 9 to 61 months). In univariate analysis, high risk FLIPI score at induction was predictive of RR (p = 0.002). Partial response to induction (p = 0.082) trended to significance. Other factors not predictive of RR included: age, gender, high grade histology (grade 3a), previous chemotherapy received, time from diagnosis to induction therapy and anthracycline-based induction. A Cox regression model was constructed with FLIPI score and anthracycline-based induction as covariates. FLIPI score was independently and significantly predictive of RR (HR 2.43; 95% CI, 1.4 to 4.1; p = 0.001). Of the 22 pts who were RR, 18 (81.8%) required subsequent chemotherapy with only 9 achieving at least a partial response. Ten pts (45.5%) required more than 1 line of chemotherapy post-progression with a median time to next line of therapy of 9 months (95% CI, 2.9 to 15.1; see figure). Among the RR pts, 5 (22.7%) showed evidence of transformation on biopsy at initial resistance and an additional 3 (13.6%) were clinically suspected. Within 12 months of resistance, a further 3 pts in the RR group demonstrated biopsy-proven transformation. Overall, 10 pts (45.5%) transformed (biopsy-proven) with no transformation in the RS group. During follow-up, 9 deaths occurred, all in those with RR, 5 following biopsy-proven transformation. The median PFS and OS in the RR group were 17 months and 47 months, respectively. Table 1 Characteristics RS (n = 110) RR (n = 22) Age (MEAN) 58.9 58.9 Gender (females) 43.6% 40.9% High histological grade (3a) 8.4% 9.1% Previous treatment (yes) 15.5% 13.6% Alkylator 11.8% 13.6% Number of lines of previous treatment >1 4.5% 4.5% Mean time from diagnosis to induction (months) 30.3 28.1 Induction chemo R-CVP based 78.2% 86.4% R-CHOP based 18.2% 9.1% Other 3.6% 4.5% Response to induction PR 77.3% 72.7% CRu 12.7% 0% CR 10.0% 4.5% SD/PD 0% 22.7% FLIPI score at induction Low (0, 1, 2) 57.8% 18.2% Intermediate (3) 26.6% 40.9% High (4 or 5) 15.6% 40.9% Stage 3 or 4 88.2% 100% High tumor burden at diagnosis (GELF criteria) 43.6% 40.9% We demonstrated that the incidence of rituximab resistance in FL on first exposure to rituximab in our population was 16.7%. FLIPI score was predictive for RR and was independent of anthracycline-based induction regimens. Pts with RR had a high rate of histologic transformation (36.3% within 12 months post RR) and a shorter PFS/OS with a poor response to next therapy. Biopsies to confirm transformation should be performed in all pts demonstrating RR, and new therapies are needed for this group of pts. Disclosures: Crump: Ortho Johnson & Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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; Millennium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Honoraria; Ortho Biotech: Honoraria; Roche: Honoraria.

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Trends In Outcomes In Core Binding Factor Acute Myeloid Leukemia: A SEER Database Analysis

Blood ◽

10.1182/blood.v122.21.3880.3880 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3880-3880 ◽

Cited By ~ 1

Author(s):

Andrew M. Brunner ◽

Traci Blonquist ◽

Hossein Sadrzadeh ◽

Yi-Bin Chen ◽

Donna S. Neuberg ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Seer Database ◽

Core Binding Factor ◽

Advisory Committees ◽

Patients Âgés ◽

Binding Factor ◽

Acute Myeloid

Abstract Acute myeloid leukemia with chromosomal alterations impacting the core binding factor transcription complex (CBF-AML), specifically t(8;21) and inv(16), are associated with a greater responsiveness to cytarabine-based chemotherapies and a more favorable prognosis. The latter has been primarily gleaned from outcomes of large clinical trials of AML. However, to date, there is limited population-based outcomes data on CBF-AML. We therefore performed an epidemiologic retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database to assess survival trends for CBF-AML at the population level between 2000 and 2010. Patients and Methods Patients with a diagnosis of CBF-AML between 2000 and 2010 were identified using the SEER 18 registries database. We included patients with a diagnosis code of inv(16)/t(16;16) AML (Code 9871) or t(8;21) AML (Code 9896) diagnosed between January 2000 and December 2010. Patients were divided into cohorts based on age at diagnosis: 15-44 years old, 45-64 years old, 65-74 years old, and 75-84 years old. Disease incidence was calculated, as were early mortality rates, defined as death within 1 month. Overall survival (OS) was estimated using the method of Kaplan and Meier. Cox regression was performed to estimate predictors of survival by specific CBF-AML type, age cohorts, race/ethnicity, gender, year of diagnosis, number of primary malignancies, and residence. Results We identified 777 patients with a new diagnosis of CBF-AML between 2000 and 2010. The incidence of CBF-AML increased with advancing age (ages 15-44, 0.06 per 100,000 people; ages 45-64, 0.13; ages 65-74, 0.25; ages 75-84, 0.28). Median OS for all patients was 22 months, and the combined 3-year OS was 44.3% (Fig. 1). Median OS increased from 16 months during the period encompassing 2000 and 2002 to 25 months during the period from 2006 to 2008 (p=0.002) (Fig. 2). The rate of early death was 13%, which increased with age (15-44 5%, 45-64 10%, 65-74 20%, 75-84 33%; P<0.0001). OS also worsened with advancing age; patients ages 75-84 had a 3 year OS of 9.3% and an increased HR for mortality compared to patients ages 15-44, who had a 3 year OS of 68.7% (HR 5.61, P<0.0001) (Fig. 3). Of note, worsening OS with advancing age was observed even among the subset of patients alive at 1 month. Black race was associated with an increased HR for mortality compared to white non-Hispanic patients (HR 1.50, P=0.03). Patients with inv(16) disease had an improved OS compared to patients with t(8;21) disease (HR for mortality 0.65, P<0.0001). The 3 year OS for patients with inv(16) disease was 57.3%, while for those with t(8;21) disease it was only 35.5% (Fig. 1). Conclusion In spite of historically favorable prognoses associated with CBF-AML in clinical trials, we found poorer survival in the general population. Unlike inv(16) disease, patients with t(8;21) CBF-AML did not appear to have a favorable OS. Survival was significantly worse among African Americans and the elderly. The reason for these differences is unknown, and merits further evaluation. Disclosures: Chen: Otsuka Pharmaceuticals, Inc.: Research Funding; Seattle Genetics: Consultancy, Research Funding; Bayer / Onyx: Research Funding. Fathi:Seattle Genetics: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity’s Board of Directors or advisory committees; Agios: Membership on an entity’s Board of Directors or advisory committees; Millenium: Research Funding.

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M3P Sequencing Panel Identifies TP53 Mutational Status As a Prognostic Factor in Chemotherapy-Naive Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.2984.2984 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2984-2984

Author(s):

Davine Hofste op Bruinink ◽

K. Martin Kortüm ◽

Mark van Duin ◽

Mathijs A. Sanders ◽

Remco Hoogenboezem ◽

...

Keyword(s):

Prognostic Factor ◽

Board Of Directors ◽

Research Funding ◽

Somatic Mutations ◽

Prognostic Markers ◽

P Value ◽

Advisory Committees ◽

Mutational Status ◽

Tp53 Mutational Status

Abstract Introduction Multiple myeloma (MM) is characterized by a highly variable disease course, which can be traced to initiating and acquired genomic events. Whole exome analysis of matched tumor and germline DNA from 287 MM patients identified recurrently somatically mutated genes (RSMGs) (Lohr et al. - Cancer Cell 2014, Bolli et al. - Nat Commun 2014). Despite the fact that these RSMGs affect pathways that are biologically important in MM, the clinical relevance of many of these genes in the context of conventional prognostic markers remains to be elucidated. Aims The aims of this pilot study were: (1) To validate the prevalence of RSMGs in our newly diagnosed MM patient cohort; (2) To assess the correlation between RSMGs, clinical parameters and outcome; (3) To thereby identify the potential clinical usefulness of introducing RSMG mutational profiling in larger MM trial cohorts. Material and Methods CD138+ enriched MM cells and peripheral blood were obtained with informed consent from chemotherapy-naive patients, participating in 3 clinical trials: HOVON-65/GMMG-HD4, HOVON-87/NMSG-18 and Carthadex (EudraCT number 2004-000944-26, 2007-004007-34 and 2009-014922-40, respectively). Matched tumor and germline DNA were sequenced on an Ion Torrent sequencing platform (PGM, Life Technologies), using the M3 P Mutational Panel v3.0, comprising 1327 customized oligos (Life Technologies), targeted at the coding sequences of 88 MM-relevant genes, including the RSMGs. Somatic mutations were considered positive when present in >=10% of tumor reads and <=10% germline reads, with a minimal coverage of 10x and being non-synonymous, or splice donor variants. All statistical analyses were performed in SPSS version 23, using the log-rank and Mann-Whitney U-test, with the Bonferroni test to correct for multiple comparisons. Results A total of 206 DNA samples were sequenced from 103 patients (HOVON-65/GMMG-HD4 (n=16), HOVON-87/NMSG-18 (n=67), Carthadex (n=20)) with an average coverage of 574x in tumor DNA, 451x in germline DNA and an overall coverage of 98%. We collected follow-up data from 102/103 patients, with a median follow-up time of 30 months. 168 somatic mutations were detected in 44/88 genes. 82% of patients had at least 1 somatic mutation. Genes most frequently mutated were: (1) NRAS (26%), (2) KRAS (22%), (3) DIS3 (14%), (4) FAM46C (9%), (5) TP53 (7%) and (6) BRAF (6%) (Figure 1). Of note, NRAS and KRAS mutations were mutually exclusive in our cohort. Moreover, all TP53 mutations were located in its DNA binding domain. Three out of 6 BRAF mutations were predicted to cause a V600E amino acid change. We focused on these 6 RSMGs in all further analyses. Correlating mutational status with Progression Free Survival (PFS) and Overall Survival (OS) showed that TP53 mutated patients had a significantly shorter PFS compared to those with wildtype TP53 (adj. p-value=0,018; n=7 versus n=95). Comparing the mutational status of the 6 RSMGs, transplant versus non-transplant protocol, number of mutated genes in the M3 P panel, del17p and t(4;14) status, EMC92 score and ISS stage between patients with a PFS <=1 year and >1 year (n=23 versus n=79), only showed a significant correlation with TP53 mutational status (adj. p-value=0,012). TP53 mutational status remained the only significant prognostic factor when comparing patients with an OS <=1 year and >1 year (adj. p-value=0,003; n=13 versus n=89). When comparing the number of mutated genes, del17p and t(4;14) status, EMC92 score, transplant versus non-transplant protocol and ISS stage between TP53 mutated and wildtype MM, TP53 mutated patients had a significantly higher number of mutated genes in the M3 P panel (adj. p-value=0,001). Conclusions (1) With the M3 P Mutational Panel, we confirm the published prevalence of RSMGs in MM in our cohort of chemotherapy-naive patients. NRAS, KRAS, DIS3, FAM46C, TP53 and BRAF are the most frequently mutated genes. (2) TP53 mutational status is the strongest unfavorable prognostic factor in our cohort and it seems to be associated with greater mutational burden. Validation in a more extensive population is planned. (3) This warrants further investigation of the mutational status of these genes in larger clinical trial cohorts, enabling a more robust comparison with conventional prognostic markers in a multivariate analysis. Disclosures Broijl: Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Zweegman:Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding. Sonneveld:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Research Funding; SkylineDx: Membership on an entity's Board of Directors or advisory committees.

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Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing JAK1/2 Inhibitor Therapy

Blood ◽

10.1182/blood.v128.22.4263.4263 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4263-4263

Author(s):

Jay Spiegel ◽

Caroline Jane McNamara ◽

Andrea Arruda ◽

Tony Panzarella ◽

James A. Kennedy ◽

...

Keyword(s):

Treatment Failure ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Inhibitor Therapy ◽

Jak Inhibitor ◽

Jak Inhibitors ◽

Advisory Committees ◽

Number Of Patients

Abstract Introduction: The advent of next generation sequencing (NGS) has brought intense interest to the complex genetic landscape of myeloproliferative neoplasms (MPN). However, data regarding clinical outcomes in the context of novel MPN therapies such as JAK inhibitors are scarce. Limited data indicate that high molecular risk signature (HMR, presence of at least one mutation in ASXL1, EZH2, IDH1/2, SRSF2) or multiple mutations may be associated with decreased spleen response and a shorter time to discontinuation of Ruxolitinib in myelofibrosis (Patel et al, Blood 2015). Methods: All myelofibrosis patients seen in the MPN program at Princess Margaret Hospital between November 2009 and May 2016 and treated with JAK1/2 inhibitor therapy were identified. NGS molecular profiling of 54 genes (39 hotspot region; 15 complete coding region coverage) was performed on peripheral blood or bone marrow samples using the TruSight Myeloid Sequencing Panel. Reporting was restricted to well-covered, exonic nonsynonymous, intronic splice site, and known pathogenic synonymous variants. Variants with global mean allele frequency >1% were identified using multiple population databases (1000 genomes, ESP, ExAC) and excluded. The primary endpoint was time from start of JAK1/2 inhibitor therapy to treatment failure (TTF) defined as treatment discontinuation, progression to accelerated phase or leukemic transformation, spleen progression or death. Secondary endpoints included best spleen, anemia and IWG response achieved by 48 weeks of treatment and overall survival. Response was assessed according to the 2013 revised IWG-MRT criteria. Transfusion dependency was assessed as any transfusion in 12 weeks prior to treatment or being identified as transfusion dependent in medical history. Results: Of 159 patients treated with JAK1/2 inhibitors at our institution, 102 met the inclusion criteria (see Table 1). Patients were excluded if; no sample was available for analysis (19), short use of JAK inhibitor prior to transplant (9), active clinical trial (5), in accelerated phase/acute leukemia (4) and others (20). First JAK inhibitor used was ruxolitinib in 77 patients and momelotinib in 25. At least one mutation was identified in every patient. Twenty (20%) patients had one mutation, 32 (31%) had 2 mutations and 50 (49%) patients had ≥ 3 mutations. Eighty (82%) patients had the JAK2V617F mutation, 15 (15%) had mutations in CALR, 4 (4%) had MPL mutations and one patient was triple negative. One patient had mutations in both CALR and JAK2 while another had mutations in MPL and CALR. Forty-eight (47%) patients had mutations consistent with HMR profile. Mutation profile is summarized in Table 2. With median follow-up of 2.5 years, 51 (50%) patients experienced treatment failure. On univariate analysis, TTF was associated with DIPSS, pre-treatment transfusion status and Hb <100 prior to initiating JAK inhibitor therapy. However, TTF was not associated with specific driver mutations, the number of mutations or HMR profile. Exploratory analysis of genes mutated in ≥5% of the population showed EZH2 (p=0.004) and CBL (p=0.005) mutated patients had shorter TTF. Multi-variable analysis employing anemia <100 and DIPSS with either of the number of mutations or HMR profile did not show any association with TTF. There was a trend towards TTF in patients with Hb<100 (HR 2.21, 95%CI: 0.99-4.95, p=0.05). Of 102 patients, 91 were evaluable for spleen response with 43 (47%) achieving a spleen response by 48 weeks of treatment. Twelve (23%) of the 53 patients evaluated met criteria for anemia response. Neither spleen nor anemia response was associated with the use of a particular JAK inhibitor. Of the 95 patients with at least 48-week follow-up, best response while on treatment was clinical improvement and spleen response in 29 (31%) and 19 (20%) patients respectively. Conclusions: In this study of myelofibrosis patients treated with JAK inhibitors, EZH2 and CBL mutated patients had shorter TTF. We did not find any association between TTF and number of mutations or other high risk mutations such as ASXL1/SRSF2. Anemia was the only significant independent predictor of shorter TTF. Our findings highlight the need for multicenter collaborative studies on a large number of patients and cautious use of mutation profiling results in routine clinical decision making with current treatment approaches. Spiegel and McNamara are co-primary authors. Disclosures Panzarella: Cellgene: Consultancy. Schimmer:Novartis: Honoraria. Schuh:Amgen: Membership on an entity's Board of Directors or advisory committees. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kamel-Reid:BMS: Research Funding. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

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The Increased Burden of Sickle Cell Disease in Italy: Findings from the Greatalys (Generating Real world Evidence Across ITALy In SCD) Study

Blood ◽

10.1182/blood-2021-148273 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1950-1950

Author(s):

Lucia de Franceschi ◽

Gian Luca Forni ◽

Chiara Castiglioni ◽

Claudia Condorelli ◽

Diletta Valsecchi ◽

...

Keyword(s):

Board Of Directors ◽

Index Date ◽

Healthcare Resource ◽

Data Availability ◽

Annual Number ◽

Italian Population ◽

Advisory Committees ◽

Specialist Services ◽

Day Hospitals

Abstract Introduction. Sickle Cell Disease (SCD) is an evolving public health issue with a significant impact on patient survival, quality of life and costs for health systems also in Italy, a multiethnic country where epidemiology has deeply changed. We present final results from the GREATalyS study that aimed to better understand the SCD burden in Italy in terms of prevalence, clinical features, treatments and resource consumption in the clinical practice setting. Methods. Retrospective observational analysis of administrative databases for health resources consumption from a representative sample of Region/Local Health Units in Italy, covering approximately 15.3 million inhabitants. All patients with ≥1hospitalization (outside Emergency Room, ER) with main or secondary discharge diagnosis of SCD (with/without crisis) identified by ICD-9-CM codes were included between January-2010 to December-2017 (up to December 2018 for epidemiologic analysis). Prevalence of SCD in 2018 was projected to the Italian population. Patients were followed-up from the first diagnosis identified within the inclusion period (index date) to death or end of data availability. Treatments and healthcare resource consumption were evaluated on patients with at least 1 year of data availability before and after index date. SCD treatments were classified as SCD-specific, SCD-related, SCD-complication-related. Both day hospitals and ordinary hospitalizations were evaluated. Vaso-occlusive crisis (VOCs) (identified by hospitalization discharge diagnosis for SCD with crisis) and main SCD organ complications were assessed during follow-up. Mean annual healthcare resource costs were analyzed during follow-up according to the NHS perspective in terms of overall treatments, all-cause hospitalizations and out-patients services. Results. SCD prevalence in 2018 was 13 cases per 100,000 inhabitants. Prevalence projected to Italian population estimated in total 7,977 SCD patients in Italy in 2018 (of whom 1,690 and 6,287 were <18 and ≥18 years, respectively, figure 1): 1,279 were estimated with crisis, 5,894 without crisis and 804 unspecified. The study population included in the analysis comprised 1,816 patients (mean age 43.8 years, 58.4% female). Of them, 74.3% were without diagnosis of crisis, 16.1% with crisis, and 9.6% unspecified. Hematology and general medicine were the most frequent admission/discharge hospital departments for a subcohort of patients for which these data were available. During the first year of follow-up (index date included), 50.7% of patients had one all-cause hospitalization, 27.8% had 2, 10.4% had 3 and 11.1% had ≥4, in the second year 44% had at least one hospitalization, while in the third and fourth years 38.2% and 35.8%, respectively (table 1). During the available follow-up period (mean years±SD: 4.9±2.2) the average length of hospitalization stays (table 2) was around 8 days (ordinary hospitalizations) and 130 days (day hospitals). Proportion of patients with a VOC or one SCD complication was 3.7% and 15.2%, with 2 was 2.3% and 6.2% and with ≥3 was 7.7% and 12.8%, respectively. The mean annual number of SCD specific drugs was 0.6±2.7, of SCD related drugs was 3.2±4.5 and of SCD-complications-related drugs was 8.6±10.5. Antibacterials were the more frequently prescribed drugs (53-63%), followed by drugs for acid related disorders (35-48%) and antithrombotic agents (25-34%). Considering all available follow-up, mean annual number of all drugs was 14.9, of hospitalizations was 1.1 and of outpatient specialist services 5.3. Total mean annual cost per patient was €7,917 (€2,201 for prescribed drugs, €3,320 for hospitalizations, and €2,397 for outpatient specialist services, figure 2). Conclusions. This Italian real-world study may have revealed a SCD sub-population probably not noticed yet to SCD centers of reference, and still probably underestimated since ER flows were not present. Similarly, also VOC could be underestimated as only most severe episodes requiring hospitalization were captured. Proportion of patients with antithrombotic agents might be an indicator of the underlying multiorgan complications. The present data describe an SCD population with high resource utilization and heavy economic burden and warrants further efforts to increase an earlier patient identification that could lead to a timely and comprehensive treatment with less SCD-related complications. Figure 1 Figure 1. Disclosures Forni: Bluebirdbio: 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. Castiglioni: Novartis Farma SpA: Current Employment. Condorelli: Novartis Farma SpA: Current Employment. Valsecchi: Novartis Farma SpA: Current Employment. Premoli: Novartis Farma SpA: Current Employment. Fiocchi: Novaris Farma SpA: Current Employment.

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Fludarabine, Cytarabine, G-CSF and Gemtuzumab Ozogamicin (FLAG-GO) Regimen Results in Better Molecular Response and Relapse-Free Survival in Core Binding Factor Acute Myeloid Leukemia Than FLAG and Idarubicin (FLAG-Ida)

Blood ◽

10.1182/blood-2019-126014 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 290-290 ◽

Cited By ~ 3

Author(s):

Gautam M. Borthakur ◽

Jorge E. Cortes ◽

Farhad Ravandi ◽

Guillermo Garcia-Manero ◽

Tapan M. Kadia ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Fusion Transcript ◽

Gemtuzumab Ozogamicin ◽

Newly Diagnosed ◽

Relapse Free Survival ◽

Core Binding Factor ◽

Advisory Committees ◽

Free Survival ◽

Binding Factor

Background: A regimen comprising of fludarabine, cytarabine, G-CSF (FLAG) has been our frontline treatment for patients with core binding factor acute myelogenous leukemia (CBF-AML) since 2007, initially in combination with gemtuzumab ozogamicin (FLAG-GO) (at 3 mg/m2 on day 1 in induction and and in 2 of the planned 6 post-remission cycles) and after withdrawal of GO from US market in combination with idarubicin at 6 mg/m2 on days 3 and 4 in induction and in one post remission cycle during cycles 3-6 (FLAG-Ida). Fusion transcripts, RUNX1-RUNX1T1 or CBFB-MYH11, were assessed at base line and monitored every 2-3 months by quantitative reverse transcriptase polymerase chain reaction (qRTPCR) during consolidation therapy. Results: Between April 2007 and January 2018, 162 patients (Inv 16 =84, 8;21= 78) with newly diagnosed CBF-AML have been treated, median age 49 years (range, 19-78 years, 15% older than 65 years). Fifty-seven (35%) patients were treated with FLAG-GO. Amongst all patients, 95% (N=154) achieved complete remission (CR), 6 (4%) achieved CR with incomplete platelet recovery (CRp) and 2 patients died within first 4 weeks. Of the planned total of 7 cycles of therapy, median number of cycles of therapy delivered is 5 (range 1-7); prolonged cytopenias being the limiting factor in delivery of all planned cycles. With median follow up of 6.5 years, the 5 year overall survival (OS) is 71% and relapse free survival (RFS) is 75%. Patients treated with FLAG-GO and FLAG-Ida were comparable in age, cytogenetic subgroups and presence of kinase (KIT, FLT3, RAS) mutations. OS was not significantly different (p=.7) among treatment regimens but RFS was significantly better among patients treated with FLAG-GO (p=.02) (Fig.1). RFS at 5 years was 87% with FLAG-GO regimen while the same was 68% for FLAG-Ida regimen. Presence of KIT (p=.6) or any kinase mutation (KIT,RAS or FLT3) (p=.8) did not impact RFS. Reduction of fusion transcript ratio by 3 log at end of induction (p=.01) (Fig.2), by 4 log at end of cycle 3-4 (p=.03) and end of all cycles (p=.001), resulted in better RFS. FLAG-GO regimen but not cytogenetic subgroups was associated with better reduction in fusion transcript. Seventy-six percent of patients treated with FLAG-GO achieved reduction of fusion transcript to <0.01 by mid-consolidation while the same was 42% for patients treated with FLAG-Ida (p=0.002). Conclusion: FLAG-GO or FLAG-Ida regimen results in high remission rates among patients with newly diagnosed patients with CBF-AML with low induction mortalities. Induction consolidation with FLAG-GO results in better RFS and quantitative reduction in fusion transcript ratio, compared to FLAG-Ida. Serial quantitative monitoring of fusion transcript identifies patients with better chances of sustained remission. Disclosures Borthakur: PTC Therapeutics: Consultancy; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Eli Lilly and Co.: Research Funding; Agensys: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Polaris: Research Funding; Cantargia AB: Research Funding; GSK: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Tetralogic Pharmaceuticals: Research Funding; Oncoceutics, Inc.: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Merck: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; NKarta: Consultancy; Strategia Therapeutics: Research Funding. Cortes:Sun Pharma: Research Funding; Biopath Holdings: Consultancy, Honoraria; Merus: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Ravandi:Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding. Garcia-Manero:Novartis: Research Funding; AbbVie: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding. Daver:BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Karyopharm: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Agios: Consultancy; Servier: Research Funding; Celgene: Consultancy; Astellas: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; NOHLA: Research Funding; Jazz: Consultancy; Incyte: Consultancy, Research Funding; Glycomimetics: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; BMS: Research Funding; Immunogen: Research Funding; Astex: Research Funding; Cyclacel: Research Funding.

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Deep Molecular Response in Imatinib First-Line 418 Newly Diagnosed CP CML Patients.

Blood ◽

10.1182/blood-2018-99-113044 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3014-3014

Author(s):

Franck Emmanuel Nicolini ◽

Vincent Alcazer ◽

Pascale Cony-Makhoul ◽

Stephanie Dulucq ◽

Sandrine Hayette ◽

...

Keyword(s):

Board Of Directors ◽

Univariate Analysis ◽

Molecular Response ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Free Survival ◽

Deep Molecular Response ◽

Chi2 Test

Abstract Introduction Deep molecular response (DMR) are now highly desirable goals in the treatment of CP-CML, especially in the front-line setting, because it can lead to a definitive treatment-free remission (TFR). However, such a goal is difficult to attain and does not concern the majority of patients (pts), but currently the precise number of pts able to access to TFR is unknown. Aims We aim to determine the number or newly diagnosed CP-CML pts reaching DMR, stable DMR, and access to TFR, on Imatinib (IM, Glivec®) first-line. Methods We retrospectively analyzed in an observational study, a cohort of newly diagnosed CP-CML pts treated with IM first-line 400 mg daily alone in our 3 reference centers between 2000→2018. All pts were followed according to the ELN recommendations 2006, 2010 and 2013. Clinical data were extracted from medical files, and responses (hematologic, cytogenetic, molecular) were analysed according to standard methods. Molecular results were standardised according to the ELN/Eutos programs since 2003, and were all expressed as BCR-ABLIS in %. DMR have been defined according to the ELN (NCP. Cross et al., Leukemia 2015). Stability of DMR has been defined as a stable if ≥2 years at least on 4 datapoints. TFR has been proposed to pts presenting the only current recommended criteria: MR4.5 ≥2 years at least on 4 datapoints [(Rea et al., Cancer 2018)], in the 3 centers involved, within clinical trials, pioneered in our country, or now as a clinical routine recommendation. Loss of MMR was the trigger for TKI resumption after IM cessation for TFR. Overall survival (OS), progression-free survival (PFS), failure-free survival (FFS, defined as progression to advanced phases death, loss of CHR, CCyR, or MMR, discontinuation of IM for toxicity, primary cytogenetic resistance) were analysed since IM initiation in intention-to-treat. Results Four hundred and eighteen pts have been included in this study, with a median age of 60.7 (48-70) years at diagnosis, with 57% males and 43% females. Sokal score (n=401) was low in 32%, intermediate in 51% and high in 17%. ACA were present at diagnosis in 5.5% of the pts (NA in 1.44%). Major BCR transcripts were found in 98% of pts, and atypical transcripts in 1.9%. CHR was reached in a median of 1 (0.85 to 1.64) month of IM, <10% BCR-ABL transcript (IS) level at 3 months was found in 81% of the pts, and only 9.5% of pts were in MMR at 3 months. The median follow-up after IM initiation is 77.4 (0.9-231.5) months, 125 (30%) pts have switched to TKI2 for IM resistance or intolerance. Overall, 252 (60%) pts reached MR4, 127 (30%) stable MR4, 170 (41%) MR4.5, and 82 (20%) stable MR4.5. The median time on TKI necessary for obtaining stable MR4.5 is 15.6 (5.9-28) months. The cumulative incidence of MR4.5 at 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months were 12.5%, 23.4%, 31.6%, 36.72%, 43.55%, 48.7%, 48.3%, 52.98%, 54.03%, 59.18% respectively (Figure 1A.). The cumulative incidence of stable MR4.5 at 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months were 5.76%, 11.5%, 17.83%, 21.82%, 26.35%, 28.13%, 28.13%, 29.13%, 29.13%, 29.13% respectively (See figure 1B.). Seventeen (13%) and 10 (12%) pts have switched IM→TKI2 before obtaining a stable MR4 and a stable MR4.5 respectively. Overall, 41 (10%) pts have reached the TFR criteria and stopped their TKI and 23 (56%) never lost their MMR after cessation, with a median follow-up of 41.7 (9.4-121.8) months. In an univariate analysis, only gender (female vs male, 39% vs 61% for no MR4.5 and 53.66% vs 46.34% for stable MR4.5, p=0.028, Pearson's CHI2 test), and MMR at 3 months (yes vs no, 3.74% vs 96.26% for no MR4.5 and 17.46% vs 82.54% for stable MR4.5, p<0.001, Pearson's CHI2 test) were identified variables impacting on stable MR4.5. A multivariate analysis could not be performed on so few discriminant factors identified in the univariate analysis. Conclusions Only 42 out 418 (10%) of the newly diagnosed CP-CML pts on IM first-line in our study reach the TFR criteria we recommended, and only 22 over 418 pts (5%)will finally definitively stop any TKI durably within the limits of this retrospective observational study. Urgent strategies in order to increase the access to definitive TFR are needed. Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Incyte Biosciences: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; Incyte: Other: Travels for attending to Congress; Novartis: Consultancy, Other: Writing support, Travels for attending to Congress. Dulucq:BMS: Consultancy; Incyte: Consultancy. Hayette:Incyte: Consultancy. Mahon:BMS: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Incyte: Speakers Bureau. Etienne:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau.

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Measurement of Serum microRNAs in US Veterans with Monoclonal Gammopathy of Undetermined Significance

Blood ◽

10.1182/blood-2018-99-114821 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5576-5576

Author(s):

Weixin Wang ◽

Youn K Shim ◽

Joel E Michalek ◽

Emily Barber ◽

Layla M Saleh ◽

...

Keyword(s):

Board Of Directors ◽

Monoclonal Gammopathy ◽

Research Funding ◽

Plasma Cells ◽

Univariate Analysis ◽

Serum Levels ◽

Advisory Committees ◽

Rank Regression ◽

Study Base

Abstract Background Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic condition arising from clonal plasma cells and has the risk of transformation to multiple myeloma (MM). Dysregulated expression of microRNAs (miRs) has been well demonstrated in MM, but miRs are not as well characterized in MGUS. We previously found an increased risk for MGUS in Vietnam veterans exposed to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here we report the effect of age on serum levels of 13 miRs in MGUS cases and controls from that study cohort. Methods The study base population comprised 958 US veterans who participated in the 2002 follow-up of the Air Force Health Study (AFHS). A total of 49 MGUS cases were identified by using their serum stored at the AFHS 2002 follow-up (Landgren O et al. JAMA Oncology, 2015). The current study included 47 MGUS cases and 85 controls. The controls were selected from the veterans who did not have MGUS, did not have a history of tumors, and whose TCDD level was below the third quartile value among the study base. Quantitative real-time PCR (qPCR) was used to determine the serum levels of 13 miRs (let-7a, let-7i, miR-16, miR-20a, miR-21, miR-34a, miR-106b, miR-146a, miR-181a, miR-192, miR-205, miR-335 and miR-361) that were previously shown to be dysregulated in MM or other cancers . The cycle threshold (Ct) values obtained from qPCR were normalized by using spiked-in cel-miR-39 as a control. Univariate rank regression was used to examine the relationships between relative expression of each miR and age, and each miR and MGUS status (MGUS vs control); each miR-MGUS relation was also examined with adjustment for age. All miR values were analyzed in log2 units. Continuously distributed age was summarized by the median and interquartile range (IQR): age variation with MGUS status was assessed with Kruskal-Wallis test. All statistical testing was two-sided with a significance level of p<0.1. Corrections for multiple comparisons were not made. We used R for rank regression analysis and SAS Version 9.4 for Windows for all other analyses. Results Overall MGUS cases were older than controls (median, controls 66 years [IQR 61, 69] versus MGUS 67 years [IQR 64, 71], p=0.03). Rank regression analysis showed that age was significantly and negatively correlated with the serum levels of 9 (let-7a, let-7i, miR-146a, miR-361, miR-106b, miR-16, miR-20a, miR-21, and miR-335) of the 13 miRs examined in controls. Among MGUS cases, age was significantly negatively correlated with only 5 (let-7a, miR-146a, miR-106b, miR-16, and miR-20a) of the 13 miRs and positively correlated with miR-181a and miR-205 (Table 1). In the univariate analysis of the miR-MGUS relationship, the serum levels of 4 miRs (let-7a, miR-106b, miR-16, and miR-21) were significantly associated with MGUS. However, none of these miRs remained significant after adjusting for age. In both adjusted and unadjusted analyses, the miR levels were lower in MGUS cases than in controls with the exceptions of miR-205 (unadjusted) and miR-335 (adjusted). Conclusions and Discussions In this study population, serum levels of the majority of miRs tested were negatively correlated with age in controls. Most of the same miRs were similarly decreased in MGUS with age, with the exception of miR-181a and miR-205 which were positively correlated with age. miR-181a is an important regulator of apoptosis, that is altered in many cancers, and was previously shown to be elevated in plasma cells of MM and MGUS. miR-205 inhibits tumor suppressors PTEN and SMAD4, and has been shown to be increased in several cancers. Of note, based on univariate analysis, several miRs were significantly differentially expressed in MGUS, but failed to remain significant after adjusting for age effect. This finding underscores the importance of assessing the need for age adjustment when analyzing serum miR data. We are currently exploring this data set to determine whether TCDD levels had any independent effect on miR levels in this population. Note: The first two authors contributed equally. Disclosures Landgren: Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Karyopharm: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees.

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