The Impact of Insurance Status at Diagnosis on Overall Survival in Chronic Myeloid Leukemia: A Population-Based Analysis

Abstract Introduction: Survival among patients diagnosed with chronic myeloid leukemia (CML) has markedly improved with the advent of tyrosine kinase inhibitors. Nonetheless, access to care, including medication cost and adherence, may be barriers to therapeutic effectiveness. We performed a population-based analysis to determine if insurance status at the time of CML diagnosis influenced patient outcomes. Methods: We used the Surveillance, Epidemiology, and End Results Program (SEER) database (November 2014 submission) to identify patients age 15 or older, diagnosed with CML between 2007 and 2012 (SEER ICD-O3 recodes 9863 and 9875). We included patients with documented insurance status at diagnosis and categorized them as either private insurance, Medicaid coverage, or uninsured. We excluded patients with unknown insurance status at diagnosis. The primary outcome was overall survival according to insurance status. We performed a stratified analysis looking at patients age 15-64 and patients 65 or older; we did not include uninsured patients over age 65 in the analysis (n=16) due to Medicare eligibility. Covariates of interest in multivariable analysis included age at diagnosis, race, ethnicity, sex, and marital status at diagnosis. Overall survival was compared by log-rank test and estimated by the method of Kaplan and Meier. P-values were significant to the 2-sided 0.05 level. Results: 5784 patientswere diagnosed with CML between 2007 and 2012 and had insurance status documented at diagnosis. Of patients age 15-64, uninsured and Medicaid patients were younger, more often non-white race and Hispanic ethnicity, and less often married (Table 1). Over age 65, Medicaid patients were more often female, non-white race and Hispanic ethnicity, and less often married. Median follow up was 32 months. Among patients age 15 to 64, being uninsured or having Medicaid was associated with worse survival compared to insured patients (5-year OS uninsured 72.7%, Medicaid 73.1%, insured 86.6%, p<0.0001) (Figure 1A). For patients over age 65, there was no difference in 5-year OS between patients with Medicaid and those with other insurance (40.2% vs. 43.4%, p=0.0802). In multivariable analysis of patients age 15-64, compared to insured patients, there was increased mortality among patients who were uninsured (HR 2.156, p<0.0001) or on Medicaid (HR 1.972, p<0.0001). There was worse survival with increased age (HR 1.046 per year, p<0.0001), male sex (HR 1.282, p=0.0279) and, compared to married persons, being single (HR 1.883, p<0.0001). For patients over age 65 at diagnosis, only age was associated with increased mortality (HR 1.078 per year, p<0.0001). Conclusions: CML patients under age 65 without insurance or with Medicaid had significantly worse survival compared to patients with insurance. This difference was not noted with patients over age 65; whose survival was relatively poorer regardless of insurance status, as previously described (Cancer 2013;119:2620). Marital status and race/ethnicity also impacted survival. Despite highly effective therapies currently available for CML, these findings suggest that many patients may not have access to or receive appropriate care, in part related to insurance coverage. Table 1. Patient Demographics Age 15-64 p-value Age 65+ p-value (3626 patients) (2142 patients) Uninsured Medicaid Insured Medicaid Insured Total, n (%) 321 (8.9%) 595 (16.4%) 2710 (74.7%) 190 (8.9%) 1952 (91.1%) Age, median (range) 44 (18-64) 45 (15-64) 50 (15-64) <0.0001 75 (65-97) 76 (65-102) 0.5388 Gender, n (%) 0.0482 0.0074 Male 203 (63%) 328 (55%) 1603 (59%) 86 (45%) 1087 (56%) Female 118 (37%) 267 (45%) 1107 (41%) 105 (55%) 865 (44%) Race, n (%) <0.0001 <0.0001 White 231 (72%) 402 (68%) 2112 (78%) 131 (69%) 1724 (89%) Black 68 (21%) 114 (19%) 313 (12%) 26 (14%) 144 (7%) American Indian 2 (1%) 25 (4%) 13 (0.5%) 2 (1%) 7 (0.4%) Asian, Pacific Islander 15 (5%) 48 (8%) 215 (8%) 30 (16%) 65 (3%) Unknown 5 (2%) 6 (1%) 57 (2%) 1 (0.5%) 12 (0.6%) Hispanic Ethnicity, n (%) <0.0001 <0.0001 Non- 234 (73%) 420 (71%) 2341 (86%) 151 (79%) 1813 (93%) Hispanic Hispanic 87 (27%) 175 (29%) 369 (14%) 39 (21%) 139 (7%) Marital Status, n (%) <0.0001 <0.0001 Single 141 (46%) 281 (50%) 588 (23%) 41 (23%) 153 (9%) Married/partner 123 (40%) 194 (34%) 1652 (65%) 67 (37%) 1069 (59%) Divorced/separated/widowed 45 (15%) 90 (16%) 288 (11%) 72 (40%) 578 (32%) Figure 1. Survival of patients (A) age 15-64 and (B) age 65+ by insurance status at diagnosis. Figure 1. Survival of patients (A) age 15-64 and (B) age 65+ by insurance status at diagnosis. Disclosures Fathi: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Ariad: Consultancy; Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Addition of Rituximab Improves Outcome of HIV Negative Patients with Burkitt Lymphoma Treated with the Lmba Protocol: Results of the Randomized Intergroup (GRAALL-Lysa) LMBA02 Protocol. (IGR sponsored LMBA02, NCT00180882)

Blood ◽

10.1182/blood.v120.21.685.685 ◽

2012 ◽

Vol 120 (21) ◽

pp. 685-685 ◽

Cited By ~ 6

Author(s):

Vincent Ribrag ◽

Serge Koscielny ◽

Krimo Bouabdallah ◽

Gilles Salles ◽

Olivier Casasnovas ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

P Value ◽

Intensive Chemotherapy ◽

Advisory Committees ◽

Extension Group ◽

Disease Extension ◽

Group B ◽

Hiv Negative

Abstract Abstract 685 Background: Intensive chemotherapy is now considered as a standard of care in adult patients with Burkitt Lymphoma (BL). Although some single arm studies suggested that adding rituximab to these intensive short-course regimen could improve patientÕs outcome, no randomized study have been reported so far. Methods: To evaluate the potential benefit of adding rituximab to intensive chemotherapy, we conducted a phase III trial comparing the standard LMBA protocol (Divine et al, Ann Oncol 1995) to the same regimen plus rituximab. Rituximab (375 mg/m2) was given on day 1 and 6 during the first 2 courses of COPADM. Patient eligibility criteria included age >18 years, HIV negativity and previously untreated BL. The primary study objective was event-free survival (EFS). A study sample size of 250 pts was estimated in order to detect a 15% gain in EFS (two-side test, power 90%, type 1 error 5%). Secondary objectives were safety and overall survival. Treatment was adapted on disease extension (group B vs C) and age for patients from the C group (age <40; 40–59 and >59). Group C included patients with bone marrow and/or CNS involvement, and group B all the other patients. Methotrexate, cyclophosphamide and cytarabine doses were adapted to age in the group C. Lenograstim was given prophylactically to the pts. The randomization was stratified on disease extension (group B vs C) and age. Results: From October 2004 to September 2010, 257 patients from 45 centers were included; 128 in the Rituximab arm and 129 in the standard arm. Median age was 47 (26% were > 60), M/F ratio was 2.5, serum LDH level was > normal in 75% of the patients, and 11% had a performance status (PS)>2. The two treatment arms were well balanced for pretreatment characteristics, except for age and PS. Patients were older in the Rituximab arm (30%>60 years old vs 17% in the standard arm) or had a higher PS>2 (17% with PS>2 vs 7%). With a median follow-up of 38 months (range 0.3 to 79), patients treated in the rituximab arm had a better EFS (3 year EFS 76%; 95% CI: 69–84 vs 64% in standard arm; 95%CI: 55–72; Logrank P value stratified on treatment group=0.046), and Overall Survival (3 year OS 82%; 95% CI: 77–90 vs 71% in standard arm; 95%CI: 63–79; Logrank P value, stratified on treatment group=0.016) (Figure). Fifty-eight patients died. Causes of death were lymphoma (9 in the rituximab arm and 22 in the standard arm), toxicity (9 in the rituximab arm and 7 in the standard arm), and other causes (4 in the rituximab arm and 7 in the standard arm). Safety was similar in both arms for duration of grade 4 neutropenia, number of platelet or red cell transfusions, minor or major infection. Conclusions: The addition of rituximab to LMBA protocol improves EFS and OS in adult BL HIV negative. No adverse and/or increased toxicity was observed when rituximab was added to this intensive chemotherapy regimen. Toxic death rate was similar to our previous phase II experience despite a higher median age in this randomized multicenter trial. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Sanofi-Aventis: Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Ruxolitinib is approved in the United States and Canada for the treatment of myelofibrosis and is being investigated in combination with panobinostat, an investigational product, in this indication. This abstract reports on a clinical trial conducted outside the US. All patients have provided written informed consent. Salles:roche: Membership on an entity's Board of Directors or advisory committees. Herbrecht:Pfizer: Advisory board member Other. Coiffier:roche: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Different Clinical Implications of Kinase Domain BCR-ABL1 Variants Detected in Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia Patients

Blood ◽

10.1182/blood-2019-127069 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5368-5368

Author(s):

Ricardo Sanchez ◽

Rosa Ayala ◽

Gonzalo Carreño Gomez-Tarragona ◽

Espino Maria Jose ◽

Beatriz Cuevas ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Poor Prognosis ◽

Lymphoblastic Leukemia ◽

Kinase Domain ◽

Categorical Variables ◽

P Value ◽

Advisory Committees

Background: Kinase domain (KD) mutations is a common resistance mechanism, secondary to the tyrosine-kinase inhibitors (ITKs) treatment in the case of chronic myeloid leukemia (CML) and Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL) patients. Sanger sequencing is the gold standard technique and already the currently recommended method for BCR-ABL1 KD mutation detection. However, Sanger sequencing has limited sensitivity and cannot firmly identify populations with variant allele frequencies (VAF) < 15-20%. Next-generation sequencing (NGS) allow us the screening of mutations in the whole KD with variants with a VAF greater than 1%. The aim of this study is to evaluate the clinical and prognostic implications of CML and Ph-positive ALL patients who have been studied for mutations in BCR-ABL1 by NGS. Methods: Seventy CML and Ph-pos ALL patients have been studied for BCR-ABL1 mutations between years 2015-2017. The study reason was warning or failure according to European Leukemia Net recommendations in the case of CML patients, and diagnostic or relapse in the case of ALL patients. Clinical characteristics of the patients are depicted on Table 1. Categorical variables are described as frequency, and quantitative variables as medians. Contingency tables were used to analyze associations between categorical variables (χ2). Median test was used to compare medians of continuous variables between groups. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between patients using the log-rank test. Results: We have found 37 patients with mutations (51%), the most frequent being p.T315I, p.L248V and p.L387M. 28 out of 59 were found in CML (47%) vs 9 out of 13 (69%) in ALL. Of the 37 patients with mutations, double mutations have been found 10 times (27%). In the 72 analyses performed, 62 mutations were found in total, 41 of them were variants of uncertain significance (VUS) and 21 were well-known mutation. The median levels of BCR-ABL1 (IS) at the time of analysis were 3.00 (0.01-196.18) %. Regarding CML patients, we have found 12 and 16 cases with pathogenic mutations and VUS, respectively. The mean survival for CML and ALL were 75.2 months (CI 95%, 65.7-84.6) and 24.7 months (13.3-36.2), respectively. There are significant differences between the overall survival curves for patients with CML who have mutations in BCR-ABL1 compared to those who have VUS or do not (p-value = 0.024, n=59), suggesting a second role of the VUS variants in the resistance of the patients to the TKI. These two groups have no significant differences in ALL patients (p-value= 0.32, n=13). Overall survival at 10 years from the date of diagnosis is 74% for CML patients with mutations and 90% for CML patients without mutations. Data dropped significantly for ALL patients, but the number of cases is too low. Conclusions: - Mutations have been identified in 47% of CML patients studied in the case of failure or warning and 69% of the patients of ALL at diagnosis or relapse moments. - The identification of pathogenic variants has poor prognosis in patients with CML (p = 0.024), however no differences were observed in ALL. - The identification of VUS is not associated to poor prognosis and these variants could not confer resistance to ITK. Disclosures Sevilla: Rocket Pharmaceuticals, Inc.: Honoraria, Patents & Royalties: Inventor on patents on lentiviral vectors filled by CIEMAT, CIBERER and F.J.D and may be entitled to receive financial benefits from the licensing of such patents; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rocket: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Honoraria. Steegmann:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. García Gutiérrez:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Incyte: Honoraria, Research Funding.

Download Full-text

Presence of Extrachromosomal DNA (ecDNA) Impacts Both Progression Free and Overall Survival and Is an Independent Poor Prognostic Marker in Multiple Myeloma

Blood ◽

10.1182/blood-2021-151647 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 461-461

Author(s):

Parth Shah ◽

Anil Aktas-Samur ◽

Mariateresa Fulciniti ◽

Raphael Szalat ◽

Masood A. Shammas ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Copy Number ◽

Research Funding ◽

P Value ◽

Newly Diagnosed ◽

Extrachromosomal Dna ◽

Publicly Traded ◽

Advisory Committees

Abstract Background Focal amplifications and rearrangements drive tumor growth and evolution in cancer. Focally amplified regions often involve the juxtaposition of rearranged segments of DNA from distinct chromosomal loci into a single amplified region and nearly half of these regions can be explained by circular, extrachromosomal DNA (ecDNA) formation. Cancer-associated ecDNA shows a unique circular placing ecDNA at the interface of cancer genomics and epigenetics. As formation of ecDNA represents a manifestation of genomic instability, we have investigated presence and prognostic impact of ecDNA in multiple myeloma (MM). Methods Whole genome (WGS) and transcriptome (RNAseq) sequencing data from CD138 purified MM cells from 191 uniformly-treated newly diagnosed MM patients were used for this analysis. Copy number variants (CNV), single nucleotide variants (SNV) and structural variants (SV) were identified on all WGS samples using Facets, Mutect2 and Manta. Seed data from these CNV results was passed to the AmpliconArchitect tool to determine presence of focally amplified and rearranged segments of DNA. Seed CNV thresholds were set for a minimum CNV size of 100kb and a copy number of equal or greater to 5. Extrachromosomal calls were then annotated using the Amplicon Classifier to determine the presence of ecDNA. Multivariate survival analysis was performed after segregating samples into the conventional myeloma risk classifications including translocations, copy number alterations, ISS, age and mutations associated with risk. Differential expression analysis was performed on transcriptomic data using DEseq2. Results We identified 6.8% of the newly diagnosed patients with ecDNA, 12.5% with complex non-cyclic DNA amplifications and 10.1% with linear amplifications. ecDNA and complex events were targeting MM dependent genes, including MYC/PVT1, IRF4 as well as known driver genes such as CDYL and TRAF2. We further evaluated association between ecDNA, complex rearrangements, linear amplification and patients with none of these amplification types and found that patients with ecDNA had significantly poor PFS (median PFS 22 months vs. 41 months) and OS (median OS 41 months vs. 105 months). Patients having ecDNA in their MM cells did not show any significant enrichment for known translocations, double hit or TP53 mutations. In a multivariate model including ecDNA and all other known MM risk features, ecDNA was found to be an independent predictor of progression free survival.(HR 2.6, CI: 1.26 -5.6, p=0.0082) and overall survival (HR 7.94 CI:3.5-17.9 p < 0.0001). Patients with ecDNA have higher mutational load probability(8798 vs 6982, effect size = 0.64 , probability is 91.1). However, this was not reflected in heterogeneity by using MATH score. We found that patients with ecDNA are likely to have BRAF mutations (OR= 25.07 [2.57 - 330 95% CI], p value = 0.002), however overall RAS/RAF pathway mutations were similar to other patients. Patients with ecDNA showed fragile DNA with more breaks (median segments 197 vs. 125.5, p value = 0.001). Although ecDNA is defined as copy number gain with fragments having 5 or more copies, overall genomic gain between ecDNA and other patients were similar. However, overall genomic loss in patients with ecDNA were higher than others (7% vs. 4.2%, p = 0.06). By differential gene expression analysis we noted 98 differentially expressed genes in MM cells with ecDNA. The downregulated geneset involved pathways responsible for cell death as well as the RAS pathway. Interestingly, CD38 was upregulated in the ecDNA dataset suggesting greater potential for CD38 targeting therapies in these patients. Conclusions ecDNA, as an unique marker of perturbed genomic integrity, is observed in a subset of patients and is an independent prognostic marker in newly diagnosed MM patients. As patients with ecDNA are not fully captured by other risk features its incorporation in an expanded definition of a high risk group of multiple myeloma should be investigated. Future studies will endeavor to explore the biological mechanism through which ecDNA are formed and influences outcomes in myeloma. Figure 1 Figure 1. Disclosures Richardson: Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Celgene/BMS: Consultancy, Research Funding; Secura Bio: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Perrot: Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Thakurta: Oxford University: Other: Visiting Professor; BMS: Current Employment, Current equity holder in publicly-traded company. Anderson: Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Celgene: Consultancy; Pfizer: Consultancy.

Download Full-text

Only Hotspot SF3B1 K700E Mutation Is an Independent Predictor of Overall Survival in Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2020-141446 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25

Author(s):

Rashmi Kanagal-Shamanna ◽

Guillermo Montalban Bravo ◽

Koji Sasaki ◽

Carlos E. Bueso-Ramos ◽

Elias Jabbour ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

P Value ◽

Aberrant Splice ◽

Low Grade ◽

Advisory Committees ◽

Pathologic Features ◽

Significant Difference ◽

Advisory Role

SF3B1 mutated (SF3B1mut) MDS is associated with increased ring sideroblasts (RS) and favorable outcome. IWG-PM proposed that SF3B1mut MDS be considered a distinct entity in the absence of other unfavorable features. However, not all SF3B1mut MDS have similar clinical course. Hotspot K700E SF3B1mut leads to aberrant splice junctions and large-scale mRNA downregulation by activating a cryptic splice site. The functional effects of SF3B1mut outside of K700E is not clear. The outcome can also be altered by concomitant gene mutations and karyotype. In this study, we studied the clinical-pathologic features and outcome in a single-institutional series of 94 SF3B1mut and 415 SF3B1wt MDS, and explored the differences between K700E and non-K700E subgroups. All untreated MDS patients diagnosed over a 3-year duration who underwent NGS were selected. Overall survival was calculated from diagnosis to death/ last follow-up. Univariate (UVA) Cox proportional hazards regression was used to identify any association of variables with outcome followed by multivariate modeling (MVA) (p-value 0.200 cutoff). Of 509 patients, 94 (19%) had SF3B1mut: 59 men, 35 women; median age: 74 (39-92) years. Baseline characteristics: Table 1. Compared to SF3B1wt, SF3B1mut had a significantly higher median age (74 vs. 70, p=0.0008), MCV (105 vs. 96, p<0.0001), platelet count (188 vs. 78, p<0.0001) and lower BM blasts (2 vs. 4, p=0.003). SF3B1mut were less frequently therapy-related (18% vs. 34%, p=0.002), significantly enriched in R-IPSS VL/L and WHO MDS-RS and MDS with iso del(5q). Majority (~66%) had concomitant mutations: TET2 (25%), DNMT3A (21%), RUNX1 (15%), TP53 (10%), ASXL1 (7%), BCOR (4%), IDH1/2 (4%), SRSF2 (3%), RAS (3%) and EZH2 (3%) (Fig 1B). ~10% showed complex karyotype (CK). Among SF3B1mut, hotspot K700E mutation was seen in 55 (~60%). Non K700E mutations (n=39, 40%) frequently involved codons: H662, K666 and R625, seen in 8 patients each (Fig 1A). SF3B1 K700E showed a higher median RS% (50% vs. 34%; p=0.038), ANC (2.4 vs. 1.8, p=0.005) and a trend for higher platelet (196 vs. 124, p=0.05). SF3B1mut were less likely MDS-EB than non-K700E (22% vs. 49%, p=0.008). All 4 SF3B1mut patients that fit WHO criteria for MDS with isolated del(5q) had K700E (Table). The frequency of RUNX1 mutation was significantly higher in non-K700E cases (26% vs. 7.3%, p=0.012); mutations in BCOR (p=0.02), IDH2 (p=0.07) and SRSF2 (p=0.07) were exclusively noted in non-K700E cases (Fig 1C). There was no significant difference in TP53mut or CHIP-associated mutations DNMT3A, ASXL1 and TET2 or SF3B1 VAF. There was no significant differences in diploid vs. CK. However, K700E had lower CCCS categories (0/1, n=39; 2/3/4, n=10 vs. 0/1, n=19; 2/3/4, n=17); p=0.011). Majority were treated with HMA [16/17 (94%) K700E; 15/19 (79%) non-K700, 217/ 277 (78%) SF3B1wt]. SF3B1mut had better OS than SF3B1wt in all MDS (NR vs. 25.2 months, p=0.0003; fig 1D), low-grade MDS (NR vs. 41.3 months, p=0.0015; fig 1E) and MDS-RS (NR vs. 22.3 months, p=0.0004; fig 1F). Four (7.3%) K700E died compared to 9 (23%; p=0.036) non-K700E. The outcome of non-K700E was similar to SF3B1wt, in all MDS, low-grade MDS and MDS-RS (median OS, NR for both; p=0.021). By UVA, the following associated with worse outcome: higher BM blasts, lower hemoglobin, platelet and MCV, prior chemo-radiation, CK, higher R-IPSS, absence of mutations in SF3B1 K700E, TET2 and U2AF1 and presence of TP53mut. Non-K700E did not associate with OS. By MVA, lower hemoglobin, higher R-IPSS, absence of SF3B1 K700E and presence of TP53mut were independent predictors of worse OS. Within MDS-RS categories, independent prognostic factors of worse OS included lower platelet, presence of mutations in non-K700E SF3B1mut, ASXL1, SRSF2 and TP53. TP53mut/CK was seen in 10% SF3B1mut MDS. No survival differences were noted between SF3B1mut with or without TP53mut/CK (median OS, NR) and SF3B1wt without TP53mut/CK (44.3 months), but TP53mut/CK with SF3B1wt MDS had a worse outcome (median OS, 12.9 months, HR 1.46, p=0.001; fig 1G). Same findings were noted within low-grade MDS and MDS-RS, suggesting SF3B1mut negates the poor prognostic effect of TP53mut/CK. About 40% SF3B1mut MDS show non K700E mutations. K700E and non K700E SF3B1mut MDS show distinct clinical and mutational profiles, with K700E showing a significantly better OS compared to non K700E and SF3B1wt. Only SF3B1 K700E independently predicted for worse OS in MDS. Figure Disclosures Sasaki: Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Honoraria. Jabbour:Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding. Garcia-Manero:Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Onconova: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy.

Download Full-text

Incidence and Risk Factors of Second Malignancies Among Medicare Beneficiaries with Newly-Diagnosed Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms Receiving Cytoreductive Therapy with Hydroxyurea

Blood ◽

10.1182/blood-2019-127568 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 330-330

Author(s):

Rong Wang ◽

Rory M Shallis ◽

Scott F. Huntington ◽

Amer M. Zeidan ◽

Steven D. Gore ◽

...

Keyword(s):

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Risk Model ◽

Population Based ◽

Insurance Status ◽

Advisory Committees ◽

Population Based Study ◽

Solid Malignancies

Introduction: Myeloproliferative neoplasm (MPN) patients (pts) are known to have a higher incidence of second malignacies (SMs), including both solid tumors and hematological malignancies, when compared to the general population. The etiology of SM and its connection to MPN is not entirely clear, but may be due to the presence of a shared genetic predisposition, the natural progression of MPN (as it relates to myeloid malignacies), and/or an unintended consequence of cytoreductive treatment. Hydroxyurea (HU) is a guideline-recommended cytoreductive therapy for high-risk MPN patients. This population-based study aimed to evaluate the effect of HU on the development of SM among patients with MPNs. Methods: We conducted a retrospective cohort study of older adults (age 66-99 years) who were diagnosed with MPN including polycythemia vera (PV), essential thrombocythemia (ET) and primary or post-PV/ET myelofibrosis (MF) (International Classification of Diseases for Oncology, 3rd edition, code 9950, 9961, 9962) in 2007-2015 and included in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Patients were required to have continuous enrollment in Medicare Parts A and B and not enrolled in health maintenance organizations from one year before MPN diagnosis through end of follow-up (death, 12/31/2016 or change of insurance status, whichever came first). To capture patients' treatment with HU, we further restricted patients to have continuous Part D coverage from diagnosis to the end of follow up. SMs were ascertained using SEER data. Patients treated with ruxolitinib, busulfan or interferons before the occurrence of SM or end of follow-up, whichever came first, were excluded. We categorized SM as solid or hematological (including non-myeloid and myeloid) malignancy (HM). The cumulative incidence function of SM was computed via a competing risk model. Death, changing of insurance status and development of a SM other than cancer of interest were considered competing events. Gray's test was utilized to assess difference across strata. Multivariable competing risks regression models were performed to assess the impact of HU on the development of SM. Age at MPN diagnosis, sex, race, Elixhauser comorbidity score, marital status, zip code level median household income, eligibility for dual insurance, and SEER region were variables adjusted for in the multivariable model. All statistical tests were two-sided and performed with SAS Version 9.4. Results: The study followed 3,122 patients (1,212 PV, 1,509 ET and 401 MF) up to 9.5 (median 2.58) years. The median follow-up was 2.91 years (range 0.02-9.50) and 1.76 years (range 0.01-9.50) for HU users and non-users, respectively. The median age at MPN diagnosis was 77 (range 66-99) years. Compared with those who did not receive HU, HU users were more likely to be female, older, have fewer comorbidities, and live in higher income areas. A total of 264 patients developed a SM, including 179 solid, 21 non-myeloid, and 64 myeloid HMs. The cumulative incidence of SM was 11.3% (95% confidence interval [CI] 9.6%-13.2%) and 11.7% (95% CI 9.5%-14.2%) in 1986 (63.6%) HU users and 1,136 (36.4%) non-users, respectively (Gray's test, p=0.23). As shown in Figures 1-3, among HU users, the cumulative incidence was 7.6% (95% CI 6.2%-9.2%), 0.7% (95% CI 0.4-1.2), and 3.0% (95% CI 2.1-4.1%) for solid malignancies, non-myeloid and myeloid HMs, respectively. Among non-HU users, the cumulative incidence for solid malignancies, non-myeloid and myeloid HMs was 8.0% (95% CI 6.1%-10.2%), 1.0% (95% CI 0.5%-1.7%), and 2.7% (95% CI 1.8%-4.0%), respectively. The Gray's test showed no statistically significant differences in the three types of SMs between HU users and non-users (all p > 0.25; Figures 1-3). In the multivariable competing risk model, after adjusting for socio-demographic variables and comorbidities, the risk of solid SM (hazard ratio [HR]=0.85, 95% CI 0.63-1.15, p=0.29), non-myeloid (HR=0.74, 95% CI 0.31-1.78, p=0.49) and myeloid HM (HR=0.93, 95% CI 0.53-1.64, p=0.81) did not differ by HU status. Conclusions: In this large population-based study of older MPN patients, incidence of solid and hematologic SM was similar among HU users when compared to non-users, reaffirming current cytoreductive management guideline recommendations. Disclosures Wang: Celgene Corporation: Research Funding. Huntington:Genentech: Consultancy; Pharmacyclics: Honoraria; DTRM Biopharm: Research Funding; Bayer: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; AbbVie: Consultancy. Zeidan:BeyondSpring: Honoraria; Seattle Genetics: Honoraria; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Astellas: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Cardinal Health: Honoraria; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Davidoff:Celgene Corporation: Consultancy, Research Funding. Ma:Celgene Corporation: Research Funding. Podoltsev:Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; Arog Pharmaceuticals: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: 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; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Samus Therapeutics: Research Funding; Kartos Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; AI Therapeutics: Research Funding.

Download Full-text

Similar 1 Year Survival of Patients Receiving Plerixafor (Mozobil*®) Plus G-CSF Versus Placebo Plus G-CSF Mobilized Autologous Grafts: Results From Two Phase 3 Randomized Trials in Patients with NHL or MM Undergoing Autologous Transplantation After Front-Line or Rescue Mobilization.

Blood ◽

10.1182/blood.v114.22.2319.2319 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2319-2319

Author(s):

Ivana N Micallef ◽

Patrick Stiff ◽

Edward Stadtmauer ◽

Brian J. Bolwell ◽

Sachin Marulkar ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

P Value ◽

Phase 3 ◽

Two Phase ◽

Advisory Committees ◽

Kaplan Meier ◽

Cd34 Cells ◽

Equity Ownership

Abstract Abstract 2319 Poster Board II-296 Background: Data from two phase 3 clinical trials indicate that plerixafor plus G-CSF is safe and more effective than G-CSF alone in mobilizing CD34+ hematopoietic stem cells (HSC) for autologous HSC transplantation (auto-HSCT) in patients with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM). Herein we report 1-year overall survival in patients with NHL or MM who have undergone auto-HSCT with cells mobilized with plerixafor plus G-CSF compared to placebo plus G-CSF. Furthermore, we also report 1-year overall survival in patients with NHL who failed mobilization on either arm and entered a rescue protocol. Methods: Data were obtained from two prospective, randomized, double-blind, placebo-controlled, phase 3 clinical trials that compared the safety and efficacy of plerixafor (0.24 mg/kg/day SQ) plus G-CSF (10 mg/kg/day) with placebo plus G-CSF for mobilization of HSC for autologous HSCT in patients with NHL or MM. In the NHL study, patients in either study arm who failed mobilization (&0.8 ×106 CD34+ cells/kg in 2 days or &2 × 106 CD34+ cells/kg in 4 days) were eligible to enter the rescue protocol and received plerixafor + G-CSF mobilization. Overall survival in patients was estimated by the Kaplan-Meier method. Results: In the NHL study, 135/150 (90.0%) patients in the plerixafor group compared with 82/148 (55.4%) patients in the placebo group, underwent transplantation (p&0.001) with a median (range) of 5.41 (1.95-17.6) and 3.85 (1.98-8.74) × 106 CD34+ cells/kg, respectively (p&0.001). A total of 62 patients (10 from the plerixafor arm and 52 from the placebo arm) failed mobilization and proceeded to rescue mobilization with plerixafor + G-CSF. Of these, 52 patients (84%) proceeded to transplantation with a median (range) of 3.8 (1.1-10.5) x 106 CD34+ cells/kg. Kaplan-Meier estimates of 1-year overall survival for patients in the plerixafor and placebo groups in the primary ITT population (rescue patients were censored as of consent date for rescue) were 76.0% and 64.7%, respectively. Kaplan-Meier estimate of 1-year overall survival in the rescue group was 83.7%. The Log rank p-value comparing all 3 survival estimates (plerixafor, placebo and rescue) was 0.765 (Figure 1A). In the MM study, 142/148 (95.9%) patients in the plerixafor group and 136/154 (88.3%) patients in the placebo group underwent transplantation (p=0.014) with a median (range) of 5.40 (1.20-16.74) and 3.96 (1.76-16.88) × 106 CD34+ cells/kg, respectively (p&0.001). In this trial, Kaplan-Meier estimates of 1-year overall survival in the plerixafor and placebo groups were 93.6% and 95.8%, respectively (Log-rank p-value=0.771; Figure 1B). Conclusions: These data suggest that overall survival at 1 year is similar between patients with MM or NHL mobilized with plerixafor plus G-CSF compared to placebo plus G-CSF. Furthermore, in the NHL study, patient survival in the rescue protocol was similar to that seen in the phase III trial. Collection of follow-up data on overall survival is ongoing. Disclosures: Micallef: Genzyme Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stiff:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stadtmauer:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bolwell:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marulkar:Genzyme Corporation: Employment, Equity Ownership. Hsu:Genzyme Corporation: Employment, Equity Ownership. DiPersio:Genzyme: Honoraria.

Download Full-text

Hematopoietic Cell Transplantation with or without Sorafenib Maintenance for Patients with FLT3-ITD Acute Myeloid Leukemia in CR1

Blood ◽

10.1182/blood.v126.23.864.864 ◽

2015 ◽

Vol 126 (23) ◽

pp. 864-864 ◽

Cited By ~ 5

Author(s):

Andrew M. Brunner ◽

Shuli Li ◽

Amir T. Fathi ◽

Vincent T Ho ◽

Richard M. Stone ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Multivariable Analysis ◽

Control Group ◽

Advisory Committees ◽

Landmark Analysis ◽

Median Date ◽

The Impact ◽

Disease Free

Abstract Introduction: Patients with acute myeloid leukemia (AML) with internal tandem duplications in the fms-like tyrosine kinase 3 receptor (FLT3-ITD) are at high risk for relapse despite allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1).We have previously shown sorafenib, an oral FLT3/multikinase inhibitor, to be safe as maintenance therapy after HCT (BBMT 2014;20:2042). We performed a retrospective study to evaluate the impact of sorafenib maintenance on outcomes of adult patients with FLT3-ITD AML undergoing HCT in CR1. Methods: We identified consecutive patients (n=80) at 2 institutions with AML between 2008 and 2014, with FLT3-ITD at diagnosis, who underwent HCT in CR1. Patients given sorafenib in remission after HCT were in the "sorafenib" group, and others were the "control" group. We identified the median date of sorafenib initiation, and performed a landmark analysis including only controls alive without relapse at that date. The primary outcome was overall survival (OS). We performed multivariable analysis, accounting for age >60, conditioning intensity, NPM1 status, cytogenetic risk, and donor type, to estimate the impact of sorafenib maintenance on OS, disease-free survival (DFS), non-relapse mortality (NRM), and time to relapse from the estimated date of sorafenib initiation. Cumulative incidence of grade 2-4 acute GVHD (aGVHD) and chronic GVHD (cGVHD) requiring systemic immunosuppression were estimated from date of transplant. Results: We identified 26 sorafenib patients and 54 control patients. Median follow up was 22.1 mo. (range, 6.3-49.8) for survivors in the sorafenib group, and 37.5 mo. (range, 12.4-88.9) in the control group (p=0.020). The median time to sorafenib was 68 days after transplant; subsequent analysis therefore included 26 sorafenib patients and 41 control patients alive without relapse at day +68. There were no significant differences in patient characteristics (Table 1). Two patients in the control group had concomitant FLT3-TKD mutations. Patients on sorafenib had improved 2-year OS compared to controls in the landmark analysis (83% vs. 58%, p=0.019, Figure 1). In multivariable analysis, sorafenib maintenance significantly improved OS (HR for death 0.146, p=0.0047) and DFS (HR 0.091, p=0.0005). Of patients alive without relapse at d+68, sorafenib maintenance was associated with improved 2-year DFS (85% vs. 52%, p=0.0047) and lower 2-year cumulative incidence of relapse (9.5% vs. 41%, p=0.0065). After 68 days, 2 sorafenib patients and 4 controls developed aGVHD. There was no difference in 2-year NRM (5.7% vs. 7.6%, p=0.61) or cumulative cGVHD at 1 year (50% vs. 37%, p=0.31). Conclusions: Sorafenib maintenance after HCT is associated with significantly improved DFS and OS among patients with FLT3-ITD AML undergoing HCT in CR1, with no difference in GVHD or NRM. These findings suggest a potential benefit of sorafenib and possibly other FLT3 inhibitors after HCT for FLT3-ITD AML, and support a randomized controlled trial of FLT3 inhibition after HCT. Table 1. Patient Demographics Control n=41 Sorafenib n=26 P-value Age (median, range) 53 (25,72) 54.5 (20,74) 0.39 HCT Age (median, range) 53 (25,73) 55 (20,74) 0.44 Gender (male, %) 12 (29%) 12 (46%) 0.20 Race (white, %) 35 (85%) 24 (92%) 1.00 ECOG at Diagnosis* 0.43 0 7 (39%) 7 (50%) 1 7 (39%) 7 (50%) 2 3 (17%) 0 3 1 (6%) 0 Antecedant Disease 0.58 De Novo 32 (78%) 22 (85%) tAML 4 (10%) 3 (12%) Prior MDS or MPN 5 (12%) 1 (4%) Cytogenetic Risk 1.00 Favorable 2 (5%) 1 (4%) Intermediate 35 (88%) 23 (88%) Adverse 3 (8%) 2 (8%) NPM1 mut# 20 (74%) 14 (56%) 0.25 CEBPA mut (n) 0 2 1.00 Induction Treatment 0.37 7+3 based induction 39 (95%) 23 (88%) Other induction 2 (5%) 3 (12%) TKI prior to HCT 10 (24%) 7 (27%) 1.00 ECOG at HCT+ 0.63 0 13 (32%) 6 (25%) 1 18 (44%) 14 (58%) 2 10 (24%) 4 (17%) HCT Intensity 1.00 Myeloablative 23 (56%) 14 (54%) Reduced intensity 18 (44%) 12 (46%) Donor Type 0.49 Matched 36 (88%) 21 (81%) Mismatched 5 (12%) 5 (19%) aGVHD prophylaxis 0.61 CNI and Methotrexate 24 (59%) 17 (65%) *Diagnosis ECOG missing in 23 control and 12 sorafenib patients #NPM1 testing performed on 27 control and 25 sorafenib patients +HCT ECOG missing in 2 sorafenib patients Figure 1. Disease-free and Overall Survival for FLT3-ITD AML patients, with or without sorafenib maintenance after HCT. Landmark analysis was performed from median date of sorafenib initiation (d+68). Figure 1. Disease-free and Overall Survival for FLT3-ITD AML patients, with or without sorafenib maintenance after HCT. Landmark analysis was performed from median date of sorafenib initiation (d+68). Figure 2. Figure 2. Disclosures Off Label Use: Sorafenib for FLT3-ITD AML. Fathi:Takeda Pharmaceuticals International Co.: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Exelexis: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone:Celator: Consultancy; Karyopharm: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; AROG: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Amgen: Consultancy; Roche/Genetech: Consultancy; Merck: Consultancy; Juno: Consultancy; Agios: Consultancy. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Chen:Bayer: Consultancy, Research Funding.

Download Full-text

Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood-2019-123887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1956-1956

Author(s):

Amy Wang ◽

Justin Kline ◽

Wendy Stock ◽

Satyajit Kosuri ◽

Andrew S. Artz ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Stem Cell ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Advisory Committees ◽

Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: 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, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

Download Full-text

Outcome of Autologous Stem Cell Transplantation in Waldenström's Macroglobulinemia

Blood ◽

10.1182/blood-2018-99-116496 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2149-2149

Author(s):

Romil Patel ◽

Neeraj Y Saini ◽

Ankur Varma ◽

Omar Hasan ◽

Qaiser Bashir ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Cell Transplantation ◽

Research Funding ◽

Advisory Committees ◽

First Remission ◽

Relapsed Disease

Abstract Introduction: The role of autologous hematopoietic stem cell transplantation (auto-HCT) in the management of patients with Waldenström Macroglobulinemia (WM), a rare, indolent lymphoma, has not been established. We had previously published our experience with auto-HCT in a small cohort of WM patients1. Here, we present an updated analysis of auto-HCT with a larger cohort of WM patients. Methods and study population: The study cohort was comprised of 29 patients who underwent high-dose chemotherapy and auto-HCT at MD Anderson Cancer Center (MDACC). The Kaplan-Meier method was used to create survival curves. Overall survival (OS) was defined as the duration from date of transplant to death or last date of follow-up in living patients. Progression-free survival (PFS) was defined as the duration from date of transplant to either progressive disease or death, whichever occurred first. Results: Median age at auto-HCT was 60 (range, 43-75 years). Eight patients (28%) had concurrent light chain amyloidosis (AL). Of the five patients who had MYD88 testing completed, 3 were positive for the MYD88 mutation. Additionally, of these 3 patients, 2 were also positive for CXCR4 mutation. Patients received a median of 2 lines (range 1-6) of therapy prior to auto-HCT; 3(10%) patients had primary refractory disease, 8(28%) were in first remission, and 18 (62%) had relapsed disease. Median time from transplant to last follow-up for the surviving patients was 5.3 years. Preparative regimens received by the patients were: Melphalan (n=20), BEAM-R (n=2), Busulfan/Melphalan (n=1), Cyclophosphomaide/Etoposide/total body irradiation (n=1), Thiotepa/Busulfan/Cyclophosphamide (n=1), and Carmustine/Thiotepa (n=1). Three patients further went on to receive allogeneic transplant either after relapse from auto-HCT or due to disease transformation to aggressive lymphoma. Twenty-eight patients achieved engraftment with a median time to neutrophil engraftment of 11 days (range, 10-15 days). One patient suffered primary graft failure due to progression of disease and died 84 days after transplant. Non-relapse mortality was 3.4% at 1 year. All patients were eligible for response evaluation. The median OS from diagnosis was 12.2 years. Overall response rate was 96%: complete response (n=8, 27.6%), very good partial response (n=5, 17.3%), partial response (n=15, 51.7%), and progressive disease (n=1, 3.4%). PFS and OS at 5 years were 43.3% and 62.9%, respectively. Median PFS and OS from auto-HCT were 4.1 and 7.3 years (Fig. 1A). The median OS from auto-HCT in first remission + primary refractory and relapsed disease was 8.2 years and 4.1 years, respectively.16 patients were alive at the time of censoring while 13 patients had died. Causes of death include relapsed disease (n=6), secondary malignancy (n=2), infection (n=1), chronic graft-versus-host disease (n=1), and unknown (n=3). 8 patients (28%) were positive for concurrent AL amyloidosis. The sites of amyloid involvement were kidneys (n=2), lungs (n=1), bone marrow (n=1), heart(n=1), lymph nodes(n=1), gastrointestinal tract (n=1) and subcutaneous fat aspirate(n=5). The median overall survival for patients with amyloid involvement (n=8) was 12 years. On univariate analyses, the number of chemotherapy regimens prior to transplant (≤ 2 vs >2 lines) was the strongest predictor of overall survival (p=0.03, HR 0.3, CI: 0.09-0.9, log-rank) and PFS (p=0.001, HR 0.24, CI: 0.07-0.85, log-rank). The median PFS in patients with ≤ 2 lines and > 2 lines of therapy was 71 months versus 19 months, respectively (Fig. 1B). Conclusion: Auto-HCT is safe and feasible in selected patients with WM, with a high response rate and durable remission even in patients with relapsed or refractory disease. References: Krina Patel et.al. Autologous Stem Cell Transplantation in Waldenstrom's Macroglobulinemia. Blood 2012 120:4533; Disclosures Thomas: Celgene: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Array Pharma: Research Funding; Amgen Inc: Research Funding. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Orlowski:Takeda: Consultancy; Celgene: Consultancy; Spectrum Pharma: Research Funding; Janssen: Consultancy; Kite Pharma: Consultancy; Sanofi-Aventis: Consultancy; BioTheryX: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Patel:Poseida Therapeutics, Inc.: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Celgene: Research Funding.

Download Full-text

Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-124541 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5468-5468

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Lin Gu ◽

Guan Xing ◽

Nishan Rajakumaraswamy ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Dose Reduction ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

Download Full-text