scholarly journals Treatment Utilization and Characteristics Among Patients with Higher-Risk Myelodysplastic Syndromes According to Hypomethylating Agent Use

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5030-5030
Author(s):  
Amer M. Zeidan ◽  
Victoria Divino ◽  
Mitch DeKoven ◽  
Drishti Shah ◽  
Elizabeth Wang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Supportive Care ◽  
Research Funding ◽  
Treatment Utilization ◽  
Leadership Position ◽  
Newly Diagnosed ◽  
Comorbidity Burden ◽  
The Us ◽  
Support Research

Abstract Introduction: Hypomethylating agents (HMAs) are standard of care treatment for patients with higher-risk myelodysplastic syndromes (HR-MDS) who are ineligible for stem-cell transplantation or intensive chemotherapy. Until recently, approved HMAs included intravenous or subcutaneous azacitidine and decitabine, which should be administered for a minimum of 4-6 cycles to elicit response in the absence of progression or unacceptable toxicity. In real-world clinical practice, underutilization of HMA therapy has been documented; however, prior estimates have utilized data preceding 2016. The study objectives were to understand recent treatment utilization and characteristics among patients newly diagnosed with HR-MDS in the United States (US). Methods: This retrospective observational study utilized the IQVIA PharMetrics ® Plus database which comprises adjudicated claims for more than 190 million unique patients across the US. Adult patients newly diagnosed with HR-MDS from July 1, 2016 through December 31, 2019 were included. Patients had ≥1 inpatient claim or ≥2 outpatient claims >60 days apart with diagnosis codes for high grade MDS lesions and/or refractory anemia with excess blasts (RAEB), and continuous enrollment for 6 months prior to and ≥180 days following the index date (index date = first diagnosis claim). Patients had a variable follow-up period up to 1 year post-index, and were followed through June 30, 2020. Patient characteristics at baseline, and treatment utilization based on observed MDS-related therapy (HMAs and supportive care), over the variable follow-up period were evaluated. Results: A total of 371 patients were included; the mean age of patients at baseline was 69.2 years and 57.7% were male. Of these, 61 (16.4%) patients received no HMA and no supportive care over the variable follow-up period following diagnosis. Half (n=182, 49.1%) received no HMA but received supportive care, and the remainder (n=128, 34.5%) received HMA therapy over the variable follow-up period; 45 (12.1%) received decitabine as the first HMA in a mean of 89.2 days from diagnosis, and 83 (22.4%) received azacitidine as the first HMA in a mean of 51.1 days from diagnosis (Table). Patients receiving no HMA therapy but with supportive care were older (mean age 70.6 years; 45.6% aged ≥75 years) and had higher comorbidity burden (mean Charlson Comorbidity Index [CCI] 2.5) than the other cohorts (mean age 66.6-68.8 years; 24.4-37.7% aged ≥75 years; CCI 1.2-2.0). For example, a higher proportion of patients receiving no HMA therapy but with supportive care had baseline renal disease (21.4%) compared to the other cohorts (4.9-15.6%). Patients receiving no HMA or supportive care in this study had a similar mean age compared to those who received HMAs (68.8 vs 66.6-68.0 years), but tended to have lower comorbidity burden (CCI 1.2 vs 1.9-2.0). Conclusions: In this real-world study using contemporary data, utilization of HMA therapy among patients with HR-MDS in the US was low, with only around one-third of patients receiving HMAs. Patients who did not receive HMAs but received supportive care tended to be older and have higher comorbidity burden than those who received HMAs, suggesting potential barriers for physicians in prescribing HMAs to older, frailer patients. Figure 1 Figure 1. Disclosures Zeidan: Pfizer: Other: Travel support, Research Funding; Jazz: Consultancy; Jasper: Consultancy; AstraZeneca: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Genentech: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Consultancy; Geron: Other: Clinical Trial Committees; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; BeyondSpring: Consultancy; Astex: Research Funding; Astellas: Consultancy; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Agios: Consultancy; ADC Therapeutics: Research Funding; Acceleron: Consultancy, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Divino: IQVIA: Current Employment, Other: IQVIA received funding for this study from Epstein Health in connection with this study. DeKoven: IQVIA: Current Employment, Other: IQVIA received funding for this study from Epstein Health in connection with this study. Shah: IQVIA: Current Employment, Other: IQVIA received funding for this study from Epstein Health in connection with this study. Wang: IQVIA: Current Employment, Other: IQVIA received funding for this study from Epstein Health in connection with this study. Bey: Taiho Oncology: Current Employment. Salimi: Taiho Oncology: Current Employment. Epstein: Epstein Health: Current Employment; Fate Therapeutics: Other: Holds leadership position; Veracyte: Other: Holds leadership position; Illumina: Other: Holds leadership position; Merck: Consultancy; Radius Health: Consultancy; Halozyme: Consultancy; Intra-Cellular Therapies: Consultancy; Taiho Oncology: Consultancy; Otsuka: Consultancy.

Mortality and Morbidities During Long-Term Follow-up After Recovery From Thrombotic Thrombocytopenic Purpura (TTP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 362-362 ◽  
Author(s):  
Jessica A. Reese ◽  
Zayd L. Al-Nouri ◽  
Cassandra C. Deford ◽  
Lauren M. Stewart ◽  
Deirdra R. Terrell ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Trial ◽  
Relative Frequency ◽  
Research Funding ◽  
Population Data ◽  
Term Survival ◽  
The Us ◽  
Initial Episode

Abstract Abstract 362 Introduction Since recovery from an acute episode of TTP is typically assumed to be complete, subsequent survival has been commonly assumed to be normal except for the risk of death with relapse. However we have observed unexpectedly high mortality among patients in the Oklahoma TTP-HUS Registry who had recovered from their initial episode of TTP. Therefore we documented long-term survival and compared the mortality of our patients to the US population data. To investigate possible risk factors for increased mortality, we documented the frequency of common risk factors for poor health outcomes: abnormal renal function, increased body mass index (BMI), hypertension (HTN) and diabetes (DM). Methods We included all 68 Oklahoma TTP-HUS Registry patients whose initial episode was associated with severe ADAMTS13 deficiency (<10%), 1995–2010. Health outcome measures for renal function were glomerular filtration rate (GFR) and urine albumin-creatinine ratio (ACR). BMI and HTN and DM preceding TTP were documented at the time of the initial episode. HTN, DM, GFR, and ACR were documented on patients who survived their initial episode at the time of their last follow-up. HTN and DM were documented by the use of regularly prescribed medication. GFR was estimated by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. ACR was quantified on a random urine sample. Population data were obtained from the National Health and Nutrition Examination Survey (NHANES); we calculated expected proportions based on the age, race, and gender composition of our patient group. We used survival data analysis to compare the mortality of the patients to the U.S. population; we used one way chi-square to compare the relative frequency of BMI, GFR, ACR, HTN and DM of the patients to the expected proportions from the US population. Results Fifty-five of the 68 consecutive patients survived their initial episode of TTP. At the time of their initial episode, the median age of the 55 patients was 39 years (range 9–71); 44 (80%) were women; 20 (36%) were black. Median follow-up to August 1, 2012 was 9.5 years (range, 2.3–16.7 years). At the time of their initial episode, BMI was significantly greater than the US population (p<0.001); in 15 (27%) of the 55 patients, BMI was >40 kg/m2, indicating morbid obesity. Although the relative frequency of hypertension (16%) and diabetes (9%) was not different from the US population preceding the initial episode of TTP, the relative frequencies were significantly greater than the US population at the time of their last follow-up (hypertension, 47%, p<0.001; diabetes, 22%, p=0.003). The GFR (measured in all 55 patients) and ACR (measured in 37 patients) were not different from the US population (p=0.374 and p=0.053). Nineteen (35%) patients have had 1–4 subsequent episodes of TTP. Eleven (20%) of the 55 patients have died (median age at death, 51 years; range, 41–82), a mortality proportion significantly greater than the age/race/gender matched U.S. population (Table). Two of the 11 patients died during their first relapse. Although relapsed TTP was not an apparent cause of death in the remaining 9 patients, 2 deaths were sudden and unexpected; 7 followed prolonged illnesses: congestive heart failure/myocardial infarction (3), sepsis (2), respiratory failure, ovarian cancer. Conclusion Long-term survival after recovery from an acute episode of TTP is significantly less than the age/race/gender-matched US population. Although relapse contributes to increased mortality, the significantly increased relative frequency of hypertension and diabetes are important and previously unrecognized risk factors for poor health outcomes in TTP survivors. Disclosures: Terrell: Baxter, Inc.: Consultancy; Amgen, Inc.: Consultancy. Kremer Hovinga:Baxter Healthcare: Consultancy, Research Funding. George:Alexion, Inc.: Consultancy; Baxter, Inc.: Consultancy; Amgen, Inc.: Consultancy, PI for clinical trial involving romiplostim, PI for clinical trial involving romiplostim Other, Research Funding.

scholarly journals Survival of Mantle Cell Lymphoma in the Era of Bruton Tyrosine Kinase Inhibitors: A Population-Based Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 182-182
Author(s):  
Mengyang Di ◽  
Can Cui ◽  
Shalin K. Kothari ◽  
Amer M. Zeidan ◽  
Nikolai Podoltsev ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Research Funding ◽  
Age Groups ◽  
Population Based ◽  
Sensitivity Analyses ◽  
Mantle Cell ◽  
All Cause Mortality ◽  
Bruton Tyrosine Kinase ◽  
Support Research

Abstract Background: Despite advances in chemoimmunotherapy and stem cell transplantation, mantle cell lymphoma (MCL) has historically been difficult to treat. Patients with advanced age and high-risk features (e.g. blastoid/pleomorphic features, high MIPI score, complex karyotype, TP53 mutation) face particularly poor outcomes with standard chemoimmunotherapy. Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), was approved for second-line use in MCL in 2013. Other BTKis - acalabrutinib and zanubrutinib were approved in 2017 and 2019, respectively. BTKi provides a well-tolerated chemotherapy-free option for these hard-to-treat subgroups, especially the older patients. In this population-based study, we evaluated survival outcomes prior to and after the approval of ibrutinib, and hypothesized that survival benefit observed early after approval would be greatest in older patients not typically candidates for consolidative transplantation in the first-line setting. Methods: Using the Surveillance, Epidemiology, and End Results database, we included all adult patients diagnosed with MCL in the years 2007-2018 and followed them to the end of 2018 or death, whichever came first. The pre-BTKi era was defined by year of diagnosis 2007-2011, and the BTKi era was between 2014 and 2018. The years 2012-2013 were considered as a "washout" period to allow practice change related to the approval of ibrutinib. As age plays an important role in treatment decisions, including whether to use consolidative transplantation, patients were divided based on age at diagnosis: &lt;60, 60-69, 70-79, and ≥80 years. Outcomes of interest included all-cause mortality, and mortality from MCL (MFM). We applied multivariable Cox proportional hazards regression model for all-cause mortality, adjusting for age, sex, race, stage, and median household income at census level, and reported adjusted hazard ratio (HR) with 95% confidence interval (CI). We also conducted multivariable competing risk analyses for MFM, considering all other causes of death as the competing events, and reported subhazard ratio (sHR) with 95% CI. To eliminate potential confounding by duration of follow-up among patients diagnosed in different periods, we used only three-year follow-up data for primary analyses, and all available follow-up data for sensitivity analyses. Results: We identified 7,625 individuals diagnosed with MCL during our study period (3,424 and 4,201 diagnosed during 2007-2011 and 2014-2018, respectively). The majority were male (71%) and white (90%), with 49% of patients 70 years or older. The median follow-up was 9.2 and 2.4 years for patients diagnosed during 2007-2011 and 2014-2018, respectively. The 3-year all-cause mortality and 3-year MFM rates were 39.8% and 27.3%, respectively, in the overall population. Both the 3-year all-cause mortality and MFM increased as age increased. The 3-year all-cause mortality was lower in the BTKi era among all age groups, except patients &lt;60 years old, and the 3-year MFM was lower in the BTKi era among all age groups. The numeric difference of 3-year outcomes was more substantial in patients aged 70-79 for both all-cause mortality (pre-BTKi era: 47.8%, BTKi era: 40.4%) and MFM (pre-BTKi era: 33.9%, BTKi era: 27.5%) (Table, Figure A and B). In the multivariable analyses, risk of death was significantly lower during the BTKi era in the 60-69 (HR:0.85, 95% CI: 0.72-1.00) and 70-79 (HR: 0.80, 95% CI: 0.70-0.92) age groups. MFM was also significantly lower during the BTKi era in these two age groups (60-69: sHR: 0.78, 95% CI: 0.64-0.94; 70-79: sHR: 0.76, 95% CI: 0.65-0.90, Table). The results were largely unchanged in sensitivity analyses (results not shown). Conclusion: In this large population-based cohort analysis of individuals diagnosed with MCL, overall and lymphoma-specific survival improved in the BTKi era. At a median follow up of 2.4 years in our BTKi cohort, significant survival benefits were observed in those older than 60 but less than 80 years of age, and the observed benefits were greatest in the 70-79 age group. Future real-world studies should examine the impact of novel agents on treatment patterns and outcomes of MCL over a longer follow up period. Figure 1 Figure 1. Disclosures Kothari: Incyte pharmaceuticals: Consultancy, Honoraria; Karyopharm pharmaceuticals: Consultancy, Honoraria. Zeidan: Amgen: Consultancy, Research Funding; Astellas: Consultancy; Jasper: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; BeyondSpring: Consultancy; Acceleron: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Astex: Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy; Agios: Consultancy; ADC Therapeutics: Research Funding; Jazz: Consultancy; Genentech: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Geron: Other: Clinical Trial Committees; Pfizer: Other: Travel support, Research Funding; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding. Podoltsev: PharmaEssentia: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Bristol-Myers Squib: Honoraria; CTI BioPharma: Honoraria; Celgene: Honoraria; Blueprint Medicines: Honoraria; Pfizer: Honoraria. Neparidze: Janssen: Research Funding; Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding. Huntington: AbbVie: Consultancy; TG Therapeutics: Research Funding; SeaGen: Consultancy; DTRM Biopharm: Research Funding; Flatiron Health Inc.: Consultancy; Novartis: Consultancy; Bayer: Honoraria; Pharmacyclics: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Genentech: Consultancy; Servier: Consultancy; Thyme Inc: Consultancy; Celgene: Consultancy, Research Funding.

scholarly journals Treatment Patterns, Adverse Events, and Economic Burden in a Privately Insured Population of Newly Diagnosed Patients with Chronic Lymphocytic Leukemia in the United States

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3557-3557 ◽  
Author(s):  
Shaum Kabadi ◽  
Ravi K Goyal ◽  
Saurabh P Nagar ◽  
James A Kaye ◽  
Keith L Davis ◽  
...  
Keyword(s):  
Health Care ◽  
Adverse Events ◽  
Systemic Therapy ◽  
Research Funding ◽  
The United States ◽  
Treatment Patterns ◽  
Newly Diagnosed ◽  
The Us ◽  
Privately Insured

Abstract Introduction: Contemporary data describing treatment patterns, adverse events (AEs) and outcomes in CLL patients in clinical practice is lacking. We conducted a retrospective cohort study and assessed treatment patterns, AEs, health care resource use (HCRU), and costs in patients with newly diagnosed CLL. Methods: Using a nationally representative population of privately insured patients in the US, adult patients with CLL were selected if they had continuous health plan enrollment for ≥12 months before the first CLL diagnosis without any evidence of any CLL-directed treatment. Treatment patterns up to 4 lines of therapy (LOT) and occurrence of AEs during CLL therapies were assessed. Mean per-patient monthly HCRU and costs were assessed overall and by number of unique AEs. Results: Of all patients meeting the selection criteria (n=7,639; median age, 66 years), 18% (n=1,379) received a systemic therapy during study follow-up. The most common systemic therapy regimens, regardless of therapy line, were bendamustine/rituximab (BR) (32%), rituximab monotherapy (24% [including maintenance]), ibrutinib monotherapy (15%), and fludarabine/cyclophosphamide/ rituximab (FCR) (14%). Of these, BR was the most common LOT-1 regimen (28.1%), while ibrutinib was the most common regimen in LOT-2 (20.8%) and in LOT-3 (25.5%). Use of idelalisib was limited to 1.6% of all patients receiving systemic therapy; however, an increasing trend was observed as patients moved from first to fourth LOT (<1% in LOT-1, 3.1% in LOT-2, 4.7% in LOT-3, and 8.6% in LOT-4). AEs identified during the most common treatments for CLL are presented by treatment regimen in Table 1. The mean monthly all-cause and CLL-related costs, among patients treated with a systemic therapy, were $7,943 (SD=$15,757) and $5,185 (SD=$9,935), respectively. Figure 1 depicts mean monthly costs by care setting and number of AEs, among all patients. Mean (SD) monthly all-cause costs during the post-index date follow-up were $905 ($1,865) among those with no AEs, $1,655 ($5,364) among those with 1-2 AEs, $2,883 ($8,483) among those with 3-5 AEs, and $6,032 ($13,290) among those with ≥6 AEs. Conclusions: This population-based study yielded recent real-world evidence on treatment patterns, AEs, HCRU, and costs in patients enrolled in health plans in the US. Immunochemotherapy, particularly BR, remained the preferred frontline therapy for CLL, whereas ibrutinib was the preferred therapy in LOT-2 and LOT-3, during the study period. This study demonstrates that the AE burden associated with current treatment alternatives for CLL is substantial, and the management of AEs occurring during treatments may have a significant impact on the overall health care costs. Disclosures Kabadi: AstraZeneca: Employment. Goyal:RTI Health Solutions: Employment, Research Funding. Nagar:RTI Health Solutions: Employment, Research Funding. Kaye:RTI Health Solutions: Employment, Research Funding. Davis:RTI Health Solutions: Employment, Research Funding. Mato:Celgene: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Sunesis: Honoraria, Research Funding; TG Therapeutics: Research Funding; Janssen: Consultancy, Honoraria; Acerta: Research Funding; Prime Oncology: Speakers Bureau; Regeneron: Research Funding.

scholarly journals Pre-Transplant Monocytic Myeloid-Derived Suppressor Cell Frequency Has No Prognostic Role for Outcome after Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in Remission

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5255-5255
Author(s):  
Colin Godwin ◽  
Jonathan R. Fromm ◽  
Brenda M. Sandmaier ◽  
Marco Mielcarek ◽  
Brent Wood ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Median Frequency ◽  
Prognostic Role ◽  
Support Research ◽  
Acute Myeloid

Abstract INTRODUCTION: Emerging data indicate myeloid-derived suppressor cells (MDSCs) adversely impact outcomes of patients with a variety of malignancies. However, it is less clear how MDSCs affect acute myeloid leukemia (AML) disease biology or the response of AML patients to treatment. Here, we studied a cohort of people with AML undergoing hematopoietic cell transplantation (HCT) in first complete remission (CR1) to examine the relationship between the monocytic subtype of MDSCs (M-MDSCs), pre-transplant measurable residual disease (MRD) status, and outcome after HCT. PATIENTS AND METHODS: Adults ≥18 years of age were included if they underwent first allogeneic HCT with myeloablative or nonmyeloablative conditioning for AML in CR1 from April 2006 until October 2014. Prospective MRD testing in bone marrow aspirates was performed routinely via 10-color multiparameter flow cytometry (MFC) as part of the pre-transplant work-up. Pre-transplant MFC data were used retrospectively to quantify M-MDSCs as the proportion of monocytes (identified by side scatter properties and CD14 positivity) with low or negative expression of HLA-DR. M-MDSC frequency was then expressed as a percentage of the total number of viable cells in the sample. Available combinations of antigens measured by MFC did not allow for the identification of other MDSC subsets (e.g. granulocytic MDSCs). RESULTS: We identified 349 adults undergoing allogeneic HCT for AML in CR1 for whom pre-transplant MRD testing was performed and for whom follow-up data were available. Of these, 8 had to be excluded because of insufficient MFC events available for identification of M-MDSCs. In the remaining 341 patients, M-MDSC frequency ranged from <0.001% to 6.53%, with a median of 0.18% (25th percentile: 0.06%; 75th percentile: 0.40%). Patients with lower (i.e. <median) frequency of M-MDSCs were less likely male (p=0.01) and more likely had recovered neutrophil and platelet counts (p=0.001) than patients with higher (i.e. ≥median) frequency of M-MDSCs. There was no difference with regard to all other examined characteristics (age, WBC and cytogenetic risk at diagnosis, type of AML, median CR duration before HCT, donor type, and conditioning intensity). The proportion of MRD positive ("MRDpos") patients was similar between those with lower vs. higher M-MDSC frequency (18.8 vs. 24.6%, p=0.20). Moreover, while MRD negative ("MRDneg") patients (n=267) differed statistically significantly from MRDpos patients (n=74) with regard to several characteristics such as more favorable disease risk and lower proportion of secondary AML, there was only a statistically non-significant trend toward lower M-MDSC frequency in MRDneg patients (0.16% [range <0.001-5.61%] vs. 0.22% [range <0.001-6.53%], p=0.09). The median follow-up time after HCT among all survivors was 5.8 (range, 2.0-11.4) years. The time was slightly longer for survivors with lower compared to those with higher M-MDSC frequency (6.1 [range 2.6-11.4] vs. 5.1 [range 2.0-11.3] years; p=0.0076). Stratified by the median M-MDSC frequency, the 3-year estimates of overall survival were similar for patients with lower and higher pre-HCT M-MDSCs (58.2% [95% confidence interval 50.4-65.2%] vs. 57.6% [49.8-64.7%]), as were 3-year estimates for relapse free survival (53.5% [45.7-60.7%] vs. 48.3% [40.6-55.6%]), 3-year estimates of the cumulative incidence of relapse (31.8% [24.9-38.8%] vs. 34.6% [27.6-41.8%]), and 3-year estimates of non-relapse mortality (14.7% [9.9-20.5%] vs. 17.0% [11.8-23.0%]). Analyses restricted to the subset of patients undergoing myeloablative (MA) conditioning or those undergoing MA conditioning in MRDneg remission showed qualitatively similar results. CONCLUSIONS: In the largest study to date examining the role of M-MDSCs in AML, we found no convincing evidence for a prognostic role of these cells for adults undergoing allografting in CR1. Disclosures Walter: Actinium Pharmaceuticals, Inc.: Other: Clinical trial support, Research Funding; Amgen Inc.: Other: Clinical trial support, Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership, Other: Clinical trial support, Research Funding; Aptevo Therapeutic: Consultancy, Other: Clinical trial support, Research Funding; Covagen AG: Consultancy, Other: Clinical trial support, Research Funding; Seattle Genetics, Inc.: Consultancy, Other: Clinical trial support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer: Consultancy.

scholarly journals 2nd cycle Remission Achievement with 7+3 Is Associated with Shorter Survival in Adults with Newly Diagnosed Acute Myeloid Leukemia: Analysis of Recent SWOG Trials

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3978-3978
Author(s):  
Megan Othus ◽  
Elihu H. Estey ◽  
Guillermo Garcia-Manero ◽  
Brent Wood ◽  
Derek Stirewalt ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Study Protocol ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Over Time ◽  
Support Research ◽  
Acute Myeloid

Abstract Background: Intensive chemotherapy will induce a complete morphologic remission (CR) in many adults with acute myeloid leukemia (AML). Whether it matters that a remission is obtained early, i.e. with the first cycle of chemotherapy, has remained controversial. Data from historic and contemporary trials with double induction chemotherapies showed patients who achieved a CR with the first induction cycle were less likely to relapse than those requiring 2 courses of therapy to enter CR. Contrasting these findings, an analysis of 6 ECOG (now ECOG-ACRIN) trials conducted between 1983 and 1993 indicated patients who achieved a CR after 1 or 2 cycles of induction chemotherapy had similar prognoses. The relationship between timing of remission achievement and outcome has not been examined in contemporary cohorts of people treated with 7+3 for AML. Here, we used data from adults participating in 5 SWOG trials between 1983 and 2015 and studied the association between prognosis and need for 7+3 reinduction therapy and how it has changed over time. Patients and Methods: We analyzed 1247 patients randomized to 7+3 arms on 5 SWOG studies and restricted to patients age 65 or younger: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), and S1203 (n=261). S8600 enrolled patients in the 1980s, S9031 and S9333 in the 1990s, S0106 in the 2000s, and S1203 in the 2010s. S9031 and S9333 were analyzed together. All 5 protocol gave 7+3 per contemporary standard, which changed over time: in S8600, S9031, and S9033, the cytarabine and daunorubin doses were 200mg/m2 and 45mg/m2, in S0106 100mg/m2 and 60mg/m2, and in S1203 100mg/m2 and 90mg/m2. CR was defined morphologically. Overall survival (OS) was measured from the date of study registration/randomization to date of death due to any cause; patients last known to be alive were censored at the date of last contact. Relapse-free survival (RFS) was measured from the date of CR to the first of relapse from CR or death due to any cause; patients last known to be alive in CR were censored at the date of last contact. OS and RFS were estimated using the Kaplan-Meier method. Multivariable Cox regression models included covariates (modeled quantitatively unless otherwise specified): age at study registration, gender, cytogenetic risk, pre-study white blood cell counts (WBC), pre-study platelets, pre-study marrow blasts, type of AML (secondary vs. de novo), indicator of receiving reinduction and study/protocol. We analyzed study/protocol separately and also grouped the studies by twenty-year period (S8600/S9031/S9333 representing 1980s and 1990s vs. S0106/S1203 representing 2000s and 2010s). Results: In multivariable analysis in the older studies, CR achievement only upon reinduction chemotherapy was not significantly associated with OS (hazard ratio (HR)=1.19 [95% confidence interval: 0.89-1.59], P=0.25) or RFS (HR=1.15 [0.86-1.54], P=0.34). These findings are similar to those reported by Rowe and colleagues on 1,980 adults with newly-diagnosed AML treated on 6 consecutive ECOG trials conducted in the 1980s and early 1990s. In contrast, in the contemporary studies we found receiving 2 cycles of induction chemotherapy before CR is documented was associated with worse OS (HR=1.82 [1.24-2.66], P=0.002) and RFS (HR=1.90 [1.34-2.70], P<0.001). Models evaluating the statistical interaction between the two time periods was significant (OS P=0.046; RFS P=0.016). One trial, S0106, had MRD data (n=70). Among patients with CR on the first cycle, having a negative MRD test (n=55) was associated with statistically significantly better OS (P=0.049) and a trend toward better RFS (P=0.098) compared to having a positive MRD test (n=15). Conclusion: These findings indicate adults with newly-diagnosed AML treated on more recent cooperative group trials who achieve remissions early, i.e. with the first cycle of 7+3 chemotherapy, have better survival outlooks than those who need 2 cycles of chemotherapy to enter a CR, even after adjustment for other risk factors. Need for a second cycle of induction therapy may therefore serve as a post-treatment prognostic factor to refine risk-stratification of adults with AML undergoing curative-intent therapy. Support: NIH/NCI grants CA180888 and CA180819 Acknowledgment: The authors wish to gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106. Figure. Figure. Disclosures Walter: Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer, Inc: Consultancy; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding.

scholarly journals Evaluation of International Working Group 2006 Response Criteria in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agent Monotherapy in the Frontline Setting

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3701-3701
Author(s):  
Jan Philipp Bewersdorf ◽  
Wei Wei ◽  
Anna Jaiani ◽  
Prital Patel ◽  
Rajni Mehta ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Clinical Trials ◽  
Myelodysplastic Syndromes ◽  
Working Group ◽  
Research Funding ◽  
Response Criteria ◽  
The Impact ◽  
Support Research

Abstract Introduction: Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients (pts) with myelodysplastic syndromes (MDS). Response in MDS is based on the modified International Working Group (IWG) 2006 criteria. Prior studies focusing on unselected MDS pts showed that achieving a complete remission (CR) was associated with favorable overall survival (OS). However, the association of other outcomes with OS was less clear and only 20% of HMA-treated MDS pts achieve a CR. For example, pts who achieved &lt;5% bone marrow (BM) blasts are currently classified as marrow CR (mCR), which has not been associated with OS improvement. Therefore, interpreting the significance of mCR reported in various clinical trials is challenging. Clinically meaningful reduction in bleeding or infectious complications can occur at improvements in absolute neutrophil count (ANC) and platelet counts that do not meet the current thresholds used for CR (ANC ≥1.0 × 10 9/L, platelets ≥100 × 10 9/L, and Hb &gt;11 g/dL). To avoid missing clinically meaningful benefits when studying new drugs in clinical trials, a clearly defined response criterion that is less stringent than CR but still captures clinically meaningful hematologic improvement (HI) is needed. Here we sought to evaluate the impact of current IWG 2006 response criteria as well as CRh on OS of pts with HR-MDS treated with frontline HMA monotherapy. Methods: We included all adult (≥18 years) MDS pts treated with frontline HMA (azacitidine [AZA], decitabine [DEC], or ASTX727) monotherapy between 1/1/2012 and 12/31/2020 at Yale University. We decided to use HMA monotherapy as it is the standard care for HR-MDS and to minimize the impact of therapy choice confounding the association of achieved response with OS. Pts were excluded if they received prior treatments for MDS aside from erythropoiesis-stimulating agents and if no baseline with at least one follow-up BM study were available for response assessment. We collected patient and disease characteristics (transfusion burden, IPSS/IPSS-R score, cytogenetics, molecular studies) at baseline. Best responses were assessed based on IWG 2006 criteria for MDS. We defined CRh as &lt;5% BM blasts, platelets ≥50 × 10 9/L, ANC ≥0.5 × 10 9/L and no peripheral blood blasts. We followed pts until death or last follow-up and recorded dates of allogeneic hematopoietic cell transplant (HCT) if applicable. Date of data cut-off for survival status was 5/31/2021. We performed Kaplan-Meier analysis to estimate the duration of overall survival and we used log rank test to test the difference in OS between subgroups of pts. Multiple comparisons were adjusted using the Bonferroni method. Results: A total of 100 pts was included in this analysis (Table 1). Median age was 68 years (yrs; range, 23 - 86), 60% were males, and 79% and 18% of pts received AZA and DEC, respectively. Median number of HMA cycles was 6 (interquartile range [IQR]: 4-10), and 33 pts (33%) underwent HCT. During follow-up, 46 pts (48%) progressed to AML. At a median follow-up of 1.5 yrs (IQR: 0.9 - 2.3 yrs), median OS for the entire pt cohort was 1.9 yrs (Figure 1). OS by response category is shown in Table 2. Median OS was not reached for patients who achieved a CR (95% CI: not reached [NR] - NR) as compared to 1.9 yrs (95% CI: 1.5 yrs - NR) and 2.0 yrs (95% CI: 1.2 yrs - NR) among pts with mCR + HI and mCR without HI, respectively. Median OS among patients with stable disease (SD) was similar (2.0 yrs [95% CI: 1.5 yrs - NR]). Finally, we explored the prognostic value of CRh and found a median OS of 1.9 yrs (95% CI: 1.5 yrs - NR), which appeared comparable to mCR +/- HI or SD. Similar results were found with censoring at time of HCT (Figure 2). Discussion: In this retrospective analysis of MDS pts treated with HMA monotherapy in the frontline setting, achieving CR as best response was associated with improved OS compared with mCR +/- HI and SD. However, as the numbers were small these results should be interpreted with caution, and other clinically relevant outcomes such as freedom of transfusion, infectious or bleeding complications, and patient-reported outcomes were not captured in the current analysis. Our results also apply only to MDS pts treated with HMA monotherapy in the frontline setting. The prognostic implications of CRh need to be evaluated in larger patient cohorts. To overcome these limitations, we are currently in the process of expanding the study to a much larger multi-center, international analysis. Figure 1 Figure 1. Disclosures Neparidze: Eidos Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Janssen: Research Funding. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Podoltsev: PharmaEssentia: Honoraria; Pfizer: Honoraria; CTI BioPharma: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Bristol-Myers Squib: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Brunner: GSK: Research Funding; Aprea: Research Funding; Keros Therapeutics: Consultancy; Agios: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Acceleron: Consultancy; Takeda: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Janssen: Research Funding. Zeidan: AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding; Gilead: Consultancy, Other: Clinical Trial Committees; Epizyme: Consultancy; Amgen: Consultancy, Research Funding; BioCryst: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Acceleron: Consultancy, Research Funding; Agios: Consultancy; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Jasper: Consultancy; ADC Therapeutics: Research Funding; Jazz: Consultancy; Astex: Research Funding; Daiichi Sankyo: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Geron: Other: Clinical Trial Committees; AstraZeneca: Consultancy; Pfizer: Other: Travel support, Research Funding; BeyondSpring: Consultancy; Ionis: Consultancy; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Janssen: Consultancy; Astellas: Consultancy.

scholarly journals Treatment Patterns Among Newly Diagnosed Multiple Myeloma Patients in the United States Veteran Population (2010-2015)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5952-5952
Author(s):  
Kejal Parikh ◽  
Shivani Pandya ◽  
Safiya Abouzaid ◽  
Onur Baser ◽  
Lin Xie ◽  
...  
Keyword(s):  
Research Funding ◽  
Cox Regression ◽  
Treatment Patterns ◽  
Novel Therapies ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Chemotherapy Agent ◽  
The Us ◽  
Equity Ownership

Abstract Background: Despite a relatively higher incidence in the veteran population, there are few real-world claims-based analyses to describe Multiple Myeloma (MM) treatment patterns among this patient population (Landgren O, Blood, 2006). This study aimed to assess treatment patterns among newly diagnosed MM (ndMM) patients using the US Veteran Health Administration (VHA) data. Methods: This retrospective study identified adult patients with ≥2 claims for MM (ICD-9-CM code: 203.0x) 30 days apart and ≥1 treatment during identification period (1OCT2011-31MAR2015) from the VHA dataset. The initial course of therapy (COT1) date was the index date and included all treatments prescribed within 60 days of this date. Patients were required to have continuous enrollment for 12 months pre- and ≥6 months post-index date unless patients died within 6 months (follow up period), ≥1 full cycle of therapy with a valid COT1 regimen, no evidence of prior MM diagnosis or treatment (including autologous stem cell transplant (ASCT)), and no evidence of ASCT in the follow up period. A subsequent COT (COT2) was defined as the earliest occurrence of: the addition of a new drug or switch in regimen after the first 60 days, restart of a previous regimen after >180-day gap, or a dose increase from maintenance to relapse therapy. Dexamethasone/prednisone[d] which were assumed to be included regardless of whether or not they were observed during the study period did not impact the ongoing COT. Treatment patterns during the follow-up period were initially examined among patients treated with novel (lenalidomide [R] and/or bortezomib [V] with or without chemotherapy agents) and non-novel therapies (≥1 chemotherapy agent, steroid monotherapy) and then compared among those initiating Rd and Vd. Time to next treatment (TTNT) was defined as the duration from initiation of COT1 plus any gaps before COT2. Kaplan Meier and Cox regression analyses were performed to evaluate TTNT and assess the impact of various predictors on TTNT among patients initiating Rd and Vd. Results: Of 1,183 patients that met the inclusion criteria, 55.4% (n=655) were treated with novel therapies and 44.6% (n=528) with non-novel therapies. Among patients treated with novel therapy, the majority initiated Rd (47.8%; n=313) as COT1 followed by Vd (31.2%; n=204), Vd with cyclophosphamide (11.5%; n=75), RVd (6.6%; n=43), Vd with a chemotherapy agent (2.4%; n=16) and Rd with a chemotherapy agent (0.6%; n=4).Rd initiators were significantly older (75.1 vs 70.6 years, p=0.0002) and a higher percentage was white (69.7% vs 47.0%; p<0.0001) than Vd treated patients. While the Charlson Comorbidities Index score did not differ between the two groups (3.6 vs 4.0, p=0.0583), a significantly higher percentage of patients treated with Vd had some comorbidities including hepatitis and renal disease. Among patients with laboratory tests, patients treated initially with Vd had lower hemoglobin (10.8 vs 11.4 g/dl, p=0.0012) and higher serum creatinine (2.3 vs 1.4 mg/dl, p<0.0001) during the pre-index period. The overall average treatment duration in COT1 was significantly longer among patients treated with Rd vs Vd (10.9 vs 7.0 months, p<0.0001). Among patients who were still on active COT1, the mean duration in COT1 was longer among patients treated with Rd than Vd (18.7 vs 13.3 months, p=0.0061). A significantly higher percentage of patients treated with Vd progressed to COT2 (52.5%, vs 26.2% p<0.0001) as compared to Rd. Among patients who progressed to COT2, those treated with Vd had a shorter TTNT compared to Rd (Mean: 9.3 vs 12.8 months, p=0.0049). After adjusting for baseline demographic and clinical factors using Cox regression, TTNT remained significantly shorter for Vd vs those treated with Rd (HR: 2.67, 95% CI: 1.9-3.7, p <0.0001). Conclusion: Slightly over half of MM patients in the US Veteran population were treated with a regimen containing novel therapies; Rd and Vd were the most commonly observed among these. Patients treated initially with Vd had a significantly shorter TTNT compared to those treated with Rd. The difference remained significant after controlling for baseline characteristics including markers for higher disease severity among patients on Vd. Disclosures Parikh: Celgene Corporation: Employment, Equity Ownership, Research Funding. Pandya:Celgene: Research Funding. Abouzaid:Celgene Corporation: Employment, Equity Ownership, Research Funding. Baser:Celgene: Research Funding. Xie:Celgene: Research Funding. Patel:Celgene: Consultancy.

scholarly journals Bortezomib Induction and Maintenance in Patients with Newly Diagnosed Multiple Myeloma: Long-Term Follow-up of the HOVON-65/GMMG-HD4 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 27-27 ◽  
Author(s):  
Pieter Sonneveld ◽  
Hans-Juergen Salwender ◽  
Bronno Van Der Holt ◽  
Laila el Jarari ◽  
Uta Bertsch ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Negative Impact ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Long Term Follow Up ◽  
Support Research

Abstract Background: We reported better PFS and OS in transplant eligible patients with newly diagnosed Multiple Myeloma (MM) who were treated with bortezomib during induction and maintenance, when compared with standard treatment in the HOVON-65/GMMG-HD4 trial. (P. Sonneveld et al., J Clin Oncol 30:2946-2955, 2012). Here the long-term follow up data are presented. Methods: 827 eligible patients were randomized to induction therapy with VAD (vincristine, doxorubicin, dexamethasone) or PAD (bortezomib, doxorubicin, dexamethasone) followed by high-dose melphalan (once or twice) and autologous stem cell transplant. Maintenance consisted of daily thalidomide (T) 50 mg (VAD arm) or 2-weekly bortezomib (B) 1.3 mg/m2 (PAD arm) for 2 years. The primary endpoint was progression-free survival (PFS) adjusted for ISS stage. Results: After a median follow up of 91.4 months (maximum 119) 410 patients are alive. Response rates were VAD/HDM/T: CR 25%, ≥VGPR 56%, ≥PR 83%; PAD/HDM/B: CR 37%, ≥VGPR 76%%, ≥PR 91%, The median duration of maintenance therapy was 14 months (thalidomide) and 23 months (bortezomib), respectively. Main reasons for discontinuation were toxicity (T: 31%; B: 11%), disease progression (T: 33%; B: 36%) or normal completion (T: 28%; B: 48%). Of 827 patients in the analysis, 206 are alive without progression/relapse. PFS was significantly better in the bortezomib arm, i.e. median 34 versus 28 months (HR=0.77, 95% CI=0.65-0.90, p=0.001). Median overall survival (OS) was 90 months in the bortezomib arm vs 83 months in the control arm, but 42% at 9 years in both arms. We used the restricted mean survival time (RMST) method to compare OS between the two treatment arms In univariate analysis. The difference in RMST8y was 4.8 months (95% CI 0.2-9.5, p=0.04) in favor of the bortezomib arm. A landmark analysis in patients who had received HDM starting at 12 months showed a significant PFS advantage of bortezomib in all patients (p=0.02), in patients in VGPR/PR (p=0.02) but not in CR (p=0.19). For OS there was no advantage for bortezomib in either group. PFS at 60 months in bortezomib treated patients was not different when single vs double HDM/ASCT was administered, i.e. 28% vs 27%. However, OS at 60 months was 71% vs 60% in favor of double HDM/ASCT (p=0.04). Subgroup analysis was performed based on presence/absence of adverse FISH (CA) in 395 patients treated with double HDM/ASCT. PFS at 60 months for each abnormality (CA or no CA) in bortezomib vs standard arm is given in Table 1 Table 1.PFS at 60 months, %OS at 60 months, %FISHnBortezomib armpStandard armBortezomib armpStandard Armt(4;14) yes/no50/29516% vs 27%0.048% vs 24%52% vs 75%0.0133% vs 64%add(1q) yes/no113/23116% vs 32%0.00510% vs 28%57% vs 79%0.00143% vs 70%del(17p) yes/no39/31222% vs 27%0.475% vs 24%65% vs 72%0.4818% vs 66% These data show that bortezomib treatment combined with double HDM/ASCT significantly improves PFS and OS in patients with del(17p) and almost abrogates the negative impact of this CA. In t(4;14) and add(1q) some improvement is observed, however the negative impact remains significant. In high-risk patients presenting with elevated creatinine >2 mg/dL bortezomib significantly improved PFS at 60 months (32% vs 5%) (p=0.001) and OS at 60 months (66% vs 21% months (p<0.001)). OS at 8 years was 46% vs 12%. Finally, OS from progression/relapse was not different between patients treated in the bortezomib vs standard arm (OS at 72 months: 33% vs 35%, p=0.73) Conclusions: We conclude that bortezomib leads to a significant and lasting improvement of PFS and OS. Bortezomib significantly reduces the high-risk impact of del(17p) and renal impairment on survival. This trial was registered as NTR213; EudraCT no. 2004-000944-26.and supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and an unrestricted grant from Janssen. The GMMG group received grants for this trial by Novartis, AMGEN, Chugai and Roche. Disclosures Sonneveld: SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Blau:MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria; Janssen: Honoraria, Research Funding. Zweegman:celgene: Honoraria, Research Funding; takeda millennium: Honoraria, Research Funding; onyx: Honoraria. Weisel:Noxxon: Consultancy; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support; BMS: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding. Broijl:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Scheid:Janssen: Honoraria; Celgene: Honoraria. Potamianou:Janssen: Employment. Hose:Takeda: Other: Travel grant; EngMab AG: Research Funding. Kersten:takeda millennium: Research Funding; janssen: Honoraria, Research Funding; roche: Honoraria, Research Funding. Duehrsen:Alexion: Honoraria; janssen: Honoraria. Lokhorst:Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Amgen: Honoraria. Goldschmidt:celgene: Honoraria, Research Funding; janssen: Honoraria, Research Funding; novartis: Honoraria, Research Funding; chugai: Honoraria, Research Funding; onyx: Honoraria, Research Funding; millennium: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

scholarly journals Addition of Crenolanib to Induction Chemotherapy Overcomes the Poor Prognostic Impact of Co- Occurring Driver Mutations in Patients with Newly Diagnosed FLT3-Mutated AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1436-1436 ◽  
Author(s):  
Aaron D Goldberg ◽  
Robert H. Collins ◽  
Richard M. Stone ◽  
Roland B. Walter ◽  
Chatchada Karanes ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Driver Mutations ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Support Research

Abstract Background: Patients with AML harboring FLT3 mutations have poor clinical outcomes. Furthermore, FLT3 mutations frequently co-occur with other driver mutations, such as NPM1 with DNMT3A, WT1, and RUNX1, that are associated with poor prognosis. Crenolanib is a highly potent and specific type-I FLT3 inhibitor, which has shown promising safety and efficacy in combination with chemotherapy. Here we report the outcomes of newly diagnosed FLT3 mutated AML patients treated with crenolanib and intensive 7 + 3 based chemotherapy (NCT02283177) by baseline genomic profile. Methods: Patients were treated on clinical trial with 7+3 induction chemotherapy combined with crenolanib, consolidation with high-dose cytarabine (HiDAC) combined with crenolanib, and/or allo-HCT followed by crenolanib maintenance. Of 44 pts enrolled and treated, 36 had sequencing performed at baseline. The median survival follow-up for these patients was 20.7 months with data cut off July 25, 2018. A post hoc analysis was performed to assess the impact of genomic profile on patient outcomes using published data from the German-Austrian AML Study Group as a historical control. Results: Concurrent FLT3-ITD, NPM1, and DNMT3A mutations ("triple mutant") were present in 10 pts. These patients demonstrated improved OS with crenolanib treatment compared with historical controls. Similarly, patients with FLT3-ITD and WT1 mutations (n = 6) showed dramatically improved outcomes, with no deaths occurring by 18 months. Patients with FLT3 (ITD or TKD) and RUNX1 mutations (n = 10) also had improved OS. Conclusions: This analysis suggests that adding a potent pan-FLT3 inhibitor can overcome the poor prognostic implication of adverse mutations co-occurring with mutated FLT3. These data support the combination of crenolanib with chemotherapy to improve the overall outcome of FLT3 mutated AML with diverse mutational profiles. Hence, a randomized trial has been initiated of standard chemotherapy combined with either crenolanib or midostaurin in newly diagnosed patients with FLT3-mutant AML (NCT03258931). Table. Table. Disclosures Goldberg: AROG: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Abbvie: Research Funding. Collins:Arog Pharmaceuticals: Research Funding; Celgene Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Agios: Research Funding. Stone:Ono: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Arog: Consultancy, Research Funding; Merck: Consultancy; Fujifilm: Consultancy; Jazz: Consultancy; Orsenix: Consultancy; Astellas: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; AbbVie: Consultancy; Amgen: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Cornerstone: Consultancy. Walter:Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer, Inc: Consultancy; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding. Wang:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Novartis: Speakers Bureau. Tallman:AROG: Research Funding; AbbVie: Research Funding; Orsenix: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding; BioSight: Other: Advisory board.

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