PTPN11 Mutations Are Associated with Poor Outcomes across Myeloid Malignancies

Background: Gain of function mutations of the PTPN11 gene encoding SHP2 tyrosine phosphtase are commonly seen in juvenile myelomonocytic leukemia and rarely observed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In AML, PTPN11 mutation (mt) is associated with poor outcomes (Alfayez et al. Leukemia 2020). However, PTPN11 is not well characterized in other myeloid malignancies. Patients and Methods: Between 2013 and 2019, all pts with myeloid malignancies and PTPN11 mt at Moffitt Cancer Center were identified with clinical variables obtained at time of diagnosis. Newly diagnosed and previously treated patients (pts) were included. Overall survival was calculated from time of PTPN11 detection by next generation sequencing. Results: We identified 78 PTPN11-mt pts, AML (56), MDS (14), MDS/MPN (4) and PMF (4). The majority (63%) of PTPN11-mt were detected at time of diagnosis. Median age was 68 years. Cytogenetics included normal (49%), complex (15%), chr. 7(19%) and chr. 5 (8%) abnormalities. Co-mutations observed in >10% were DNMT3A, NPM1, TET2, ASXL1, RUNX1, BCOR, FLT3 ITD, U2AF1, NRAS and SRSF2. In multivariate analysis including age, karyotype category and allogeneic hematopoietic stem cell transplant (AHSCT), U2AF1 was an independent covariate for inferior survival (HR 3.9 p=0.001). In newly diagnosed PTPN11-mt pts, PTPN11 VAF >20% was associated with worse outcomes (OS 8.9 vs 20.5mo p=0.043). AHSCT, which occurred 30% of pts, (n=23) was associated with improved OS (24.4 vs 5.5mo p<0.001). WWe then compared PTPN11-mt to wild type (wt) pts among each disease category. In PTPN11-mt AML (n=56 vs n=380 in wt AML), there was female predominance (54% vs 39% p=0.04), platelet count was higher (65 vs 45 p=0.02) and no PTPN11-mt had favorable cytogenetics (0 vs 9% p=0.02). NPM1, NRAS and SRSF2 were more prevalent in PTPN11-mt AML (p<0.05). There was no difference in ORR and CR rates between mt and wt patients when comparing induction chemotherapy or hypomethylating agent. Among PTPN11-mt AML pts 32% underwent AHSCT vs 26% in wt (p=0.34). PTPN11-mt AML pts who underwent AHSCT had an OS of 24.4 vs 42.7 mo. (p=0.025) whereas OS in pts that did not undergo AHSCT was 5.6 vs 10.1 mo. (p=0.04). In our cohort, AHSCT significantly improved outcomes for PTPN11-mt AML pts (OS 5.6 vs 24.4 p=0.001). Of the 13 pts that underwent AHSCT in PTPN11-mt AML, 92.3% (n=12) received induction chemotherapy. Finally, in multivariate analysis including age, ECOG, sAML, ELN and AHSCT, PTPN11 was an independent predictor of poor outcomes (HR 1.58 p=0.015). WNext, we evaluated pts with PTPN11-mt (n=14) vs wt (n=106) MDS. PTPN11-mt MDS pts had higher bone marrow blast % (9 vs 3 p=0.026) and more pts with MDS-EB1/2 by WHO (11/14 (79%) vs 49/105 (46%) p=.043). Interesting however, no PTPN11-mt MDS pts had complex karyotype and there was no difference in IPSS-R categories between groups. ASXL1, RUNX1 and SRSF2 were more frequently co-mutated in PTPN11-mt MDS (p<0.05) however no pts had monocyte % >10. In newly diagnosed cohort, there were no responses to frontline HMA (ORR 0/5 (0%) for mt vs 16/34(47%) wt p=0.066). Additionally, PTPN11-mt MDS had significantly worse outcomes (OS 8.7 vs 22.3 mo. p=0.001). In multivariate analysis include age, IPSS-R and AHSCT, the survival disadvantage was maintained (HR 2.9 p=0.018). WFinally, although rare, we evaluated pts with PTPN11-mt MDS/MPN and PMF. We first compared the 4 PTPN11-mt MDS/MPN (3 CMML, 1 MDS/MPN-U) pts to a cohort of 62 PTPN11-wt MDS/MPN (53 CMML). Clinical characteristics were similar between the two cohorts with the exception of increased blast % (10 vs 4) and lower baseline hemoglobin (7.6 vs 10.9) neither of which was significant. Median time to AML transformation was 1.7 mo. in PTPN11-mt. PTPN11-mt MDS/MPN had significantly worse outcomes compared to wild type (OS 2.2 vs 15.5 mo. p=0.001). We then compared 4 PTPN11-mt PMF pts with 49 wt. There were no clinical or mutational differences between cohorts. When evaluating newly diagnosed PMF, PTPN11-mt appeared to predict worse outcomes (OS 3.4 vs 12.3 p=.063) however this was not statistically significant due to sample size. Conclusions: The overall outcome of PTPN11-mt patients appear dismal across myeloid malignancies. In patients that are eligible, high intensity therapy followed by BMT resulted in the best outcome in PTPN11-mt AML. In conclusion, novel therapies are needed to target this high-risk subtype of myeloid malignancies. Figure Disclosures Padron: Kura: Research Funding; Incyte: Research Funding; BMS: Research Funding; Novartis: Honoraria. Kuykendall:Novartis: Research Funding; Incyte: Research Funding; BMS: Research Funding; Blueprint Medicines: Research Funding. Lancet:Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria. Sweet:Agios: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Stemline: Honoraria. Sallman:Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy; Celgene, Jazz Pharma: Research Funding. Komrokji:Novartis: Honoraria; Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Geron: Honoraria; Jazz: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Agios: Speakers Bureau.

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A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v128.22.1068.1068 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1068-1068 ◽

Cited By ~ 1

Author(s):

Anna B. Halpern ◽

Megan Othus ◽

Emily M Huebner ◽

Kaysey F. Orlowski ◽

Bart L. Scott ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Phase 1 ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

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A Phase I Study of Selinexor in Combination with Daunorubicin and Cytarabine in Patients with Newly Diagnosed Poor-Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.4040.4040 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4040-4040 ◽

Cited By ~ 3

Author(s):

Kendra L. Sweet ◽

Rami S. Komrokji ◽

Eric Padron ◽

Christopher L Cubitt ◽

Leyla Khavarian ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Febrile Neutropenia ◽

Phase I ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Poor Risk

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

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Physical and Psychological Impairments As Practical Frailty Markers in Elderly AML Fit for Intensive Chemotherapy; Interim Data of a Prospective Cohort Study

Blood ◽

10.1182/blood-2019-123584 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3831-3831

Author(s):

GI June MIN ◽

Byung Sik Cho ◽

Sung-Soo Park ◽

Silvia Park ◽

Young-Woo Jeon ◽

...

Keyword(s):

Cohort Study ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Prospective Cohort ◽

Research Funding ◽

Handgrip Strength ◽

Intensive Chemotherapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Elderly Aml

Background The comprehensive geriatric assessment (CGA) typically refers to a multidimensional assessment designed to evaluate an older person's functional ability, physical health, cognition, psychological health, nutritional status, and social support. There is a significant heterogeneity in terms of their underlying health and resilience to the burden of disease and treatments in elderly AML (eAML). To date, a few have evaluated the predictive value of CGA among newly diagnosed eAML. The purpose of this study is to investigate the potential clinical value of CGA as a screening test for frailty in eAML. We designed a comprehensive CGA battery with measures which previously validated, standardized, and widely used. This study is a single-center prospective observational cohort study focused on discriminating between those older patients who are fit for intensive therapies and those who are vulnerable and may experience excess toxicity. Patients and method This prospective cohort study is to investigate the predictive values of each domain of CGA to discriminate vulnerable patients in eAML fit for intensive chemotherapy. Between November 2016 and July 2019, we enrolled newly diagnosed eAML patients aged ≥60 years considered fit for intensive chemotherapy, who had adequate performances and organ functions. All the enrolled patients were administered various questionnaires for an initial CGA and functional evaluation divided into 3 categories; (1) Social and Nutritional support (OARS and MNA), (2) Psychological (MMSE-KC, SGDS-K, PHQ-9, NCCN distress thermometer, MADRS, and KNU-DESC), and (3) Physical function (ECOG, KIADL, SPPB, Handgrip strength, and PTA by professional ENT evaluation). Results Seventy-seven patients were enrolled, in whom the median age of 64 years (range, 60-74), 58.4% were males, and 93.5% and 77.9% of patients had on ECOG score of 0~1 and HCT-CI score of 0~2, respectively. All enrolled patients were treated with intensive chemotherapy, and 62.3% achieved the first complete remission. Three patients experienced early death within 60 days (3.9%). During induction chemotherapy, the median recovery period for neutrophil and platelet counts was 26 (range, 24-29) and 30 (range, 27-33) days, respectively. The median hospitalization days for induction chemotherapy were 32 days (range, 21-104), and infection and GI complications (NCI-CTC-AE based any grade 79.2% and 67.5% respectively) were the most common complications primarily affecting tolerance to the initial chemotherapy. The grade III to IV infection, GI complications, hepatopathy, and acute kidney injury developed in 67.5%, 42.9%, 37.7%, and 16.9% of patients, respectively. Physical impairments were significantly associated with a higher incidence of infection (intact vs. any impairments; 46.4% vs. 79.6%, p=0.003), of which handgrip strength was most accurate tool to predict infection risk (p =0.032), and a trend of more GI complications (intact vs. any impairments; 28.6% vs. 51.0%, p=0.056), resulting in prolonged hospitalization (intact vs. any impairments; 32.2±1.7 days vs. 37.5±2.1 days, p=0.088) for the period of induction chemotherapy. Psychological impairment (intact vs. any impairments; 30.9±1.3 days vs. 38.2±2.1 days, p=0.005), particularly cognitive dysfunction measured by MMSE-KC (p=0.033), was also significantly associated with prolonged hospitalization. Conclusions This data demonstrates that a significant proportion of eAML fit for intensive chemotherapy based on performance status and comorbidity had social, nutritional, physical, psychological impairments by initial CGA assessments. These interim data focusing on early events suggest that impaired physical and/or psychological functions would be useful to identify eAML with intolerance to intensive chemotherapy. This ongoing exploratory prospective study will enroll more eAML patients (targets number=100) and further follow up currently enrolled patients, which will give us invaluable data to develop practical frailty marker and a new model for fitness for intensive chemotherapy. Disclosures Kim: Takeda: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding. Lee:Achillion: Research Funding; Alexion: Consultancy, Honoraria, Research Funding. Kim:Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Hanmi: Consultancy, Honoraria; AGP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SL VaxiGen: Consultancy, Honoraria; Novartis: Consultancy; Amgen: Honoraria; Chugai: Honoraria; Yuhan: Honoraria; Sanofi-Genzyme: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Handok: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria; BL & H: Research Funding.

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NPM1 Variant Allele Frequency and Outcomes in AML

Blood ◽

10.1182/blood-2018-99-112549 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1486-1486 ◽

Cited By ~ 3

Author(s):

Maja Rothenberg-Thurley ◽

Tobias Herold ◽

Dennis Görlich ◽

Cristina Sauerland ◽

Hanna Janke ◽

...

Keyword(s):

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Type A ◽

Genetic Alterations ◽

Type B ◽

Wild Type ◽

Advisory Committees ◽

Allelic Ratio ◽

Leukocyte Counts

Abstract Background: Mutations in the NPM1 gene are among the most common genetic alterations in patients with acute myeloid leukemia (AML). NPM1 mutations predominantly occur in patients with normal or intermediate-risk abnormal cytogenetics, and define a distinct subgroup of AML patients recognized in the 2016 WHO classification. Overall, mutated NPM1 associates with favorable response to induction chemotherapy and relatively favorable overall survival. However, this prognostic impact is modulated by the presence of other gene mutations including FLT3 internal tandem duplications (ITD) and DNMT3A mutations. Recently, Patel and colleagues reported that a high variant allele frequency (VAF) of mutated NPM1 at the time of initial diagnosis associates with unfavorable outcomes in de novo AML (Blood 131:2816-25). This interesting and unexpected observation prompted us to investigate the association between NPM1 VAF and outcomes in a large AML patient cohort. Patients and Methods: We studied NPM1 mutated AML patients who had been enrolled on two successive multicenter phase III trials of the German AML Cooperative Group (AML-CG 1999, NCT00266136; AML-CG 2008, NCT01382147) and genetically characterized by amplicon-based targeted next-generation sequencing (NGS, Agilent Haloplex; Metzeler et al., Blood 128:686-98 and unpublished data). All patients had received induction chemotherapy containing cytarabine with either daunorubicin plus thioguanine or mitoxantrone. The minimum VAF for calling of insertion/deletion variants was 0.05, and samples with NPM1 coverage <100-fold (n=17) were excluded. FLT3 internal tandem duplication (ITD) status and FLT3 ITD-to-wild type allelic ratio were determined by PCR and fragment analysis from gDNA. Results: We identified 417 NPM1-mutated patients (type A mutations, 316; type B, 28; type D, 35; and other types, 38). Median patient age was 56 years (range, 19 - 86 years), and 31/414 patients (7.5%) with cytogenetic data had abnormal karyotypes. The median NPM1 VAF was 0.43 (range, 0.05 to 1.0). Type A NPM1 mutations had significantly higher VAFs than non-type A mutations (median, 0.43 vs. 0.41; P=.0002), while type B mutations had lower VAFs than non-type B mutations (median, 0.34 vs. 0.43; P=.0025) (Figure A). Age or karyotype did not associate with NPM1 VAF. NPM1 VAF, as a continuous variable, did not associate with response to induction chemotherapy (P=.6) or relapse-free survival (P=.22). A higher NPM1 VAF did, however, associate with shorter OS (hazard ratio for an increase in NPM1 VAF equal to the interquartile range, 1.14; 95% confidence interval, 1.00-1.30; P=.049). In particular, patients in the lowest quartile of NPM1 allele burden ('low NPM1 VAF') had longer OS than patients with allele burdens above the 25th percentile ('high NPM1 VAF') (median OS, 63.7 vs. 27.0 months; 5-year OS, 51% vs 42%; P=.05; Figure B). Patients with high NPM1 VAF had higher leukocyte counts (median, 46000/µl vs. 9300/µl; P<.0001) and bone marrow blast percentages (median, 85% vs. 80%; P=.0004) than patients with low NPM1 VAF. On the genetic level, patients with high NPM1 VAF more frequently had concomitant FLT3-ITD (47% vs. 37%; P=.07), and particularly FLT3-ITD with a high (≥0.5) mutant-to-wild type ratio (33% vs. 17%; P=.007), compared to patients with low NPM1 VAF. DNMT3A co-mutation was also more frequent in patients with high vs. low NPM1 VAF (63% vs. 46%; P=.002). In multivariable analyses adjusting for FLT3-ITD allelic ratio and/or DNMT3A mutation status, only the latter genetic alterations but not NPM1 VAF remained associated with OS. Conclusion: Our study confirms the recent report that adult AML patients with high NPM1 mutant allele burden have shorter survival. In our cohort, however, higher NPM1 VAF also associated with higher leukocyte counts and marrow blast percentage, and with prognostically adverse FLT3-ITD and DNMT3A mutations. After adjusting for these confounders, NPM1 allelic burden did not independently predict survival in our analysis. We therefore suspect that high NPM1 VAF may be a surrogate marker of highly proliferative AML subsets, for example those with high allelic ratio FLT3-ITD, rather than a novel independent prognostic factor. Figure. Figure. Disclosures Prassek: Jannsen: Other: Travel support; Celgene: Other: Travel support. Subklewe:Roche: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hiddemann:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Metzeler:Celgene: Consultancy, Research Funding; Novartis: Consultancy.

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Rituximab Combined with 3 Cycles of High Dose Dexamethasone Improves Response in Patients with Newly-Diagnosed, Persistent, and Chronic Immune Thrombocytopenia (ITP)

Blood ◽

10.1182/blood.v120.21.3345.3345 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3345-3345

Author(s):

Rebecca L. Elstrom ◽

Caroline Seery ◽

Christina Moll ◽

Allison Miller ◽

Julia Gabor ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Wild Type ◽

Tubulin Gene ◽

Advisory Committees ◽

Optimal Response ◽

High Dose Dexamethasone

Abstract Abstract 3345 Introduction: Adults with newly-diagnosed ITP usually respond to initial prednisone treatment but typically relapse upon its tapering or discontinuation. Patients with persistent/chronic ITP treated with prednisone have an even lower likelihood of a lasting response. Dexamethasone (Dex) has been reported to have curative effects in newly diagnosed patients. Rituximab (Ritux) is thought to be effective in newly diagnosed patients but only yields a long term response in 20–25% of chronic ITP patients. Recently, newly-diagnosed previously-untreated patients received a single cycle of 4 days of Dex 40 mg/day or 4 infusions of 375mg/m2 Ritux combined with Dex. R+Dex in that study yielded a 63% response at 6 months and 34% at 3 years without additional treatment, which was more effective than Dex alone. Methods: Given the additive activity of these two drugs, 59 patients at Weill-Cornell Medical College with ITP of any duration were treated with 4 infusions of 375mg/m2 rituximab and three 4-day cycles of high-dose dexamethasone at 2-week intervals (R+Dex). Optimal response was assessed after 8 weeks as complete remission (CR, platelet count≥100×109/L) or partial remission (PR, 50–100×109/L). Long term outcome was also assessed and both were related to clinical variables. Data was compared to that of rituximab alone using the previous study from our center (Cooper BJH 2004). AIPF values were gathered prior to treatment until 12 weeks after treatment initiation. Results: All but 5 patients had been previously treated with a median of 2 therapies (range 0–7). Assessing optimal response achieved, 44/59 (74.5%) patients responded, with a CR in 64% and a PR in 10%. Only 1/28 patients with ITP < 1yr relapsed (at 12 months). Duration of ITP less than 24 months (p=0.0426) and being an adult predicted better optimal responses (p=0.0154). Of the original 44 responders, 33/59 patients [74% of responding adults and 77% of responding children] had ongoing responses at last f/u at a median of 14 months without the need for further ITP treatment (Figure). Eleven of the 44 relapsed (25%) including the one at 12 months mentioned above. Two additional patients relapsed who had ITP for 1–2 years prior to R+Dex and the other 8 patients who relapsed had ITP for greater than 3 years, 5 of whom had had ITP for 6+ years. Additionally, 53 of the 59 patients were genotyped for β1-tubulin gene. Of the ten patients with heterozygote genotypes, 9 (90%) responded to combination R+Dex treatment and 32 of the 43 wild type patients responded to treatment (p=0.46). There were no overt differences in the AIPF levels over the first 12 weeks between responders and non-responders. No AIPF differences were seen between the heterozygote and wild type patients for the β1-tubulin gene. In our previous study of rituximab alone, 54% of the 57 adult patients responded to rituximab treatment, compared to 86% of the 36 adult patients who responded to R+Dex treatment. R+Dex responders were found to have a longer duration of lower B cell numbers when compared with responders to rituximab alone, preliminarily demonstrating the additive effect of the 2 medications. Adverse events related to R+Dex generally were mild but one patient was hospitalized with colitis, two others experienced serum sickness reactions and dexamethasone was sometimes difficult to tolerate. Conclusion: R+Dex is active and appears clearly superior to rituximab alone in this single-center, pilot study. Adults and patients who have a shorter duration of ITP (< 1–2 years) fare better but children and those with a longer duration of ITP still have a 1/3 chance of a lasting response. The absence of homozygote β1-tubulin SNP's in this population made interpretation of its effect difficult. High dose Dex is not always easy to tolerate but helps maintain the count during the treatment course of 32 days. A prospective, randomized trial is planned. Disclosures: Basciano: Alexion: Consultancy. Ghanima:Roche Pharmaceuticals: Research Funding. Bussel:Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

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Anthracycline Choices for Induction Chemotherapy Among 797 Consecutive Adult Patients with Acute Myeloid Leukemia: Daunorubicin-60 Vs Idarubicin-12 Vs Daunorubicin-90

Blood ◽

10.1182/blood-2021-147485 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1267-1267

Author(s):

Kebede H. Begna ◽

Naseema Gangat ◽

Mithun V. Shah ◽

Hassan B. Alkhateeb ◽

Mrinal M. Patnaik ◽

...

Keyword(s):

Board Of Directors ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Advisory Board ◽

Risk Category ◽

Newly Diagnosed ◽

Advisory Committees ◽

Treatment Groups

Abstract Objective : We describe the Mayo Clinic experience in 797 newly-diagnosed patients with acute myeloid leukemia (AML) serially treated with 7+3 induction chemotherapy that included 3 days of daunorubicin at a daily dose of 60 mg/m2 (dauno-60; n=239) or 90 mg/m2 (dauno-90; n=52), or idarubicin 12 mg/m2 (IDA-12; n=506). Our objective was to compare overall (OS) and relapse-free (RFS) survival outcome. Methods : Newly-diagnosed AML patients seen at our institution and received intensive induction chemotherapy were identified from the Mayo Clinic AML database. Treatment period spanned from January 2004 through May 2021. Follow-up information was updated as of June 2021. Conventional criteria were used to diagnose AML, assign cytogenetic risk category, and classify treatment response. Results : The study group included 797 patients (median age 60 years, range 18-88; 58% males): 506 (63%) patients received IDA-12, 239 (30%) dauno-60, and 52 (7%) dauno-90. The respective median (range) ages were 60 (18-88), 61 (19-82), and 53 (22-72) years (p=0.01) (Table). Primary, secondary, and therapy-related AML accounted for 65%, 25% and 10% of patients treated with IDA-12, 69%, 22%, and 9% of those treated with dauno-60, and 75%, 23% and 2% of patients treated with dauno-90, respectively (p=0.1). The corresponding frequencies of adverse karyotype were 34%, 25% and 25% (p=0.05). CR/CRi was documented in 78% (620/793) of all evaluable patients: IDA-12 80% (400/503), dauno-60 75% (175/238), and dauno-90 87% (45/52) (p=0.1). 210 (34%) patients underwent allogenic hematopoietic stem cell transplant (AHSCT), including 125 (25%), 59 (25%) and 26 (50%) patients, in the three treatment groups, respectively (p=0.0004). After a median (range) follow up 19 (0.2-203) months, 348 (54%) relapses and 518 (65%) deaths were documented. Median (range) survivals for IDA-12, dauno-60 and dauno-90 groups were 21 (0.3-243), 14.5 (0.45-198), and 27.7 (0.2-180) months (p=0.07; figure 1). The respective 1-, 3-, and 5-year OS rates were 67%, 42%, and 34% (IDA-12); 66%, 37%, and 30% (dauno-60); and 78%, 51%, and 49% (dauno-90), respectively; the trend favoring dauno-90 was no longer apparent during age-adjusted analysis (p=0.33). Multivariable analysis that accounted for age, cytogenetic risk category, FLT3-ITD/NPM1 status and AML subtype confirmed the lack of additional contribution from IDA-12 vs dauno-60 vs dauno-90 (p=0.2) while affirming the independent prognostic value of the other four variables; AHSCT carried an additional predictive value for superior survival without altering these results. A total of 348 (54%) relapses were documented: 228 (57%) in the IDA-12; 99 (57%) in the dauno-60; and 21 (47%) in the dauno-90 cohorts (p=0.7); RFS was similar in the three treatment groups (p=0.1; figure 2). Conclusion :In the current large single-institution study of consecutive adult patients with AML, neither the choice of anthracycline (idarubicin vs daunorubicin) or the dose of daunorubicin (60 vs 90 mg/m2) appeared to effect outcome in terms of remission rates or overall or relapse-free survival. The study otherwise confirms the independent favorable effect of younger age, non-adverse karyotype, FLT3-ITD-/NPM1+ status, and AHSCT. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee; Omeros: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding.

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Pretreatment Next-Generation Sequencing Is Associated with Response to Induction Chemotherapy in Patients Newly Diagnosed with Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-138561 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-34

Author(s):

Anastasia Tsagianni ◽

Konstantinos Lontos ◽

Mounzer Agha ◽

Anastasios Raptis ◽

Jing-Zhou Hou ◽

...

Keyword(s):

Board Of Directors ◽

Induction Chemotherapy ◽

Myeloid Leukemia ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Secondary Aml ◽

Tp53 Mutations ◽

Generation Sequencing ◽

Acute Myeloid

Introduction: Next-generation sequencing (NGS) has redefined the genetic landscape of acute myeloid leukemia (AML) and has prognostic and, potentially, therapeutic implications in AML.Advances in the biological understanding of AML pathogenesis have led to the approval of new targeted agents that increase the therapeutic options for the treatment of AML. Despite these approvals, induction chemotherapy is still widely used for the treatment of patients newly diagnosed with AML. Unfavorable risk cytogeneticand secondary AML have been associated with low responses to induction chemotherapy. In the current study, we investigated the predictive role of molecular abnormalities detected with NGS related to responses to induction chemotherapy in newly diagnosed AML patients. Methods:We used the Medical Archival Retrieval System to identify newly diagnosed AML patients who had NGS analysis performed at our institution.. Patients treated with induction chemotherapy at AML diagnosis were included in the analysis. Response to therapy was evaluated two weeks after therapy was initiated and at count recovery. The difference in distribution of each mutation between the patients who responded to chemotherapy after one or two courses of induction chemotherapy and non-responders was analyzed using Fisher's exact test and the Cochran-Armitage Trend test. Findings with an expected false discovery rate ≤ 10% were reported as positive. The study was approved by the University of Pittsburgh IRB committee. Results: One hundred twenty-seven newly diagnosed AML patients (median age 61 years, interquartile range 51-68 years) were treated with induction chemotherapy. Sixteen patients (13%) had favorable risk cytogenetics, 73 patients (58%) had intermediate risk cytogenetics, and 36 patients (29%) had unfavorable risk cytogenetics. The most common molecular event was an NPM1 (28%) mutation followed by DNMT3A (25%), FLT3-ITD (22%), NRAS (13%), ASXL1 (12%), TET2 (12%), and TP53 (11%) as shown in Figure 1. Eighty-five of 127 patients (67%) achieved CR after one course of chemotherapy with idarubicin and cytarabine (7+3) and 17 patients (13%) responded after a second course with mitoxantrone and etoposide. Twenty-five patients (20%) did not respond to one or two courses of induction chemotherapy. From the 102 patients that responded, measurable residual disease (MRD) data were available in 59 (58%) patients. 29% patients were MRD positive and 71% patients were MRD negative. Secondary AML and poor cytogenetics were associated with poor response. Among the 17 genes with at least 5% prevalence, only TP53 mutations were associated with worse response. TP53 mutations increased monotonically with worse outcomes; TP53 mutations were present in only 2% of those responding to one course of chemotherapy, in 18% responding to two courses, and in 38% with no response to either course (p < 0.0001). Ninety-three percent of patients (13 of 14 patients) with TP53 mutations had poor cytogenetics. After induction chemotherapy, 21% of patients with TP53 mutations achieved CR and 14% achieved morphologic leukemia-free state (MLFS); 2 patients achieved CR after one course and, after the second course, 1 patient achieved CR and 2 patients MLFS. From the 5 patients that responded, 4 had available MRD data; 2 patients were MRD positive and 2 patients were MRD negative. NPM1 mutations were associated with higher response rates to induction chemotherapy (p =0.002). Ninety-four percent of patients (32 of 34 patients) with NPM1 mutations had intermediate cytogenetics. After induction chemotherapy, 92% of patients with NPM1 mutations achieved CR and 3% achieved MLFS; 32 patients (89%) achieved CR after one course. Two patients received a second course; one patient achieved CR and one MLFS. From the 34 patients that responded, 20 patients had available MRD data; 9 patients were MRD positive and 11 patients were MRD negative. Conclusion: Among 17 gene mutations detected using NSG at AML diagnosis, only TP53 and NPMI mutations were associated with responses to induction chemotherapy. Patients with TP53 mutations at AML diagnosis were associated with lower response rates to induction chemotherapy, whereas NPM1 mutations were associated with improved response. Disclosures Raptis: INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Hou:Genentech: Consultancy, Other: PI; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Other: PI. Dorritie:Kite-Gilead: Research Funding; Juno Therapeutics: Research Funding. Sehgal:TP Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Research Funding.

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Geographical Distance from Quaternary Treatment Center Does Not Impact Choice of Upfront Therapy, Clinical Trial Participation and Outcomes in Patients with Newly Diagnosed AML

Blood ◽

10.1182/blood-2020-134645 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Samantha A Hershenfeld ◽

Steven M Chan ◽

Vikas Gupta ◽

Dawn Maze ◽

Caroline J McNamara ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Performance Status ◽

Treatment Center ◽

Newly Diagnosed ◽

Advisory Committees ◽

Quaternary Center ◽

Upfront Therapy

Upfront therapy for newly diagnosed patients with acute myeloid leukemia (AML) includes intensive induction chemotherapy with curative intent, low dose chemotherapy, best supportive care, and clinical trials. The choice between these therapies is influenced by multiple factors including age, cytogenetic and molecular mutations, and performance status. In our single payer provincial health care system, induction chemotherapy and clinical trials are only offered at a small number of specialized quaternary care centers with geographically large catchment areas. As a result, some patients are required to travel long distances for their appointments, which may constitute a barrier to care, especially among elderly patients. We therefore asked whether distance from the quaternary center influences the choice of care for AML. We reviewed the records of patients ≥18 years of age diagnosed with AML from 2015-2017 and assessed at our quaternary care center in Toronto, Canada. We compared upfront therapy choice and survival between patients living close versus distant from the cancer center (empirically defined as <50 km versus >50km) and stratified by age. A total of 675 patients were assessed by our quaternary center for a new diagnosis of AML during the timeframe studied. Of those patients, 477 (71%) patients lived ≤50km, and 198 (29%) patients lived >50km from the quaternary center. The overall median distance from patient residence to the quaternary center was 33.2km (range: 1-1791km), and the median distance of patients in the >50km group was 93km (range: 50.2-1791km). Age, sex, baseline Eastern Cooperative Oncology Group Performance Status (ECOG), and cytogenetic risk were not significantly different between the two groups. There were no differences in the proportion of patients receiving induction chemotherapy or clinical trial as upfront therapy between patients living close versus distant from the quaternary center, even when stratified for age ≥70 years. There was no difference in overall survival between patients living ≤50km versus >50km from the quaternary center either overall, or when stratified by age. In conclusion, geographic distance from treatment center does not appear to impact choice of upfront therapy, access to clinical trials, or clinical outcomes in this study of newly diagnosed patients with AML treated in a single payer environment. Disclosures Gupta: Bristol MyersSquibb: 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, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Consultancy; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maze:Novartis: Honoraria; Pfizer: Consultancy; Takeda: Research Funding. McNamara:Novartis: Honoraria. Schimmer:Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria; Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock .

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RAS Mutations Are Independently Associated with Decreased Overall Survival and Event-Free Survival in Patients with AML Receiving Induction Chemotherapy

Blood ◽

10.1182/blood-2019-125319 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 18-18 ◽

Cited By ~ 1

Author(s):

Brian J Ball ◽

Meier Hsu ◽

Sean M. Devlin ◽

Christopher Famulare ◽

Sheng F Cai ◽

...

Keyword(s):

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Newly Diagnosed ◽

Event Free Survival ◽

Clearance Rates ◽

Advisory Committees ◽

Ras Mutation ◽

Free Survival ◽

Ras Mutations

Background: Activating mutations of NRAS and KRAS genes are common in newly diagnosed acute myeloid leukemia (AML), occurring in 11-16% and 4-5% of patients, respectively. RAS mutations are frequently acquired at time of progression from MDS to AML and are associated with poor survival. Next generation sequencing (NGS) at diagnosis and during complete remission has shown that RAS mutations have high clearance rates with induction chemotherapy. In the CALGB 8525 study, RAS-mutant younger patients (age <60 years) randomized to treatment with high-dose cytarabine consolidation had a lower 10-year cumulative incidence of relapse when compared to RAS WT patients. We performed a single center retrospective study to determine the outcomes of NRAS and KRAS mutated AML in patients receiving induction chemotherapy. Methods: We retrospectively reviewed the charts of patients with newly diagnosed AML treated at Memorial Sloan Kettering Cancer Center between January 1, 2014 to May 15, 2019. Patients with pathologic confirmation of AML and treatment with induction chemotherapy were included. Age < 18 years old, treatment with a pediatric induction regimen, a diagnosis of biphenotypic AML, unknown RAS mutation status at diagnosis, or treatment an outside institution were criteria for exclusion. All patients underwent NGS from a diagnostic bone marrow aspirate (BMA) with MiSeq or MSK-IMPACT platforms. Mutations present with a variant allele frequency (VAF) ≥ 1% were retained. Response was evaluated per ELN 2017 criteria. Immunophenotypic MRD was identified in BMA by multiparameter flow cytometry. Any level of residual disease was considered MRD+. Baseline characteristics were evaluated by Fisher's exact test and Wilcoxon rank sum tests. Kaplan-Meier estimates were used to summarize OS and EFS. Multivariable cox regression, including time-dependent variables was performed on univariate factors with p<0.05. Results: 202 patients, including 162 WT and 40 RAS mutant met inclusion criteria for further analysis. Mutations in NRAS and KRAS occurred in 14%, and 8% of patients, respectively with 6 patients having co-occurring NRAS and KRAS mutations. At baseline, the RAS mutant AML cohort had a significantly greater proportion of patients with AML-MRC and a trend toward fewer patients receiving allogeneic stem cell transplant. (Table 1.) Cytogenetic abnormalities were similar among RAS and WT patients. Sequencing at diagnosis revealed an increased frequency of FLT3 TKD, RUNX1, TET2, WT1, and ETV6 mutations and a decreased frequency of FLT3-ITD and TP53 mutations in the RAS mutant cohort. Response rates and MRD negative remission rates to induction chemotherapy were similar between RAS and WT AML patients (Table 2). With a median follow up of 25 months among survivors, RAS mutant AML was associated with a significant decrease in median EFS (4.9 vs. 11.4 months, p< 0.01) and a near significant decrease in median OS (12 vs. 30.1 months, p=0.057) (Figure 1 and 2). After controlling for variables with p<0.05 on univariate analysis including age, prior myeloid malignancy, AML classification, ELN risk, transplantation, and re-induction, RAS mutation was independently associated with an increased risk of death (HR 1.85, p=0.016) and decreased EFS (HR 2.19, p< 0.01) on multivariate analyses (Tables 3 and 4). Among 77 patients with paired sequencing at diagnosis and at time of CR or CRi, all RAS mutations (n=17) were cleared (Figure 3). Additionally, other RAS pathway mutations had high clearance rates including PTPN11 (n=8, 100%), NF1 (n=3, 100%, and CBL (n= 4, 80%) (Figure 3). RAS mutation clearance also occurred in 3 out of 8 patients (38%) not achieving CR or CRi after induction. RAS mutation clearance persisted in 6 out of 10 responding patients at time of relapse. Conclusions: In summary, the presence of RAS mutations in patients with AML receiving induction chemotherapy was associated with decreased overall and event free survival. RAS mutant AML was enriched among patients with AML-MRC and prior myeloid neoplasms, which was also associated with decreased survival. Lastly, treatment with chemotherapy led to a high rate of RAS mutation clearance in responders that persisted at the time of disease relapse. The poor prognosis of RAS mutant AML despite RAS mutation clearance suggests that other therapies are needed in combination with chemotherapy to improve outcomes in this high-risk population. Disclosures Cai: Imago Biosciences, Inc.: Consultancy. Viny:Hematology News: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Other: Sponsored travel. Goldberg:American Society of Clinical Oncology: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Research Funding; American Society of Hematology: Research Funding; DAVA Oncology: Honoraria; Pfizer: Research Funding; Arog Pharmaceuticals: Research Funding; Abbvie: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Celgene: Consultancy. Tallman:BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy; Cellerant: Research Funding; ADC Therapeutics: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stein:Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees.

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Predictors of Remission in Adults with Immune Thrombocytopenia Treated with Romiplostim

Blood ◽

10.1182/blood-2018-99-109791 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 735-735

Author(s):

Adrian Newland ◽

James B. Bussel ◽

Robert Bird ◽

Donald M. Arnold ◽

Craig M. Kessler ◽

...

Keyword(s):

Multivariate Analysis ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Platelet Counts ◽

Equity Ownership

Abstract Background: In adults with ITP, thrombopoietin receptor agonists (TPO-RA) are often assumed to be lifelong therapy. However, some patients achieve treatment-free remission (TFR) by maintaining hemostatic platelet counts after discontinuing TPO-RA, despite not replacing them with other ITP medications. Predictors of safely discontinuing romiplostim have varied across studies. In an analysis of 8 romiplostim studies, 27 patients achieved TFR; more remitters than nonremitters had ITP for <12 months but there were no unequivocal predictors of TFR (Bussel et. al. Hematology 2016;21:257). In a phase 2 study with forced romiplostim taper after 12 months, 24 (32%) of 75 patients achieved TFR; a higher platelet count in the first 2 months was associated with TFR (P<.05; Newland et. al. Br J Haematol 2016;172:262). Differences between remitters and nonremitters for baseline patient characteristics and time to first platelet response were not statistically significant. Analysis of romiplostim treatment at 2 centers found that 12 (28%) of 43 patients achieved TFR; splenectomized patients were more likely than nonsplenectomized patients to achieve TFR (P=.05; Marshall et. al. Haematologica 2016;101:e476). Aim: This multivariate analysis integrated data across multiple romiplostim studies in adults with ITP to explore predictors of TFR. Methods: Data were pooled for 911 romiplostim-treated patients in 13 ITP studies conducted from 2002 to 2014. All patients failed first-line treatments before study enrollment. Secondary thrombocytopenia patients were excluded. Romiplostim treatment was discontinued per dosing rules; 1 study included a forced taper after 1 year of romiplostim. Typically, the romiplostim dose was reduced for platelet counts >200×109/L and withheld, then reduced, for platelet counts >400×109/L. Concomitant ITP medication could be reduced for platelet counts >50×109/L. TFR was defined as a ≥6-month treatment-free period with platelet counts consistently ≥50×109/L. Univariate analysis with logistic regression examined potential predictors of TFR, including age, sex, ITP duration, prior splenectomy, platelet count (baseline and first 4 weeks), bleeding in the first 6 months, and baseline concurrent therapy. Multivariate analysis with logistic regression evaluated significant predictors from the univariate analysis. Results: TFR was achieved by 61 ITP study patients who received romiplostim. For remitters vs nonremitters, median baseline age was 53 years in both cohorts; 57% vs 61% were female; and 93% vs 88% were Caucasian (Table 1). Median ITP duration at study baseline was 0.5 years among remitters and 3.5 years among nonremitters. Prior splenectomy occurred in 21% of remitters and 36% of nonremitters. The number of prior ITP treatments was ≤3 for 74% of remitters and 39% of nonremitters. Baseline platelet count was <30×109/L for 80% of remitters and 78% of nonremitters. Median platelet counts on treatment during the romiplostim studies were often higher among remitters than nonremitters, despite increasing median doses of romiplostim over time for nonremitters (Figure). During the first 6 months on study, 30% of remitters and 43% of nonremitters had a bleeding event. Prior splenectomy and bleeding in the first 6 study months were significant predictors of lower odds of TFR in the univariate model but not in the multivariate model. In the multivariate model, shorter ITP duration predicted significantly higher odds of TFR, either <3 months (newly diagnosed) vs >12 months (chronic; odds ratio [OR], 4.275; P<.0001) or 3-12 months (persistent) vs chronic (OR, 2.171; P=.0408; Table 2). One limitation of this analysis was 19 of 61 patients entering TFR were from one study of newly diagnosed and persistent patients; the protocol included a forced romiplostim taper. Number of previous treatments was not included in the multivariate analysis. Conclusions: In this integrated analysis of 911 adult ITP patients across 13 studies, shorter ITP duration at baseline (≤12 months) was an independent predictor of TFR. Neither previous splenectomy (which predicted TFR in 1 study) nor bleeding were independent predictors of TFR in this much larger analysis. In total, these results imply that earlier use of romiplostim in adults with ITP could be associated with greater likelihood of achieving TFR. Future studies should also explore biologic variables as predictors of TFR. Disclosures Newland: Amgen Inc., Angle, Dova Pharmaceuticals, Argenx, Rigel, Shionogi, Novartis: Consultancy; Amgen Inc., GlaxoSmithKline, and Novartis: Research Funding; Novartis: Speakers Bureau. Bussel:Uptodate: Honoraria; Protalex: Consultancy; Momenta: Consultancy; Rigel: Consultancy, Research Funding; Prophylix: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding. Bird:Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Arnold:Novartis: Consultancy, Research Funding; UCB: Consultancy; UCB: Consultancy; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Kessler:Novo Nordisk: Honoraria, Research Funding; Biomarin: Research Funding; Genentech: Research Funding; Dimension Advisory boards: Membership on an entity's Board of Directors or advisory committees; DSMB: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mayer:Novartis: Research Funding; Amgen: Research Funding. Janssens:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Speakers Bureau; Sanofi-Genzyme: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Ad board, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Wang:Amgen: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

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