Do Not Miss Karyotyping at Chronic Myeloid Leukemia Diagnosis: An Italian Campus CML Study on the Role of Complex Variant Translocations

Background. The Philadelphia (Ph) chromosome (chr.) is the hallmark of chronic myeloid leukemia (CML) and typically results from the reciprocal translocation t(9;22)(q34;11.2). Complex variant translocations (CVT) involving one or more additional chr. are identified in less than 5% of newly diagnosed CML. There are conflicting reports about the prognostic impact of CVT in the achievement of optimal response to tyrosine kinase inhibitor (TKI), and very few studies addressed the role of frontline treatment with imatinib or second generation (2G)-TKI in patients with CVT. Aims. To assess the response to imatinib or 2G-TKI in a large cohort of newly diagnosed CML with CVT, and to explore the impact of the different chr. translocations on outcome. Methods. This observational retrospective study was conducted in 19 hematologic centers in the framework of Campus CML, a network of Italian physicians involved in the management of CML patients. All newly diagnosed CML from 2000 to 2019 were evaluated and patients with CVT were selected for the present analysis. Karyotypes were defined according to the 2016 International System for Human Cytogenetic Nomenclature. Responses to frontline treatment were retrospectively categorized according to the 2013 ELN recommendations, as they include cytogenetic milestones. Deep molecular response (DMR, i.e. MR4or better) was defined as BCR-ABLIS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Patients with DMR lasting ≥2 years and at least a Q-PCR test every 6 months were defined as stable DMR responders. Failure-free survival (FFS) was calculated from the start of frontline TKI treatment to progression to advanced phase, death, or switch to other treatments for resistance. For FFS calculation, patients were censored at TKI stop for treatment-free remission (TFR) or in case of switch for intolerance only. Differences between subgroups according to the partner chr. were presented for descriptive purposes. Results. CVT were identified in 109 (3.2%) patients from a whole population of 3,361 subjects with newly diagnosed CML. Ninety-five out of 109 patients (87%) exhibited three-way translocations, with chr. 1, 4, 6, 10, 11, 12, 14, 15 and 17 representing the most common additional partners (figure). Four- and five-way translocations were identified in 13 and 1 patients, respectively. Additional chr. abnormalities (ACA) in the Ph+ cells were observed in 15/109 (13.8%) patients and were more common in older individuals (p=0.018). Overall, median age at diagnosis was 50.6 years (range 20-90). Risk distribution according to the ELTS score was 54%, 28% and 8% for L, I and H risk, respectively (10% missing). Cytogenetic result was available before the choice of frontline treatment in 45% of cases and represented a decisive factor in 28% of them (i.e. clinicians selected a 2G-TKI or high-dose imatinib, according to the available options). Frontline TKI treatment was imatinib in 80 cases (73%) and 2G-TKI (nilotinib n=22, dasatinib n=6, bosutinib n=1) in the remaining cases. The frequency of optimal response at 3, 6 and 12 months was 48%, 45% and 53%, respectively, for imatinib-treated patients, and 76%, 83% and 76%, respectively, for the 2G-TKI cohort (p<0.05 for all comparisons). Stable DMR was achieved by 39% of patients and 42% of them attempted a TFR. After a median follow-up of 91.3 months (range 1-236), 5-year FFS was 66% (95%CI: 53.4-76.4) and 84% (95%CI: 62.4-93.6) for imatinib and 2G-TKI treated patients, respectively (p=ns). The estimated 10-year OS for the entire cohort was 84.4% (95%CI: 73.6-91). The subtype of CVT had an impact on response and long-term outcome. Patients with CVT involving chr. 1, 4, 6, 11 or 12 had a higher frequency of MMR at 12 months than patients with CVT involving chr. 10, 14, 15 or 17 (75.8% vs 30.4%, respectively, p=0.001), higher frequency of stable DMR (48.7% vs 22.2%, respectively; p=0.04) and tended to have better median FFS (p=0.07), regardless of the type of frontline TKI and of the ELTS score. Conclusions. Due to its retrospective nature, this study does not allow to define which is the optimal therapy for CML harboring CVT at diagnosis. However, our data reinforce the usefulness of bone marrow karyotyping in CML. The observed differences between partner chr. may also depend on the breaking points, which are variable. Further dissection of CVT will help to identify which are associated to a poor response to TKIs. Figure Disclosures D'Adda: Incyte: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Crugnola:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Bocchia:Incyte: Honoraria; CELGENE: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Saglio:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Roche: Research Funding.

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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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The Application of Machine Learning to Improve the Subclassification and Prognostication of Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-139013 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 28-28

Author(s):

Hassan Awada ◽

Arda Durmaz ◽

Carmel Gurnari ◽

Ashwin Kishtagari ◽

Manja Meggendorfer ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Somatic Mutations ◽

Cross Validation ◽

Steering Committee ◽

Advisory Board ◽

Advisory Committees ◽

Genomic Features ◽

Acute Myeloid

Genetic mutations (somatic or germline), cytogenetic abnormalities and their combinations contribute to the heterogeneity of acute myeloid leukemia (AML) phenotypes. To date, prototypic founder lesions [e.g., t(8;21), inv(16), t(15;17)] define only a fraction of AML subgroups with specific prognoses. Indeed, in a larger proportion of AML patients, somatic mutations or cytogenetic abnormalities potentially serve as driver lesions in combination with numerous acquired secondary hits. However, their combinatorial complexity can preclude the resolution of distinct genomic classifications and overlap across classical pathomorphologic AML subtypes, including de novo/primary (pAML) and secondary AML (sAML) evolving from an antecedent myeloid neoplasm (MN). These prognostically discrete AML subtypes are themselves nonspecific due to variable understanding of their pathogenetic links, especially in cases without overt dysplasia. Without dysplasia, reliance is mainly on anamnestic clinical information that might be unavailable or cannot be correctly assigned due to a short prodromal history of antecedent MN. We explored the potential of genomic markers to sub-classify AML objectively and provide unbiased personalized prognostication, irrespective of the clinicopathological information, and thus become a standard in AML assessment. We collected and analyzed genomic data from a multicenter cohort of 6788 AML patients using standard and machine learning (ML) methods. A total of 13,879 somatic mutations were identified and used to predict traditional pathomorphologic AML classifications. Logistic regression modeling (LRM) detected mutations in CEBPA (both monoallelic "CEBPAMo" and biallelic "CEBPABi"), DNMT3A, FLT3ITD, FLT3TKD, GATA2, IDH1, IDH2R140, NRAS, NPM1 and WT1 being enriched in pAML while mutations in ASXL1, RUNX1, SF3B1, SRSF2, U2AF1, -5/del(5q), -7/del(7q), -17/del(17P), del(20q), +8 and complex karyotype being prevalent in sAML. Despite these significant findings, the genomic profiles of pAML vs. sAML identified by LRM resulted in only 74% cross-validation accuracy of the predictive performance when used to re-assign them. Therefore, we applied Bayesian Latent Class Analysis that identified 4 unique genomic clusters of distinct prognoses [low risk (LR), intermediate-low risk (Int-Lo), intermediate-high risk (Int-Hi) and high risk (HR) of poor survival) that were validated by survival analysis. To link each prognostic group to pathogenetic features, we generated a random forest (RF) model that extracted invariant genomic features driving each group and resulted in 97% cross-validation accuracy when used for prognostication. The model's globally most important genomic features, quantified by mean decrease in accuracy, included NPM1MT, RUNX1MT, ASXL1MT, SRSF2MT, TP53MT, -5/del(5q), DNMT3AMT, -17/del(17p), BCOR/L1MT and others. The LR group was characterized by the highest prevalence of normal cytogenetics (88%) and NPM1MT (100%; 86% with VAF>20%) with co-occurring DNMT3AMT (52%), FLT3ITD-MT (27%; 91% with VAF <50%), IDH2R140-MT (16%, while absent IDH2R172-MT), and depletion or absence of ASXL1MT, EZH2MT, RUNX1MT, TP53MT and complex cytogenetics. Int-Lo had a higher percentage of abnormal cytogenetics cases than LR, the highest frequency of CEBPABi-MT (9%), IDH2R172K-MT (4%), FLT3ITD-MT (14%) and FLT3TKD-MT (6%) occurring without NPM1MT, while absence of NPM1MT, ASXL1MT, RUNX1MT and TP53MT. Int-Hi had the highest frequency of ASXL1MT (39%), BCOR/L1MT (16%), DNMT3AMT without NPM1MT (19%), EZH2MT (9%), RUNX1MT (52%), SF3B1MT (7%), SRSF2MT (38%) and U2AF1MT (12%). Finally, HR had the highest prevalence of abnormal cytogenetics (96%), -5/del(5q) (68%), -7del(7q) (35%), -17del(17p) (31%) and the highest odds of complex karyotype (76%) as well as TP53MT (70%). The model was then internally and externally validated using a cohort of 203 AML cases from the MD Anderson Cancer Center. The RF prognostication model and group-specific survival estimates will be available via a web-based open-access resource. In conclusion, the heterogeneity inherent in the genomic changes across nearly 7000 AML patients is too vast for traditional prediction methods. Using newer ML methods, however, we were able to decipher a set of prognostic subgroups predictive of survival, allowing us to move AML into the era of personalized medicine. Disclosures Advani: OBI: Research Funding; Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; Takeda: Research Funding. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; BMS: Consultancy, Honoraria, Research Funding. Carraway:Novartis: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); Stemline: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Jazz: Consultancy, Speakers Bureau. Saunthararajah:EpiDestiny: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kantarjian:Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Abbvie: Honoraria, Research Funding; Aptitute Health: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Adaptive biotechnologies: Honoraria; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria. Kadia:Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; JAZZ: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Research Funding. Sekeres:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

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Pegaspargase Can Safely be Administered in Adults Age 40 and Older with Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood-2019-124727 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3816-3816 ◽

Cited By ~ 2

Author(s):

Ryan J. Daley ◽

Sridevi Rajeeve ◽

Charlene C. Kabel ◽

Jeremy J. Pappacena ◽

Sarah E. Stump ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Hypersensitivity Reactions ◽

Newly Diagnosed ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Frontline Treatment

Introduction: Asparaginase (ASP) has demonstrated a survival benefit in pediatric patients (pts) with acute lymphoblastic leukemia (ALL) and is now part of standard-of-care frontline treatment. As a result, asparaginase preparations have been incorporated into the treatment of adult ALL to improve outcomes. Pegaspargase (PEG-ASP), a modified version of asparaginase with prolonged asparagine depletion, appears to be safe in adults up to age 40 (Stock, et al., Blood, 2019), but is associated with a unique spectrum of toxicities, the risks of which appear to increase with age. Therefore, the safety of PEG-ASP remains a significant concern in older adults w/ ALL. Methods: We conducted a single center retrospective chart review of pts age ≥40 years who received PEG-ASP as part of frontline induction/consolidation or reinduction, between March 2008 and June 2018 at Memorial Sloan Kettering Cancer Center. The primary objective was to evaluate the tolerability and toxicity of PEG-ASP based on the incidence and severity of ASP-related toxicities (hypersensitivity reactions, hypertriglyceridemia, hyperbilirubinemia, transaminitis, pancreatitis, hypofibrinogenemia, etc) according to the Common Terminology Criteria for Adverse Events, version 4.03. Laboratory values recorded were either the peak or the nadir, the more appropriate for toxicity assessment, within a 4-week period following PEG-ASP administration. Secondary objectives were to determine the total number of doses of PEG-ASP administered in comparison to the number of doses intended, and to characterize the rationale for PEG-ASP discontinuation when applicable. Fisher's exact test was used to compare the incidence of PEG-ASP toxicities with respect to pt and treatment characteristics (regimen, age, BMI, gender, Philadelphia chromosome positive (Ph+) vs. Ph-, presence of extramedullary disease, PEG-ASP dose). P values were not adjusted for multiple comparisons. Results: We identified 60 pts with ALL (40 B-ALL and 20 T-ALL) who received at least one dose of PEG-ASP. Nine pts were Ph+. The median pt age at initiation of the treatment was 53, (range, 40 to 80), and 19 pts had a BMI ≥30 kg/m2. Forty-four pts received treatment for newly diagnosed ALL, and 16 pts for relapsed disease. Table 1 lists pt baseline characteristics. Among the 44 pts with newly diagnosed ALL, 27 pts received PEG-ASP as part of pediatric or pediatric-inspired regimens at doses of 2000 - 2500 units/m2, and 1 pt received a modified dose of 1000 units/m2 due to age. The remaining 16 pts received PEG-ASP at doses of 1000 - 2000 units/m2 for consolidation, per established adult regimens (ALL-2 and L-20; Lamanna, et al., Cancer, 2013). Grade 3/4 ASP-related toxicities with a >10% incidence included: hyperbilirubinemia, transaminitis, hypoalbuminemia, hyperglycemia, hypofibrinogenemia, and hypertriglyceridemia. Frontline treatment regimens in which PEG-ASP was used in consolidation cycles only (ALL-2, L-20) were associated w/ a lower incidence of hyperbilirubinemia (p=0.009) and hypertriglyceridemia (p<0.001) compared to those regimens that included PEG-ASP during induction (pediatric/pediatric-inspired regimens) (Table 2). Younger age (40-59 vs. ≥60 years) was associated with a greater risk of hypertriglyceridemia (p<0.001) and higher PEG-ASP dose (≥2000 vs. <2000 units/m2) was associated with a greater risk of hypertriglyceridemia and hypofibrinogenemia (p=0.002 and p=0.025, respectively). Thirty-eight pts (63%) received all intended doses of PEG-ASP. Six pts stopped PEG-ASP to proceed to allogeneic hematopoietic stem cell transplantation (5 in CR1, 1 in CR2), and 7 pts stopped for hypersensitivity reactions. Hepatotoxicity was the only ASP-related toxicity that led to PEG-ASP discontinuation occurring in 5 pts (hyperbilirubinemia, N=4; transaminitis, N=1). The total number of intended doses of PEG-ASP based on regimens used was 186, and 112 were administered. Conclusion: PEG-ASP was incorporated into the treatment of 60 adult ALL pts age ≥40, with manageable toxicity. Seven pts discontinued PEG-ASP due to hypersensitivity reactions and 5 discontinued due to hepatotoxicity, but other reported toxicities did not lead to PEG-ASP discontinuation and the majority of the pts completed all intended doses of PEG-ASP. This study suggests that with careful monitoring, PEG-ASP can safely be administered in adults ≥40 years of age. Disclosures Rajeeve: ASH-HONORS Grant: Research Funding. Tallman:UpToDate: Patents & Royalties; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: 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, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; 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. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. Park:Takeda: Consultancy; Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy.

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Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis

Blood ◽

10.1182/blood-2018-99-119182 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 458-458 ◽

Cited By ~ 1

Author(s):

Gabriele Gugliotta ◽

Fausto Castagnetti ◽

Massimo Breccia ◽

Alessandra Iurlo ◽

Mariella D'Adda ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Advisory Board ◽

Molecular Response ◽

First Line ◽

Advisory Committees ◽

Deep Molecular Response ◽

First Line Treatment

Abstract BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts). AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts. METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events. RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%. The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y. SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity. Disclosures Gugliotta: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Abruzzese:Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

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Hypomethylating Agent and Venetoclax Combination Yields Comparable Outcomes to CPX-351 in Newly Diagnosed Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2019-130379 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3895-3895

Author(s):

Hannah Asghari ◽

Dasom Lee ◽

Yehuda E. Deutsch ◽

Onyee Chan ◽

Najla Al Ali ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Risk Group ◽

Newly Diagnosed ◽

Advisory Committees ◽

Acute Myeloid

Background The therapeutic landscape for acute myeloid leukemia (AML) has become complex with recent drug approvals. CPX-351 has become standard-of-care for patients (pts) with therapy-related AML and AML with myelodysplasia-related changes. Moreover, earlier phase studies combining hypomethylating agents (HMA) and Venetoclax (HMA+Ven) in the frontline setting for elderly patients have demonstrated high response rates and improved survival. Given the overlapping indications, yet lack of comparative outcome data between these therapeutic regimens, treatment decisions have become challenging in the frontline setting. Therefore, we compared the outcomes of newly diagnosed AML pts receiving HMA+Ven vs. CPX-351. Methods We retrospectively annotated 119 pts that received frontline treatment with HMA+Ven and CPX-351 at Moffitt Cancer Center and Memorial Healthcare System between 2013 and 2019. Pts were divided in two cohorts: HMA+Ven (Cohort A) or CPX-351(Cohort B). Via comprehensive chart review of each patient that received HMA+Ven, we further classified a subgroup of pts meeting criteria to receive CPX-351 as CPX-351eligible. Clinical and molecular data were abstracted for each patient in accordance with IRB requirements. Overall response rate (ORR) was the combined total of complete remission (CR), complete remission with incomplete count recovery (CRi), and morphologic leukemia free state (MLFS). Fisher's Exact method was used to determine significance. Kaplan-Meier analysis was performed to estimate median overall survival (mOS) with log-rank test to determine significance. All p-values are two-sided. Results Out of 119 total pts, 41 pts received HMA+Ven (Cohort A) and 78 pts received CPX-351 (Cohort B) with baseline characteristics outlined in Table 1. Among 111 response evaluable pts, ORR was 64.1% in Cohort A, including 28.2% with CR and 28.2% with CRi (Table 2). ORR was 50.0% in Cohort B, comprised of CR in 29.2% and CRi in 18.1%. There was no difference in ORR between Cohort A and Cohort B (64.1% vs. 50%, p 0.17). A significantly greater fraction of pts in Cohort B underwent allogeneic stem cell transplant (allo-SCT) (24.4% vs. 2.4%, p=0.004). ORR was higher in pts with European LeukemiaNet (ELN)-defined favorable/intermediate (fav/int) risk compared to adverse risk group in Cohort A (100% vs. 58.3%, p=0.03), however there was no difference in Cohort B (52.6% vs. 49.1%, p=1.0). ORR was similar among adverse risk groups in both cohorts (58.3% in Cohort A vs. 49.1% in Cohort B, p=0.47). Among responders, median time to best response was significantly longer in Cohort A (61.0 days vs. 40.5 days, p<0.0001). Median duration of response was not reached (NR) in both cohorts. Impact of somatic mutations on ORR is represented in Figure 3. Median follow-up was 6.5 months (mo) in Cohort A and 13.0mo in Cohort B. Median OS was similar in both cohorts (A vs. B, 13.8mo vs. 11.1mo, p=0.82) (Figure 1). Among responders, mOS was NR in Cohort A and 18.2mo in Cohort B (p=0.88) (Figure 2). Compared to Cohort B, mOS was superior for pts with fav/int risk disease in Cohort A (14.2mo (B) vs. NR (A), p=0.045) and not different for adverse risk group (11.1mo (B) vs. 7.3mo (A), p=0.2). Prior HMA exposure was 26.8% in Cohort A and 29.5% in Cohort B for an antecedent hematologic malignancy, however it did not impact mOS (p=0.86) or ORR (p=0.7). Early mortality rates for Cohort A and B were similar at day 30 (2.4% vs. 0%) and day 60 (4.9% vs. 3.8%). Rate of relapse was similar between cohorts A and B (16.0% vs. 30.6%, p=0.24). We then compared the outcomes of pts in Cohort B to CPX-351eligible arm from Cohort A (n=14). ORR and mOS were similar in Cohort B and CPX-351 eligible arm (ORR: 50% vs. 50%, p=1.0; mOS 11.1mo vs. 13.8mo, p=0.43). Only 1 patient (7.1%) of the CPX-351eligible arm underwent allo-SCT. Conclusion Our study demonstrates that HMA+Ven results in comparable response rates and survival outcomes to patients receiving CPX-351 when used as an initial remission therapy for patients with newly diagnosed AML, however the median follow up for patients receiving HMA+Ven was short. Survival did not appear to be impacted by a significantly greater proportion of patients proceeding to allo-SCT in the CPX-351 arm. Overall, HMA+Ven may represent a reasonable frontline remission therapeutic choice in patients with AML and a randomized trial would seem justified. Disclosures Kuykendall: Abbvie: Honoraria; Janssen: Consultancy; Incyte: Honoraria, Speakers Bureau; Celgene: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Pfizer: Consultancy, Research Funding; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Komrokji:celgene: Consultancy; Agios: Consultancy; pfizer: Consultancy; DSI: Consultancy; JAZZ: Speakers Bureau; JAZZ: Consultancy; Novartis: Speakers Bureau; Incyte: Consultancy. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau. Talati:Agios: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Honoraria; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria.

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The Role of Structural Violence in Acute Myeloid Leukemia Outcomes

Blood ◽

10.1182/blood-2020-136379 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 10-10

Author(s):

Ivy Abraham ◽

Garth Rauscher ◽

Anand Ashwin Patel ◽

William B Pearse ◽

Priya Rajakumar ◽

...

Keyword(s):

Board Of Directors ◽

Census Tract ◽

Myeloid Leukemia ◽

Research Funding ◽

Structural Violence ◽

Advisory Board ◽

Allogeneic Transplant ◽

Advisory Committees ◽

Census Tract Level ◽

Hispanic Patients

Background: Non-Hispanic Black (NHB) and Hispanic patients with Acute Myeloid Leukemia (AML) have higher mortality rates than non-Hispanic white (NHW) patients despite lower incidence, more favorable genetics, and a younger age at presentation (Darbinyan, Blood Adv. 2017). We performed a multilevel analysis of disparities in AML patients to investigate the contribution of structural violence, specifically neighborhood SES, on racial/ethnic differences in leukemia-specific survival. Methods: Adult AML (non-APL) patients diagnosed between 2012 and 2018 at six academic cancer centers in the Chicago area were included. Census tract data was collected using the FFIEC Geocoding/Mapping System and computed tract disadvantage and tract affluence scores were categorized into distribution tertiles (low, moderate, high). Time to relapse and death from leukemia were examined, adjusting for age, gender and race/ethnicity (baseline models), and for potential mediators of racial disparities including distal (Charlson Comorbidity Index (CCI), obesity, concentrated disadvantage and affluence, health insurance status), and proximal mediators (somatic mutations, and European Leukemia Network (ELN) prognostic score categories). Results Patient characteristics are shown in Table 1 (n = 822). Significant heterogeneity in age and comorbidities at diagnosis was observed, with Hispanic patients being the youngest and with the lowest CCI. Morbid obesity was more prevalent in NHB and Hispanic (23% and 20%, respectively) compared with NHW (11%) patients. Payer source also differed significantly; private insurance was twice as frequent among NHW than NHB (51% vs. 25%) patients, while the largest uninsured population was Hispanic. ELN adverse risk disease was most prevalent in NHW subjects, NPM1 mutations were least prevalent in Hispanic patients, and p53 mutations more prevalent in NHB (26%) compared to NHW (12%) and Hispanics (9%) although due to low numbers this did not reach significance (p=0.10). NHB and Hispanic patients tended to reside in more disadvantaged and less affluent areas. Treatment data was available for 764 patients (Table 2); 75% received intensive induction therapy and choice of first-line treatment did not differ by race or tract disadvantage. Allogeneic transplant rates however differed by race, age, insurance status, tract disadvantage, and ELN score. Treatment complications of induction chemotherapy, as reflected by ICU admissions during induction, were significantly lower in NHW (25%) compared to NHB (39%) and Hispanic (42%) patients. ICU admission rates were significantly higher in patients with morbid obesity and low tract affluence. Minority (vs. NHW) ethnicity was associated with a 42% increased hazard of death from leukemia (HR=1.42, 95% CI: 1.09, 1.85), and a 36% increased hazard of death from all causes (HR=1.36, 95% CI: 1.07, 1.72), each after controlling for age, gender and study site. Adjustment for continuous tract disadvantage and affluence and their interaction lowered both the hazard of leukemia and all cause death to 1.18 (95% CI: 0.88, 1.60) and 1.14 (95% CI: 0.88, 1.49), respectively. In formal mediation analysis, neighborhood SES accounted for 37% (p=0.09) and 50% (p=0.02) of the racial disparity in death from leukemia and all causes, respectively. Discussion: This study is the first to integrate data at the individual patient level with neighborhood characteristics, using census tract level variables to examine their contribution to AML patient outcomes. To date, formal mediation methods had not been employed to disentangle race/ethnic disparities in adult AML survival. Notably, our mediation analysis shows that census tract level SES explains a substantial proportion of the disparity in hazard of leukemia death. In addition, the observed disparities in treatment complications of induction chemotherapy, as reflected by ICU admissions, and the continued disparity in allogeneic transplant utilization all warrant further study. These results draw attention to the need for deeper investigation into the social and economic barriers to successful treatment outcomes for leukemia patients and represent an important first step toward designing strategies to mitigate these persistent health inequities. Disclosures Altman: Janssen: Consultancy; Syros: Consultancy; Genentech: Research Funding; Novartis: Consultancy; Amphivena: Research Funding; Amgen: Research Funding; Aprea: Research Funding; ImmunoGen: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; Fujifilm: Research Funding; Kartos: Research Funding; AbbVie: Other: advisory board, Research Funding; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Theradex: Other: Advisory Board; Immune Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; France Foundation: Consultancy; PeerView: Consultancy; PrIME Oncology: Consultancy; ASH: Consultancy; Cancer Expert Now: Consultancy. Stock:Research to Practice: Honoraria; UpToDate: Honoraria; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Society of Hematology: Honoraria; Leukemia and Lymphoma Society: Research Funding; Novartis: Research Funding; Abbvie: Honoraria, Research Funding; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Quigley:Alnylam: Speakers Bureau; Agios: Speakers Bureau; Amgen: Other: Advisory board. Khan:Celgene: Consultancy; Incyte: Honoraria; Takeda: Research Funding; Amgen: Consultancy.

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Safety and Efficacy of Midostaurin in Combination with High-Dose Daunorubicin in 7+3 Induction for Acute Myeloid Leukemia with FLT3 Mutation

Blood ◽

10.1182/blood-2019-129331 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3896-3896

Author(s):

Yehuda E. Deutsch ◽

Robert Wilkinson ◽

Amanda Brahim ◽

Stephanie Boisclair ◽

Jose Sandoval-Sus ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Cancer Center ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Safety And Efficacy ◽

Acute Myeloid

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease with varied outcomes dependent on patient cytogenetic and mutational status. Thirty percent of adults with newly diagnosed AML have a mutation in the fms-related tyrosine kinase 3 (FLT3) gene. Midostaurin is a small molecule inhibitor that acts on multiple receptor tyrosine kinases, including FLT3. The RATIFY trial showed improved overall survival (OS) and event-free survival in patients treated with daunorubicin and cytarabine (7+3) plus midostaurin (Stone et al, NEJM 2017). In this trial, a dose of daunorubicin 60 mg/m2 was administered. High dose (HD) 90 mg/m2 daunorubicin significantly improved the rate of complete remission and overall survival, including in patients with FLT3-ITD (Luskin et al, Blood 2016). HD daunorubicin has also been shown to be more effective than idarubicin in patients with FLT3-ITD AML (Lee et al, J Clin Oncol 2017). This data raises the question of whether the combination of midostaurin and HD daunorubicin would further improve outcomes of FLT3 mutated AML patients, while maintaining a tolerable safety profile. The objective of this study is to describe the safety and efficacy endpoints of FLT3 mutated AML patients treated with HD daunorubicin plus midostaurin as part of induction therapy. Methods: We retrospectively reviewed clinical and molecular data of patients at Memorial Healthcare System, Moffitt Cancer Center, and Sylvester Cancer Center with newly diagnosed FLT3 mutated AML treated from May 1st, 2017 to July 1st, 2019. Clinical data was abstracted in accordance with institutional review board approved protocol. All patients were induced with HD daunorubicin 90 mg/m2 on days 1-3, cytarabine 100 mg/m2 on days 1-7, and midostaurin 50 mg PO twice daily on days 8-21. Growth factor and antimicrobial support were used per institutional guidelines. Demographics were analyzed using descriptive statistics. OS was analyzed using Kaplan Meier method. Other efficacy outcomes were CR, CRi (assessed according to the European Leukemia Network Criteria for AML), proportion of patients needing re-induction, and proportion of patients who underwent hematopoietic stem cell transplant (HSCT). Safety outcomes were adverse events (AEs) and early (30- and 60-day) mortality. Results: Twenty-six patients were included in the final analysis. Patient characteristics are outlined in TABLE 1. All patients were FLT3 mutated, as confirmed with molecular studies. The FLT3 subtype was ITD (high) in 3 patients, ITD (low) in 16 patients, TKD in 5 patients, and both in 2 patients. Seventy-seven percent of patients achieved a CR/CRi after one induction cycle, and 96.2% attained CR after two induction cycles. Median time to ANC and platelet recovery was 28 and 26 days, respectively. One patient died during the first 60 days, due to Enterococcus sepsis. The most common non-hematological AEs were nausea (77%), diarrhea (62%), mucositis (58%), rash (54%), and increased ALT (54%). Cumulative incidence of relapse in the cohort was 28% (n=7). Four patients relapsed pre-transplant and achieved CR2 with additional therapy. All 7 of these patients had co-occurring mutations of various types. Of the 20 patients who were considered transplant eligible, 13 (65%) underwent HSCT and 4 (20%) are pending transplant. Of the 13 transplanted patients, 3 experienced relapse post-transplant. After a median follow up of 14.5 months, median OS has not been reached. Conclusion: In our multi-center experience, induction with HD daunorubicin, cytarabine, and midostaurin is clinically effective and seems to be well tolerated. Short term mortality was low and AEs were manageable, with no unexpected safety signals. Also, CR/CRi rates were higher than previously reported, suggesting that the combination of HD daunorubicin and midostaurin may improve the outcomes of patients with FLT3 mutated AML. Future analyses with larger patient samples and longer follow up are warranted to further evaluate long-term safety and efficacy for this regimen. Figure Disclosures Sandoval-Sus: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Bradley:AbbVie: Other: Advisory Board. Talati:Agios: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding.

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Phase II Trial of SGI-110 (Guadecitabine) in Philadelphia Negative Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-127663 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1666-1666

Author(s):

Pinkal Desai ◽

Niamh Savage ◽

Spencer Krichevsky ◽

Tania Curcio ◽

Sangmin Lee ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Progressive Disease ◽

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

Advisory Board ◽

Efficacy And Safety ◽

Advisory Committees

Introduction: Philadelphia negative myeloproliferative neoplasms (Ph- MPN) are hematopoietic stem cell malignancies associated with poor median survival of 12.4 months. They are often excluded from clinical trials because there are no accepted standards for treatment or assessment of disease response. SGI-110 (guadecitabine) is a second-generation DNA hypomethylating agent (HMA) that is currently in clinical trials for the treatment of myelodysplastic syndrome and acute myeloid leukemia. Guadecitabine was designed to resist degradation by protein aminases and prolong the exposure of tumor cells to the active metabolite decitabine. The purpose of this study was to test the efficacy and safety of SGI-110 in Philadelphia chromosome negative MPNs (Ph- MPN) and to also test the clinical applicability of the International IWG MDS/MPN response criteria in a prospective trial1. Methods: This is an interim analysis of an open label single-arm, single-institution study to evaluate the efficacy and safety of SGI-110 in Philadelphia chromosome negative (Ph-) myeloproliferative Neoplasms as classified by WHO, including chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), chronic myelomonocytic leukemia (CMML), myelodysplastic/myeloproliferative neoplasm unclassifiable, accelerated phase myelofibrosis and MPN unclassifiable (defined as peripheral and or bone marrow blasts of 10-19%). PV, ET and primary/secondary myelofibrosis were excluded. Patients were required to complete at least 3 cycles of guadecitabine to be considered evaluable for efficacy. Safety analyses were done on all patients who received any treatment with guadecitabine. Guadecitabine was administered subcutaneously at a dose of 60mg/m2 on days 1-5 repeated every 28 days. The IWG MDS/MPN response classification was used to assess treatment response. Results: Baseline characteristics of the study participants are presented in Table 1. Among the 20 treated patients, 2 (10.0%) were treated with previous HMAs, 3 had progressive disease, 1 transferred care, 7 were not yet evaluable for response, and 1 died after receiving only 2 cycles of treatment. Of the 13 evaluable, protocol specific response was seen in 8 (61.5%) patients: 2 (15.4%) achieved complete remission (CR), 3 (23.1%) with optimal marrow response (OMR), 3 (23.1%) with hematological response/clinical benefit (CB). Stable disease was seen in 4 patients (30.8%). Of the 7 patients that were inevaluable: 3 had progressive disease before completing 3 cycles, 2 received <3 cycles of therapy, 1 discontinued treatment due to personal choice, and 1 patient died from infection after receiving 2 cycles of treatment. The median overall survival (OS) for all evaluable patients was 27.4 months with 25.8 months for responders. Median OS for patients who achieved CR was 27.4 months and 25.0 months for OMR. For patients with CB, mean survival was 21.0 months. There was 1 patient with stable disease with prolonged survival (21 cycles), which elevated the mean survival to 26.0 months for the SD category. The median number of cycles to achieve a response was 3. The median times to first and best response were 3.6 and 3.8 months, respectively. The combination of ASXL1 and EZH2 mutations was associated with rapid progression. The most common AEs and SAEs related to guadecitabine are listed in Tables 2 and 3 respectively. Conclusion: SGI-110 was safe and well tolerated in patients with Ph negative MPN, with encouraging efficacy in this difficult-to-treat patient population. Further investigation of this agent in MDS/MPN overlap syndromes is warranted, and the present trial is ongoing. 1. Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. Mar 19 2015;125(12):1857-1865. Disclosures Desai: Cellerant: Consultancy; Astex: Research Funding; Astellas: Honoraria; Sanofi: Consultancy; Celgene: Consultancy. Lee:Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Ritchie:Celgene, Incyte, Novartis, Pfizer: Consultancy; Ariad, Celgene, Incyte, Novartis: Speakers Bureau; AStella, Bristol-Myers Squibb, Novartis, NS Pharma, Pfizer: Research Funding; Celgene, Novartis: Other: travel support; Jazz Pharmaceuticals: Research Funding; Celgene: Other: Advisory board; Pfizer: Other: Advisory board, travel support; agios: Other: Advisory board; Tolero: Other: Advisory board; Genentech: Other: Advisory board. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: 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; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: 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; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Prospective Evaluation of 18F-FDG PET/CT As Predictor of Prognosis in Newly Diagnosed Transplant Eligible Multiple Myeloma (MM) Patients: Results from the Imaging Sus-Study of the EMN02/HO95 MM Randomized Phase III Trial

Blood ◽

10.1182/blood.v128.22.992.992 ◽

2016 ◽

Vol 128 (22) ◽

pp. 992-992

Author(s):

Elena Zamagni ◽

Cristina Nanni ◽

Paola Tacchetti ◽

Annibale Versari ◽

Stephane Chauvie ◽

...

Keyword(s):

Board Of Directors ◽

Fdg Pet ◽

Research Funding ◽

Advisory Board ◽

Response To Therapy ◽

Phase Iii ◽

Newly Diagnosed ◽

Advisory Committees ◽

Pet Ct ◽

Fdg Pet Ct

Abstract F-18-fluorodeoxyglucose positron emission tomography integrated with computed tomography (FDG-PET/CT) enables to detect with relatively high sensitivity and specificity myeloma bone disease and extramedullary sites of metabolically active clonal plasma cells. FDG-PET/CT has also been used to assess and monitor the metabolic response to therapy and to predict the prognosis. One of the major limitation of PET/CT is the lack of standardized image criteria and of inter-observer reproducibility in interpreting the results. Aim of the present sub-study was to prospectively evaluate FDG-PET/CT at diagnosis, after 4 cycles of induction therapy and prior to maintenance therapy in a sub-group of patients enrolled into EMN02/HO95 MM international phase III trial. In particular, the two primary end-points were firstly to assess the prognostic significance of PET/CT at diagnosis and after therapy and secondly to standardize PET/CT evaluation by centralized imaging and revision and definition of criteria for interpretation. Seven hundred and 18 patients with newly diagnosed transplant-eligible symptomatic MM have been prospectively randomized in Italy from February 2011 through April 2014 to receive 4 cycles of bortezomib-melphalan-prednisone (VMP) vs high-dose melphalan and single or double autologous stem cell transplantation (ASCT) as intensification following induction with bortezomib-cyclophosphamide-dexamethasone (VCD). Consolidation therapy with bortezomib-lenalidomide-dexamethasone vs no consolidation was planned after VMP or ASCT(s), followed by lenalidomide maintenance until progression or toxicity. One hundred and three patients were included in the PET/CT imaging sub-study, and followed for a median of 24 months. By study design, PET/CT was performed and analysed in each of the 8 participating centres at baseline, after induction therapy and prior to the start of maintenance (EOT). Each PET scan was a posteriori re-interpreted in a blinded independent central review process, managed by WIDEN®, by a panel of 5 expert nuclear medicine physicians. They described the following characteristics: bone marrow metabolic state (BM), number (Fx) and score (Fs) of focal PET positive lesions, osteolysis (Lx), presence and site of extramedullary disease (EM), and fractures(Fr), according to the IMPeTUs criteria (Nanni et al, EJNM 2015). Moreover, a global score (GS), from 1 to 5, was given to each patient, considering the highest score among BM, Fx, Fs and EM. Concordance among reviewers on different metrics was calculated using Krippendorf's alpha (AK) coefficient Baseline characteristics of the patients were the following: median age 58 years, ISS and R-ISS stage III 15% and 10%, high-risk cytogenetics (t(4;14) ± del(17p) ±del (1p)±1q gain detected by FISH) 42%. At baseline, 78% of the patients had FLs, with a median SUVmax of 6.0. The percentages of PET positive patients for the different characteristics are summarized in table 1. The agreement among reviewer was good for BM (AK=0.49), Fx (AK=0.65), Fs (AK=0.62), Lx (AK=0.62) and EM (AK=0.40). Of all parameters, only Fx ≥ 4 was associated with worse PFS and OS (P = 0.06) Following 4 cycles of VCD, PET/CT remained positive in 59% of the patients, with a median SUVmax of 3.7. Of all parameters, only Fs ≥ 4 was predictive of worse OS (P= 0.05). Prior to maintenance therapy, PET/CT remained positive in 34% of the patients, with a median SUVmax of 3.4. Normal PET/CT findings before maintenance (66%) were associated with a significant improvement in PFS, in particular the following: presence of FLs (P=0.03), Fx ≥ 4 (P=0.001), Fs ≥2 (P=0.03), 3 (P=0.03) and 4 (P=0.006) and SUVmax ≥ 3.4 (p=0.002). GS was also predictive for PFS if ≥ 3 (P=0.033), 4 (P=0.0001) and 5 (P=0.004). The same parameters were also predictive for OS. The prognostic relevance of pre-maintenance PET/CT was retained across the randomization arm (VMP or ASCT), in terms of PFS and OS. In conclusion, PET/CT was confirmed to be a reliable predictor of outcome in newly diagnosed transplant eligible MM patients, whatever the treatment. Normalization of PET/CT before maintenance was associated with a significant improvement for PFS and OS. FDG-PET/CT is by now the preferred imaging technique for evaluating and monitoring response to therapy. Acknowledgments: this study was partially supported by a grant to Elena Zamagni from Fondazione del Monte di Bologna e Ravenna Table 1 Table 1. Disclosures Gay: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees. Larocca:Bristol-Myers Squibb: Honoraria; Janssen-Cilag: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Sonneveld:Celgene: Other: Advisory board, Research Funding; Onyx: Other: Advisory board, Research Funding; Millennium: Other: Advisory board, Research Funding; Janssen-Cilag: Other: Advisory board, Research Funding. Cavo:Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria.

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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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