Impact of Body Weight Adjusted Dose on Efficacy and Safety of Radotinib in Chronic Myeloid Leukemia
Abstract Background: Radotinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). It is typically administered as a fixed dose; however, a subanalysis of the Phase 2 study (Leuk Lymphoma. DOI 10.3109/10428194.2015.1113278) demonstrated that as the dose adjusted for body weight (Dose/BW) increased the risk of dose-limiting toxicity (DLT) significantly. Aims: To assess the impact of Dose/BW of radotinib on the occurrence of DLT as well as on the achievement of major molecular response (MMR) using the clinical data obtained from the Phase 3 study Methods: The Phase 3 study involved 160 CP-CML patients who were randomly assigned to a fixed dose of radotinib 300 mg BID or 400 mg BID regardless of BW. The authors performed a logistic regression analysis to evaluate the relationship between daily Dose/BW and the probability of achieving MMR at 12 months as well as experiencing DLT by 12 months. Chi-square test and Kaplan-Meier analysis (log-rank test) were utilized to compare the incidence of MMR and DLT, respectively, according to specific Dose/BW cut-offs. Results: Efficacy. Dose/BW of radotinib was negatively associated with the rate of MMR when controlled for gender (p = 0.033). That is, increasing Dose/BW rather decreased the likelihood of achieving MMR. More specifically, patients who received ≥13 mg/kg/d showed a significantly lower rate of MMR at 12 months (35%) than those who received <13 mg/kg/d (56%) (p = 0.045). Safety. Dose/BW of radotinib was positively associated with the rate of DLT (p = 0.003). A Dose/BW cut-off 13 mg/kg/d yielded the largest difference in the rate of DLT, such that the patients who received ≥13 mg/kg/d had a substantially higher rate of DLT (91%) than those who received <13 mg/kg/d (57%) (p <0.001). The time at which 50% of patients experienced their first DLT was also much earlier in the ≥13 mg/kg/d group (83 days) than in the <13 mg/kg/d group (194 days) (p <0.001). Conclusion: Dose adjustment of radotinib based on BW is warranted so as not to exceed 13 mg/kg/d. Therefore, a two-tier weight-based dosing regimen was developed: radotinib 300 mg BID for patients who weigh 60 kg or less, and 400 mg BID for patients who weigh more than 60 kg. A prospective clinical trial would be needed to confirm the efficacy and safety of this new dosing regimen. Disclosures Noh: Il-Yang Pharmaceutical: Research Funding. Jung:Il-Yang Pharmaceutical: Research Funding. Park:Il-Yang Pharmaceutical: Employment. Jo:Il-Yang Pharmaceutical: Employment. Shin:Il-Yang Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Lee:Il-Yang Pharmaceutical: Research Funding.
Background: In the two largest phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH), ravulizumab given every 8 weeks was noninferior to eculizumab given every 2 weeks across all efficacy endpoints. Data on efficacy and safety of ravulizumab in patients aged >65 years with PNH are limited. Aims: To compare the efficacy and safety of ravulizumab in patients with PNH aged >65 years with those aged ≤65 years. Methods: The population included patients from two phase 3 studies that assessed ravulizumab vs eculizumab in complement-inhibitor-naïve (301; NCT02946463) and -experienced (302; NCT03056040) adults with PNH. In study 301, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry and had a lactate dehydrogenase (LDH) level ≥1.5x upper limit of normal (ULN; 246U/L). In study 302, patients were aged ≥18 years with a confirmed PNH diagnosis by flow cytometry, were clinically stable on eculizumab having received ≥6 months of treatment and had a LDH level ≤1.5x ULN. Patients were randomized to either ravulizumab or eculizumab for 26 weeks after which all received ravulizumab up to 52 weeks. This prespecified analysis stratified patients by age: ≤65 or >65 years. Primary endpoints included percentage change in LDH from baseline to weeks 26 and 52, percentage of patients achieving LDH-normalization (LDH-N; LDH levels: ≤1x ULN) at weeks 26 and 52 and transfusion avoidance (TA) from baseline to weeks 26 and 52. Breakthrough hemolysis (BTH), hemoglobin (Hgb) stabilization and FACIT-fatigue score were secondary endpoints. Treatment emergent adverse events (TEAEs) were assessed as an indicator of safety. Results: A total of 58 patients aged >65 years and 383 patients aged ≤65 years were included. Disposition and medical history were similar among subgroups at baseline (Table 1). Results for primary and secondary endpoints for the two subgroups were comparable across studies and efficacy was maintained through 52 weeks. A higher proportion of treatment-experienced patients (>65 years) achieved all endpoints vs -naïve patients (Table 2). The percentage change in LDH levels from baseline to 26 and 52 weeks was similar between subgroups in study 301 (-66.5 to -80.0%) whereas in study 302, LDH levels remained stable in all subgroups up to 52 weeks (-3.7 to 22%). The percentage of patients achieving LDH-N in both studies at 26 and 52 weeks differed; 43.8-63.9% of patients aged ≤65 years achieved LDH-N compared with 21.4-77.8% of patients aged >65 years. A higher proportion of older treatment-experienced patients (57.1‒77.8%) achieved LDH-N compared with older treatment-naive patients (21.4‒50.0%) at 26 and 52 weeks. In patients aged ≤65 years in both studies, 63.7‒89.4% achieved TA. In the >65 years subgroup, 14.3‒50.0% of treatment-naive patients achieved TA whereas in study 302, 54.5‒72.7% of patients achieved TA. The number of BTH events was low, with no events reported in older patients to date. Hgb stabilization was consistent in the ≤65 year subgroup between the studies; a higher proportion of older patients in study 302 (45.5‒71.4%) achieved stabilized Hgb compared with older patients in study 301 (14.3‒35.3%). A clinically significant 3-point change was seen in FACIT-fatigue scores (indicating improvements in fatigue), with higher scores observed for ravulizumab in both subgroups (Figure 1). One patient discontinued the extension of study 301 due to lung cancer onset during the 26-week period and died following discontinuation. Headache was the most frequent TEAE. The incidence of TEAEs reported during ravulizumab treatment up to 52 weeks did not increase vs the 26-week period, with few events (Table 3) and no difference between subgroups. Conclusions: We present clinical outcomes in the largest cohort of patients with PNH (>65 years) on ravulizumab in a clinical trial setting to date. Ravulizumab was associated with similar efficacy and safety in both age subgroups and showed consistent and durable efficacy through 52 weeks of treatment. A higher proportion of patients in study 302 achieved all efficacy endpoints than in study 301, which can be due to patients' prior complement inhibitor experience. This observation was more evident in older patients. There were no BTH events in the older patients to date, and the number of infections in both subgroups was low. Ravulizumab was well tolerated in older patients with no additional safety concerns compared to younger patients. Disclosures Peffault De Latour: Apellis: 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, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Szer:Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Piatek:Alexion Pharmaceuticals: Consultancy, Research Funding. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Yu:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Background: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is a life-threatening, irreversible condition, which can lead to heart failure (HF) and, ultimately, heart transplant or death. Despite the recent approval in United States of a TTR stabilizer (VYNDAQEL®-tafamidis meglumine;VYNDAMAX™-tafamidis) for the treatment of ATTR-CM, disease progression still occurs. This study aims to determine if treatment with AKCEA-TTR-LRx (ION-682884), an antisense oligonucleotide (ASO), is safe and superior to placebo in reducing the risk of cardiovascular (CV) death or CV clinical events in patients with hereditary (hATTR-CM) or wild-type ATTR-CM (wtATTR-CM). Study Design and Methods: AKCEA-TTR-LRx (ION-682884) is a follow-on compound that incorporates the Ligand-Conjugated Antisense (LICA) technology; in this case, a triantennary N-acetyl galactosamine (GalNAc) moiety which targets the asialoglycoprotein receptors (ASGPR) expressed abundantly on the hepatocyte cell surface. In comparison to inotersen, its parent compound, ION-682884 requires a lower dose and frequency of administration (27-fold smaller; 45mg SC Q4W) to achieve a similar reduction in ATTR, providing greater patient convenience. ION-682884-CS2 (EudraCT No: 2019-002835-27) is a Phase 3 global, double-blind, randomized, placebo-controlled study assessing the efficacy and safety of AKCEA-TTR-LRx (ION-682884) in hATTR-CM or wtATTR-CM patients receiving available background standard of care (SoC) therapy. Approximately 750 patients with a history of HF due to ATTR-CM will be randomized 1:1 to receive AKCEA-TTR-LRx (ION-682884) or placebo administered by subcutaneous injection once every 4 weeks. The main inclusion criteria include confirmed diagnosis of ATTR-CM by tissue biopsy or positive PYP/DPD scan, end-diastolic interventricular septum thickness of >12mm, NT-proBNP >600 pg/mL, NYHA class I-III and 6-minute walk distance (6MWD) >150 m. The main exclusion criteria include estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2, platelet count below the low limit of normality and urine protein/creatinine ratio (UPCR) ≥ 1000 mg/g. Patients are allowed to concomitantly receive tafamidis/tafamidis meglumine as SoC for ATTR-CM, if locally approved and available, per physician's discretion. The study consists of a 120-week Treatment Period and a 20-week Post-Treatment Evaluation Period. During each study visit, subjects will undergo laboratory tests, cardiac assessments (echocardiography), and functional evaluations. Patient-reported outcomes (PRO) will also be collected. Primary efficacy endpoint is the composite of CV mortality and frequency of CV clinical events (HF-related urgent visits requiring administration of IV diuretics and/or CV-related hospitalizations) at Week 120 study visit, analyzed by the Finkelstein-Shoenfeld method. This test is based on the principle of each patient in the study being compared with every other patient in a pairwise manner in hierarchical fashion. Secondary endpoints include the change from baseline in the 6MWD, Kansas City Cardiomyopathy Questionnaire score, rate of CV mortality, CV clinical events, and all-cause of mortality at Week 120. Additional exploratory endpoints include a change from baseline in cardiac imaging parameters, renal function, biomarkers, and PROs questionnaires and disease scores. An interim analysis on change from baseline in 6MWD is also planned at Week 60. All deaths and CV clinical events will be adjudicated by an independent, blinded Clinical Adjudication Committee, using predefined endpoint criteria. Conclusions: Despite recent advances, there is still a need for more efficacious, safe and convenient treatment options for ATTR-CM. The ION-682884-CS2 is a large Phase 3 trial designed to evaluate the clinical efficacy and safety of AKCEA-TTR-LRx (ION-682884) compared to placebo for the treatment of ATTR-CM. Figure Disclosures Falk: Ionis Pharmaceuticals: Consultancy. Gertz:Ionis/Akcea: Consultancy; Alnylam: Consultancy; Proclara: Membership on an entity's Board of Directors or advisory committees; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding. Benson:Ionis Pharmaceuticals: Research Funding. Buchele:Ionis Pharmaceuticals: Employment. Brambatti:Ionis Pharmaceuticals: Employment. Tsimikas:Ionis Pharmaceuticals: Employment. Viney:Ionis Pharmaceuticals: Employment. Tai:Ionis Pharmaceuticals: Employment. Monteiro:Ionis Pharmaceuticals: Employment. Yang:Ionis Pharmaceuticals: Employment. O'Dea:Akcea Therapeutics: Employment. Karwatowska-Prokopczuk:Akcea Therapeutics: Employment. Schneider:Ionis Pharmaceuticals: Employment. Geary:Ionis Pharmaceuticals: Employment. Monia:Ionis Pharmaceuticals: Employment.
Introduction: Anemia is the predominant cytopenia observed in patients with myelodysplastic syndromes (MDS), with many patients requiring regular red blood cell (RBC) transfusions. Erythropoiesis-stimulating agents (ESAs) remain a standard of care among patients with lower-risk MDS (LR-MDS), defined by International Prognostic Scoring System-Revised (IPSS-R) as Very Low-, Low-, or Intermediate-risk MDS, and endogenous serum erythropoietin (sEPO) levels ≤ 500 U/L. Recent studies of epoetin alfa and darbepoetin alfa have demonstrated efficacy among patients with LR-MDS, but the patient population in whom a clinically significant effect is seen may be limited (Fenaux P, et al. Leukemia 2018;32:2648-2658; Platzbecker U, et al. Leukemia 2017;31:1944-1950). A novel therapeutic option that increases the frequency of response and the duration of RBC transfusion independence (TI) in patients with LR-MDS would provide an important clinical benefit in this patient population. Luspatercept is a first-in-class erythroid maturation agent with a mechanism of action distinct from ESAs (Suragani RNVS, et al. Nat Med 2014;20:408-414). It is now approved in both the US and EU for patients with LR-MDS with ring sideroblasts (RS) who require RBC transfusions and are refractory, intolerant, or ineligible to receive ESAs on the basis of results from a phase 3 study (Fenaux P, Platzbecker U, et al. N Engl J Med 2020;382:140-151). Luspatercept may also be beneficial in treating anemia in patients with ESA-naive, LR-MDS who require RBC transfusions. In a phase 2 study in anemic patients with LR-MDS, 63% of patients receiving luspatercept (0.75-1.75 mg/kg) achieved a modified hematologic improvement - erythroid (mHI-E) response (Platzbecker U, et al. Lancet Oncol 2017;18:1338-1347); when analyzed by RS status, 69% of patients with ≥ 15% RS and 43% of patients with < 15% RS achieved mHI-E response. Study Design and Methods: The COMMANDS trial is a phase 3, open-label randomized study to compare the efficacy and safety of luspatercept versus epoetin alfa in anemic patients with IPSS-R defined LR-MDS, either with or without ≥ 15% RS, who are ESA naive, and who require regular RBC transfusions. Eligible patients must be aged ≥ 18 years at time of consent, have a documented diagnosis of IPSS-R defined LR-MDS with < 5% blasts in the bone marrow, have sEPO levels < 500 U/L, and require RBC transfusions (defined as an average transfusion requirement of 2-6 RBC units/8 weeks for ≥ 8 weeks immediately prior to randomization). Exclusion criteria include prior use of ESAs (≤ 2 doses of prior epoetin alfa permitted if ≥ 8 weeks from randomization date and sEPO confirmed as ≤ 500 U/L), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), unless given for the treatment of febrile neutropenia; disease-modifying agents (e.g. lenalidomide), or hypomethylating agents; and presence of del(5q) cytogenetic abnormality. A total of approximately 350 eligible patients will be randomized in a 1:1 ratio to receive either luspatercept (starting dose 1.0 mg/kg with titration up to 1.75 mg/kg) subcutaneously (SC) once every 3 weeks or epoetin alfa (starting dose 450 IU/kg with titration up to 1,050 IU/kg) SC once every week, for a minimum of 24 weeks (Figure). Best supportive care, including RBC transfusions, may be used in combination with study treatment in both arms. Randomization will be stratified by baseline RBC transfusion burden (< 4 vs ≥ 4 RBC units per 8 weeks), RS status (with RS+ defined as RS ≥ 15%, or ≥ 5% [but < 15%] if SF3B1 mutation is present), and baseline sEPO level (≤ 200 U/L versus > 200 U/L). In addition, ≥ 40% and ≤ 60% of randomized patients will be RS+, and ≥ 25% will have sEPO > 200 U/L. The primary endpoint is the proportion of patients who achieve RBC-TI for 12 weeks within the first 24 weeks on study, with a concurrent mean hemoglobin (Hb) increase of ≥ 1.5 g/dL compared with baseline. Key secondary endpoints include duration of RBC-TI, change in Hb levels, achievement of HI-E response per International Working Group (IWG) 2006 criteria, and safety. The COMMANDS trial is registered at ClinicalTrials.gov (NCT03682536) and EudraCT (number 2017-003190-34). Disclosures Platzbecker: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria. Santini:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Merck: Research Funding. Komrokji:Geron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau; Acceleron: Honoraria; BMS: Honoraria, Speakers Bureau. Ito:BMS: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.
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.
Abstract Background: Treatment options for RBC-TD pts with lower-risk MDS without del(5q) who are unresponsive or refractory to ESAs are very limited. In a previous phase 2 study, MDS-002 (CC-5013-MDS-002), LEN was associated with achievement of RBC-transfusion independence (TI) ≥ 56 days in 26% of pts with IPSS Low/Int-1-risk MDS without del(5q) (Raza et al. Blood 2008;111:86-93). This international phase 3 study (CC-5013-MDS-005) compared the efficacy and safety of LEN versus PBO in RBC-TD pts with IPSS Low/Int-1-risk MDS without del(5q) unresponsive or refractory to ESAs. Methods: This multicenter, randomized, double-blind, parallel-group phase 3 study included RBC-TD pts (≥ 2 units packed RBCs [pRBCs]/28 days in the 112 days immediately prior to randomization) with IPSS Low/Int-1-risk MDS without del(5q), who were unresponsive or refractory to ESAs (RBC-TD despite ESA treatment with adequate dose and duration, or serum erythropoietin [EPO] > 500 mU/mL). Pts were randomized 2:1 to oral LEN 10 mg once daily (5 mg for pts with creatinine clearance 40–60 mL/min) or PBO. Pts with RBC-TI ≥ 56 days or erythroid response by Day 168 continued double-blind treatment until erythroid relapse, disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was RBC-TI ≥ 56 days (defined as absence of any RBC transfusions during any 56 consecutive days). Secondary endpoints included time to RBC-TI, duration of RBC-TI, RBC-TI ≥ 168 days, progression to acute myeloid leukemia (AML; WHO criteria), overall survival (OS), and safety. Baseline bone marrow gene expression profiles were evaluated according to the Ebert signature (PloS Med 2008;5:e35) identified as predictive of LEN response. Clinical trial identifier: CT01029262. Results: The intent-to-treat population comprises 239 pts (LEN, n = 160; PBO, n = 79). Baseline characteristics were comparable across treatment groups; median age 71 years (range 43–87), 67.8% male, and median time from diagnosis 2.6 years (range 0.1–29.6). Pts received a median of 3.0 pRBC units/28 days (range 1.5–9.8) and 83.7% received prior therapy, including ESAs (78.7%). Significantly more LEN pts achieved RBC-TI ≥ 56 days versus PBO (26.9% vs 2.5%; P < 0.001; Table). The majority (90%) of pts with RBC-TI ≥ 56 days responded within 16 weeks of treatment. Median duration of RBC-TI ≥ 56 days was 8.2 months (range 5.2–17.8). Baseline factors significantly associated with achievement of RBC-TI ≥ 56 days with LEN were: prior ESAs (vs no ESAs; P = 0.005), serum EPO ≤ 500 mU/mL (vs > 500 mU/mL; P = 0.015), < 4 pRBC units/28 days (vs ≥ 4 pRBC units/28 days; P = 0.036), and female sex (vs male; P = 0.035). RBC-TI ≥ 168 days was achieved in 17.5% and 0% of pts in the LEN and PBO groups, respectively. The incidence of AML progression (per 100 person-years) was 1.91 (95% CI 0.80–4.59) and 2.46 (95% CI 0.79–7.64) for LEN and PBO pts, respectively, with median follow-up 1.6 and 1.3 years. Death on treatment occurred in 2.5% of pts on either LEN or PBO. The follow-up period was insufficient to permit OS comparison between the 2 groups. Myelosuppression was the main adverse event (AE); in the LEN versus PBO groups, respectively, grade 3–4 neutropenia occurred in 61.9% versus 11.4% of pts, and grade 3–4 thrombocytopenia in 35.6% versus 3.8% of pts. Discontinuations due to AEs were reported in 31.9% LEN and 11.4% PBO pts; among the 51 LEN pts who discontinued due to AEs, 14 discontinuations were due to thrombocytopenia and 8 due to neutropenia. In the subset of pts evaluated for the Ebert signature (n = 203), the predictive power of the signature was not confirmed. Conclusions: LEN therapy was associated with a significant achievement of RBC-TI ≥ 56 days in 26.9% of pts with a median duration of RBC-TI of 8.2 months; 90% of pts responded within 16 weeks of treatment. These data were consistent with response rates seen in the MDS-002 trial. The overall safety profile was consistent with the known safety profile of LEN and these data suggest LEN can be safely and effectively used in this patient population. Figure 1 Figure 1. Disclosures Santini: Celgene Corporation: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria. Off Label Use: Trial of Lenalidomide in non-del5q MDS. Almeida:Celgene Corporation: Consultancy, Speakers Bureau. Giagounidis:Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Vey:Celgene: Honoraria. Mufti:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Buckstein:Celgene: Research Funding. Mittelman:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Research Funding. Shpilberg:Celgene Corporation: Consultancy, Honoraria. del Canizo:Celgene Corporation: Consultancy, Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ozawa:Celgene: Consultancy, not specified Other. Zhong:Celgene: Employment, Equity Ownership. Séguy:Celgene: Employment, Equity Ownership. Hoenekopp:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene: Research Funding.
Abstract Background: Ropeginterferon alfa-2b (Ropeg) is a novel long-acting monopegylated IFN-alpha-2b. Due to reduced dosing frequencies, better tolerability and improved compliance, Ropeg may be a favorable treatment option for long-term therapy in patients with polycythemia vera (PV). Study design: PEGINVERA phase I/II (NCT: 2010-018768-18), a prospective, open-label, multicenter study, investigated the efficacy and safety of Ropeg for long-term treatment in 51 patients aged ≥18 years with a confirmed diagnosis of PV, regardless of prior cytoreductive therapy. Following ≥1 year of 2-weekly treatment, patients who responded well to Ropeg were permitted to switch to a 4-weekly dosing regimen. Results: Baseline characteristics of the study cohort and interim safety and efficacy data were presented previously (Gisslinger et al., Blood, 2015). Fifty-one patients were treated: Median exposure to Ropeg was approximately 5.1 years (61 months; range: 0 to 87 months). Patients were treated for a median of approximately 2 years (98.9 weeks; (Q1-Q3: 69.0 - 117.4 weeks) on the 2-weekly regimen and 4 years (207.1 weeks; Q1-Q3: 158.6 - 242.0 weeks) on the 4-weekly regimen. The best observed individual hematological response for patients in the efficacy analysis set (FAS) was a complete hematological response for 27/42 (64.3%) and a partial response for 14/42 (33.3%) patients. Patients required a median of 34 weeks (Q1-Q3: 10-96 weeks) treatment to achieve a complete hematological response, and 10 weeks (Q1-Q3: 10-20 weeks) to achieve any hematological response. Switch from 2 to 4-week dosing regimen had no apparent effect on maintenance of response. With respect to JAK-2 allele burden, the best observed individual molecular response was a complete response for 12/42 (28.6%) patients and a partial response for 19/42 (45.2%) patients. Lowest JAK-2 values relative to baseline are presented by patient in Figure 1. Patients required a median of 82 weeks (Q1-Q3: 44-115 weeks) treatment to achieve a complete molecular response and 34 weeks (Q1-Q3: 18-55 weeks) treatment to achieve any molecular response. Irrespective of dosing regimen, molecular responses tended to increase over time. Most patients reported at least one adverse reaction (AR) to treatment (409 ARs in 48/51 [94.1%]); however, the majority (296 in 44 [86.3%] patients) were mild; 102 (in 34 [66.7%] patients) were moderate and 11 (in 10 [19.6%] patients) were severe. The most frequently reported ARs (frequency >20%) were arthralgia, influenza-like illness and fatigue. Twelve serious treatment emergent adverse events (TEAE) reported by 8/51 patients (15.7%) were considered to be treatment related: 2 events of depression, 2 of positive anti-thyroid antibodies, and one each of acute stress disorder, increased antinuclear antibodies, arthralgia, atrial fibrillation, fatigue, influenza-like illness, pyrexia, and increased transaminases. 25 patients completed the trial. The majority of discontinuation due to TEAE (13/21 patients) occurred in the first year, when the recommended slow up-titration of Ropeg could not be applied because of the maximum-tolerated-dose design. After the first year, only 8 additional patients discontinued because of TEAE. Conclusions: The final results of this phase I/II study of Ropeg in patients with PV support the findings of the pivotal phase III clinical trial (Gisslinger et al., Blood 2015) with respect to safety and efficacy as determined by hematological, clinical and molecular parameters. In addition, these data provide evidence that treatment with Ropeginterferon alfa-2b for up to 7 years is efficacious, well-tolerated and disease-modifying at both the 2 week and 4 week maintenance treatment regimens. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Kralovics:MyeloPro Diagnostics and Research GmbH: Equity Ownership. Krauth:BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Greil:MSD: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zoerer:AOP Orphan Pharmaceuticals: Employment. Empson:AOP Orphan Pharmaceuticals: Employment. Grohmann-Izay:AOP Orphan Pharmaceuticals AG: Employment. Klade:AOP Orphan Pharmaceuticals AG: Employment.
Background Chronic myeloid leukemia (CML) is characterized by the BCR-ABL1 fusion gene. Despite the use of tyrosine kinase inhibitors (TKIs), a minority of chronic phase (CP) CML patients fail TKI therapies and progress to blast crisis (BC), showing dismal outcomes. Although genetic studies have revealed that CML-BC frequently carries not only ABL1 mutations but other driver mutations, our knowledge about the mechanism of TKI resistance and progression to BC is still limited by a relatively small number of patients and/or genes analyzed in each study. Moreover, it remains elusive whether mutations can predict clinical outcomes of BC patients, in which few biomarkers are known. Here, we investigated a large cohort of CML patients to reveal the landscape of genetic lesions and those predicting clinical outcomes in CML. Methods We performed whole-exome sequencing (WES) of paired CP and BC samples from 52 patients and targeted-capture sequencing that covered myeloid driver genes in 32 BC and 19 CP samples. Combined with public WES data for 24 BC and 77 CP, we analyzed a total of 108 BC and 148 CP samples. Results In WES analysis of paired CP and BC samples, an average of 5.3 nonsynonymous mutations were acquired during disease progression from CP to BC. Notably, a Poisson regression model revealed that the number of acquired mutations was positively correlated with time to progression from CP to BC (P < 0.001) and negatively with TKI therapy after CP diagnosis (P = 0.0093), although the correlation of the number of driver mutations in CML-BC with time to progression was not clear. These results suggest that the use of TKI effectively reduces the size of tumor populations at risk for clonal evolution by acquiring random mutations, by which prevents BC. In CML-BC, we found frequent mutations not only in known mutational targets in other hematological malignancies, such as RUNX1, ABL1, ASXL1, BCOR/BCORL1, TP53, and WT1, but also in other genes recently reported in BC (UBE2A and SETD1B) and previously unreported mutational targets in cancer (KLC2 and NBEAL2). Deep amplicon-sequencing revealed that ASXL1 mutations were already present at the time of CP diagnosis in most cases, whereas others such as RUNX1, ABL1, and TP53 mutations were absent in CP and newly emerged during progression to BC. Some abnormalities, such as +21, +8, and ASXL1 mutations, were more enriched in myeloid than lymphoid crisis, while others, including CDKN2A/B and IKZF1 deletions, -7/del(7p), -9/del(9p), and ABL1 mutations, vice versa. By contrast, abnormalities such as RUNX1 mutations and double Ph were almost equally observed in both crises. In univariate analysis of clinical factors for overall survival (OS) in 77 CML-BC cases for whom survival information was available, TKI-containing therapy for BC was significantly associated with a better OS, whereas genetic lesions including ASXL1 and TP53 mutations, del(17p), amp(17q), +19, and +21 had a negative impact on OS. Conspicuously, patients with TP53 mutations, del(17p), and amp(17q) showed an especially dismal outcome. We then performed a multivariate analysis using a Cox proportional hazard regression model, focusing on 36 TKI-treated patients, because TKI-containing therapy has been shown to improve OS and therefore, is a standard choice of therapy. We found that ASXL1 and BCOR mutations, complex copy-number alterations, amp(17q), and +21 were independent predictors for worse prognosis. Based on the number of these unfavorable factors, patients were classified into three subgroups showing distinct prognosis, where the 2-year OS rate was 71.8%, 15.6%, and 0% for patients with 0, 1, and ≥2 risk factors, respectively (P < 0.001). Finally, we explored the genetic abnormalities and clinical outcomes in CML-CP. In CP, only ASXL1 was mutated at a frequency comparable to that in BC, while others, including TET2, KMT2D, PTPN11, RUNX1, and WT1, were mutated at much lower frequencies. Of interest, patients who later developed BC more frequently had at least one genetic abnormality, suggesting that mutations found at the time of CP might play a role in driving CML cells to BC under the pressure of TKI treatment. Conclusion Our study clarified a comprehensive registry of genetic lesions in BC in a large cohort of CML patients and their prognostic impact, which should provide a clue to the development of better therapy/management for patients with CML. Disclosures Takaori-Kondo: Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Ono Pharmaceutical: Research Funding; Thyas Co. Ltd.: Research Funding; Takeda: Research Funding; CHUGAI: Research Funding; Eisai: Research Funding; Nippon Shinyaku: Research Funding; Otsuka Pharmaceutical: Research Funding; Pfizer: Research Funding; OHARA Pharmaceutical: Research Funding; Sanofi: Research Funding; Novartis Pharma: Honoraria; MSD: Honoraria. Mitani:CHUGAI: Research Funding; Takeda: Research Funding; KYOWA KIRIN: Consultancy, Research Funding. Ogawa:Chordia Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asahi Genomics Co., Ltd.: Current equity holder in private company; Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; KAN Research Institute, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Shih:Novartis: Research Funding; Celgene: Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Abstract Abstract 622 Background: Lenalidomide is an oral IMiD® compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity, and has proven efficacy in patients with MM. The current study (MM-015) is a prospective, randomized phase 3 trial designed to evaluate the efficacy and safety of continuous lenalidomide treatment (MPR-R: melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance) vs fixed-duration regimens of melphalan and prednisone (MP) or melphalan, prednisone, and lenalidomide (MPR) in transplant-ineligible patients with NDMM. Methods: 459 patients aged ≥ 65 years with NDMM, stratified by age and International Staging System (ISS) stage were randomized to receive MPR-R, MPR, or MP. During double-blind treatment, patients received melphalan 0.18 mg/kg (D1-4), prednisone 2 mg/kg (D1-4), with or without lenalidomide 10 mg/day (D1-21) for nine 28-day cycles. Following 9 cycles of MPR, patients received maintenance lenalidomide (10 mg/day; D1-21) or placebo until progression; MP patients received placebo until progression. Patients with progressive disease (PD) could enroll in the open-label extension phase (OLEP) and receive lenalidomide at 25 mg/day (D1-21) with or without dexamethasone at 40 mg/day (D1-4, 9–12, and 17–20). The primary comparison for this trial was MPR-R vs MP. Updated data from a pre-planned interim analysis at 70% of events (median follow-up of 21 months) are presented. Results: MPR-R compared with MP resulted in a higher overall response rate (ORR; 77% vs 50%, P <.001) as well as higher rates of complete response (16% vs 4%, P < .001) and very good partial response (VGPR) or better (32% vs 12%, P < .001). Responses were more rapid in patients receiving MPR-R compared with MP (median 2 vs 3 months, P < .001), and improved over time. Overall, MPR-R reduced the risk of disease progression by 58% compared with MP (hazard ratio [HR] = 0.423, P < .001) with a higher 2-year progression-free survival (PFS) rate (55% vs 16%). PFS was extended in patients receiving continuous lenalidomide therapy vs fixed-duration MP regardless of gender, ISS stage (stage I/II vs III), kidney function (creatinine clearance ≥ 60 vs < 60 mL/min), or baseline β2-microglobulin (≤ 5.5 vs > 5.5 mg/L). A landmark analysis comparing MPR-R and MPR initiated at the beginning of cycle 10 demonstrated that maintenance lenalidomide resulted in a 69% reduced risk of progression compared with placebo (HR = 0.314, P < .001). In addition, regardless of induction response (≥ VGPR or PR), patients who received maintenance lenalidomide had longer PFS compared with placebo. Importantly, patients relapsing during MPR-R had similar second-line treatment duration (median 55 weeks) compared with those relapsing while on placebo following MPR or MP (median 68 and 54 weeks, respectively). Additionally, PD rates during the OLEP were similar across all treatments (13% for each). Thus, outcomes of patients who relapse following continuous lenalidomide are similar to those who relapse following fixed-duration regimens, suggesting maintenance lenalidomide is not associated with more aggressive relapse. Follow-up remains too short to identify significant overall survival differences between the 3 groups. MPR-R had a manageable safety profile with minimal cumulative toxicities. Discontinuation rates due to adverse events (AEs) for patients treated with MPR-R and MP were 20% and 8%, respectively. Grade 3/4 neutropenia, thrombocytopenia, and anemia occurred in 71%, 38%, and 24% of patients receiving MPR-R and 30%, 14%, and 17% of those receiving MP; no grade 3/4 peripheral neuropathy was observed. Importantly, maintenance lenalidomide was as well tolerated as placebo, with few grade 3/4 AEs. During maintenance, low rates of thrombocytopenia (3% vs 2%, respectively), neutropenia (2% vs 0%), deep vein thrombosis (1% vs 0%), and fatigue (1% vs 0%) were observed. Conclusions: MPR-R achieved a higher ORR, as well as better quality and more rapid responses vs MP. Furthermore, MPR-R compared with fixed-duration regimens of MP and MPR resulted in an unprecedented reduction in the risk of progression with a manageable safety profile, and similar rates of PD in subsequent OLEP treatment. These data suggest that continuous lenalidomide therapy with MPR-R is superior to regimens of limited duration by providing sustained disease control in transplant-ineligible patients with NDMM. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma. Delforge:Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho-Biotech: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants. Hajek:Celgene: Honoraria; Janssen-Cilag: Honoraria. Kropff:OrthoBiotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Petrucci:Celgene: Honoraria; Janssen-Cilag: Honoraria. Yu:Celgene: Employment. Herbein:Celgene: Employment. Mei:Celgene: Employment. Jacques:Celgene: Employment. Dimopoulos:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Abstract Background: Patients (pts) with secondary acute myeloid leukemia (s-AML) have poor long-term outcomes following standard induction chemotherapy with 7+3. Last year, a liposomal cytarabine and daunorubicin formulation (CPX-351) was FDA approved for upfront treatment of s-AML based on a pivotal phase 3 trial demonstrating improved overall survival in pts aged 60-75 years old (Lancet J et al; JCO 2018). Although CPX-351 treatment is indicated in all adults with s-AML, it is unclear whether CPX-351 is safe and effective in younger pts < 60 years. We sought to address this unanswered question by retrospective review of clinical experience since FDA approval at 4 large academic centers. Methods: Medical records were retrospectively reviewed at Roswell Park Comprehensive Cancer Center, Moffitt Cancer Center, University of Alabama Comprehensive Cancer Center, and Levine Cancer Institute to identify pts aged 18-59 years old with untreated s-AML defined as antecedent MDS or CMML, prior cytotoxic therapy, or AML with WHO defined myelodysplasia related changes (AML-MRC) treated with CPX-351 as induction therapy. Demographics, disease-specific variables, as well as overall outcomes were collected in accordance with the institutional review board approved protocol. Responses were defined according to the 2003 International Working Group (IWG) criteria. Demographics, baseline clinical characteristics, treatment response, and adverse events were analyzed using descriptive statistics. Overall survival was estimated utilizing Kaplan-Meier (KM) analysis. Results: Twenty-one pts with confirmed s-AML received CPX-351 therapy. Mean age was 54 years (range 42 - 59), 13 were male (62%). The majority (62%, N=13) had AML-MRC, 4 (19%) had treatment-related AML (t-AML) and 4 (19%) had MDS-MRC. Four of 5 pts had received prior hypomethylating therapy. Fourteen pts had a complex karyotype (67%), and 4 patients were found to have a normal karyotype (12%). The most common molecular event was TP53 mutation seen in 9 pts (43%), followed by FLT3-ITD identified in 3 pts (14%). At the time of analysis, response assessments were available for 16 pts. Overall response rate (CR/CRi/PR) was 25% with 1 CR (6.25%, 1/16), 1 CRi (6.25%, 1/16), and 2 PR (13%, 2/16). The remaining pts (12/16, 75%) were non-responders (Table 1). One pt has received an allogenic stem cell transplant. The most common adverse event was infection (81%, 17/21) with 3 clinically significant bleeding events. Thirty-day mortality was 14.3%, with 60-day mortality of 19.1%. Overall survival in all evaluable pts (N=21) was 7.1 months (range 0.5 - 7.4 months) (Figure 1), with mean follow up of 14.8 weeks. Conclusions: This multi-institutional retrospective analysis suggests that CPX-351 results in lower response rates (CR/CRi 12.5%) and shorter overall survival (7.1 mos) than reported in the recently published phase 3 trial data in pts aged 60-75 years old (Table 1). Potential explanations for this discrepancy include short follow up, small sample size, the retrospective design of this study, and the significant proportions of pts with complex karyotype and TP53 mutations. Historically, patients < 65 years old with s-AML have had a reported overall survival of approximately 7 months. Further investigation of this regimen in younger pts with s-AML as compared with 7+3 and other approaches is warranted. Disclosures Thota: Incyte: Speakers Bureau. Baron:Pfizer Pharmaceuticals: Other: Previously served as a consult on the Advisory Boards (May 2017).. Griffiths:Alexion Inc.: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding. Sweet:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria; Incyte: Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy; Celgene: Speakers Bureau. Wang:Jazz: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Background: Bosutinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. The efficacy and safety of bosutinib by baseline comorbidities in patients with CML resistant/intolerant to prior TKIs were investigated. Methods: The phase 4 BYOND trial (NCT02228382) is further examining efficacy and safety of bosutinib (starting dose 500 mg/day) in patients with CML resistant/intolerant to prior TKIs. Comorbidities were analyzed using the Charlson Comorbidity Index (CCI), a validated measure of the influence of relevant comorbid conditions on mortality. Scores were derived from baseline data and patients grouped by CCI score 2-3, 4-5, and ≥6. This analysis was based on ≥1 year of follow-up and included patients with Ph+ CP CML. Results: 156 patients with Ph+ CP CML (n=42 [26.9%], 48 [30.8%], and 66 [42.3%] for CCI 2-3, 4-5, and ≥6) received bosutinib. Median treatment duration was 28.9, 23.9, and 20.1 months for CCI 2-3, 4-5, and ≥6; median dose intensity was 366.7, 385.3, and 291.5 mg/day. Across CCI groups, a substantial proportion of patients attained/maintained cytogenetic and molecular responses (Table). Grade 3/4 treatment-emergent adverse events (TEAEs) rates were 64.3%, 72.9%, and 80.3% for CCI 2-3, 4-5, and ≥6. Emerging grade 3/4 TEAEs differed between groups; diarrhea and increased alanine aminotransferase (ALT) were more common for CCI 2-3 (21.4% and 23.8%, respectively) and 4-5 (18.8% and 16.7%) and pleural effusion more common for CCI ≥6 (12.1%). For CCI 2-3, 4-5, and ≥6, 19.0%, 20.8%, and 31.8% of patients discontinued treatment due to AEs and 2.4%, 2.1%, and 9.1% due to insufficient response. Most common AEs leading to discontinuation in the respective groups were increased ALT and aspartate aminotransferase (7.1% each), increased ALT (8.3%), and pleural effusion (3.0%). 10 deaths occurred (n=0 [0%], 1 [2.1%], and 9 [13.6%] for CCI 2-3, 4-5, and ≥6), 8 due to AEs (none bosutinib-related), 1 CML-related, and 1 of unknown cause. No on-treatment transformations to advanced CML occurred. Conclusions: Across CCI groups, a majority of patients with Ph+ CP CML achieved/maintained cytogenetic and molecular responses, and only 1 CML-related death was reported. Patients with CCI ≥6 showed a trend toward higher rates of TEAEs, discontinuations due to AEs, and death. Results demonstrate efficacy of bosutinib across CCI scores, including patients with important comorbidities. However, CCI stratification may enable identification of patients at higher risk of developing TEAEs who require more careful monitoring. Disclosures Gambacorti-Passerini: Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Ariad: Consultancy. Gjertsen:Astellas: Consultancy; The Norwegian Cancer Society: Research Funding; BerGenBio: Consultancy; ERA PerMed: Research Funding; ACTII AS: Equity Ownership; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy; Haukeland University Hospital / University of Bergen: Employment; KinN Therapeutics AS: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Helse Vest Health Trust: Research Funding; Research Council of Norway: Research Funding; EU Horizon 2020: Research Funding; BerGenBio AS: Membership on an entity's Board of Directors or advisory committees. Abboud:Jazz Pharma: Speakers Bureau; Novartis: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017), Research Funding; Agios: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017); Tetraphase Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NKarta: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer Inc: Employment, Equity Ownership. García Gutiérrez:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Giles:Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Novartis: Consultancy; Actuate Therapeutics Inc: Employment. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding.