ALBERT

Description: Key Points Nilotinib induced deeper molecular responses than continued imatinib in patients with minimal residual disease on long-term imatinib. These deeper responses may enable more patients to benefit from treatment-free remission trials.

Description: Abstract 694 Background: Superior rates of deeper molecular responses were achieved with nilotinib vs imatinib in patients newly diagnosed with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials—newly diagnosed patients (ENESTnd) trial. In addition, the 12-month (mo) analysis of the ENEST—complete molecular response (ENESTcmr) study demonstrated that switching to nilotinib after a minimum of 2 years on imatinib led to increased rates of major molecular response (MMR) and deeper molecular responses vs remaining on imatinib. Results from ENESTcmr are presented here with minimum 24 mo of patient follow-up. Methods: Patients with Ph+ CML-CP who had achieved complete cytogenetic responses but still had persistent BCR-ABL positivity by real-time quantitative polymerase chain reaction (RQ-PCR) after ≥ 2 years on imatinib were eligible. Patients (n = 207) were randomized to switch to nilotinib 400 mg twice daily (BID; n = 104) or to continue on the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103). Rates of MMR, MR4 (BCR-ABL ≤ 0.01% according to the International Scale [IS], corresponding to a 4-log reduction), MR4.5 (BCR-ABL ≤ 0.0032%IS, corresponding to 4.5-log reduction), and undetectable BCR-ABL via RQ-PCR with ≥ 4.5-log sensitivity were measured. Results: Among all randomized patients (intent-to-treat population), significantly more patients treated with nilotinib continued to achieve undetectable BCR-ABL by 24 mo (32.7% on nilotinib vs 16.5% on imatinib; P =.005; Table).The difference between the arms in achievement of this endpoint increased between 1 and 2 years (from 12.4% to 16.2%). The median time to MR4.5 and undetectable BCR-ABL was also significantly faster on nilotinib than on imatinib (P = .005 and .003, respectively). Cumulative rates of MR4.5 and undetectable BCR-ABL continued to be higher with nilotinib in patients without those responses at baseline, and the difference between arms appeared to increase over time. The safety profiles for nilotinib and imatinib were consistent with prior studies. By 24 mo, no patients in either arm progressed to accelerated phase/blast crisis. No patients on nilotinib died since the 12-mo analysis; 1 patient on imatinib died from metastatic prostate cancer in follow-up after discontinuation from the study. Conclusions: Switching to nilotinib led to significantly faster, deeper molecular responses in patients with minimal residual disease on long-term imatinib therapy. Since the 12-mo analysis, rates of deep molecular response (MR4.5 and undetectable BCR-ABL) have remained significantly higher in patients who did not have the response at baseline and were switched to nilotinib (vs those remaining on imatinib). In fact, the difference in favor of nilotinib increased between 1 and 2 years. These results suggest that switching to the more potent, selective tyrosine kinase inhibitor nilotinib is beneficial in patients with minimal residual disease after long-term imatinib therapy. Achievement of these deeper molecular responses (MR4.5 and undetectable BCR-ABL) after switching to nilotinib may enable a greater proportion of CML-CP patients to be eligible for future discontinuation studies. Cumulative rates of confirmed undetectable BCR-ABL by 24 mo will be presented as the confirmation assessments for several responders were not available at the time of this analysis. Disclosures: Hughes: Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding. Lipton:Novartis: Consultancy, Research Funding, Speakers Bureau. Spector:Novarits: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy. Leber:Novartis: Advisory Board Other, Honoraria, Speakers Bureau. Schwarer:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Purkayastha:Novartis Pharmaceuticals Corp: Employment. Collins:Novartis Pharmaceuticals Corp: Employment. Szczudlo:Novartis Pharmaceuticals Corp: Employment. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Teva Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Midostaurin was the first multikinase inhibitor approved in combination with daunorubicin and cytarabine induction and high-dose cytarabine (HiDAC) consolidation chemotherapy for the treatment of adults with newly diagnosed FLT3-mutation-positive (mut+) acute myeloid leukemia (AML). Approval was largely based on the results from the phase 3 RATIFY trial; patients who received midostaurin had significantly improved overall and event-free survival than those who received placebo (Stone et al, N Engl J Med, 2017). RADIUS-X (NCT02624570) is an expanded treatment protocol (ETP) designed to provide access to midostaurin during the US Food and Drug Administration's review process and to extend the understanding of the safety and tolerability of midostaurin in patients with newly diagnosed FLT3-mut+ AML. The safety profile of midostaurin in preliminary data from RADIUS-X was consistent with that in the RATIFY study (Roboz et al, Blood, 2017 [abstract 1338]). Here we report updated safety data for midostaurin during induction and consolidation and safety data during the maintenance phase. Methods: In this open-label, single-arm ETP, patients (aged ≥18 years) received 1-2 cycles of induction therapy (cytarabine plus daunorubicin [60-90 mg/m2/day] or idarubicin [12 mg/m2/day]) and up to 4 cycles of HiDAC consolidation chemotherapy plus midostaurin (50 mg twice daily [bid] on days 8-21 of each 28-day cycle), followed by up to 12 months of single-agent midostaurin (50 mg bid on days 1-28). Patients could enroll at any point before completion of a second cycle of consolidation. Patients achieving complete remission (CR) or CR with incomplete hematologic recovery (CRi) after induction proceeded to consolidation; patients who maintained a response were eligible to proceed to maintenance. The primary endpoints were safety and tolerability of midostaurin. Results: Of 111 patients screened, 103 were enrolled in the study: 47 during induction (46%) and 56 during consolidation (54%) (Figure). The median age was 58 y (range, 19-79 y); all patients were FLT3-mut+ (Table). Of 47 patients enrolled during induction, 15 received daunorubicin and 32 received idarubicin as the anthracycline. Of 35 patients who completed consolidation and entered maintenance, 9 had completed the protocol treatment and 3 remained on therapy at the data cutoff date (March 30, 2018). The CR/CRi rate for the induction phase was 74% (57% CR, 17% CRi). The relapse rate was 14% overall. The most common reason for study discontinuation was proceeding to transplant (overall, 52%; induction, 11%; consolidation, 42%; maintenance, 34%). The median duration of midostaurin exposure was 35 days (range, 3-426 days). Dose adjustment or interruption due to adverse events (AEs) occurred in 26 patients, most commonly due to febrile neutropenia (n=9) and gastrointestinal disorders (n=6). No new safety events were observed with longer follow-up. Most patients (99%) experienced ≥1 any-grade AE, mostly during induction and/or consolidation. Due to the timing of patient enrollment (up to the second cycle of consolidation), hematologic AEs were lower than reported in comparable studies. The most common AEs occurring in ≥20% of patients were febrile neutropenia (53%), nausea (42%), diarrhea (37%), anemia (36%), platelet count decreased (31%), fatigue (23%), headache (22%), and vomiting (22%). Serious AEs occurred in 50% of patients overall, most commonly febrile neutropenia (37%). AEs during induction were generally similar, regardless of anthracycline received. Overall, 9 patients discontinued due to AEs: 5 during induction (febrile neutropenia, blood bilirubin increased, electrocardiogram QT prolonged, renal impairment, and respiratory distress), 1 during consolidation (sepsis), and 1 during maintenance (leukocytosis). During maintenance, 16 of 35 patients (46%) reported any-grade AEs with midostaurin monotherapy; the most common any-grade and grade 3/4 AEs occurring in 〉1 patient were platelet count decrease (11% and 3%), nausea (9% and 0%), and oropharyngeal pain (6% and 0%).The rate of death during the study was low, with 1 death reported (disease progression). Conclusions: Midostaurin continued to demonstrate a manageable safety profile with longer follow-up and was associated with high transplant and low relapse rates. Maintenance therapy with midostaurin was well tolerated; no new safety signals were observed. Disclosures Perl: Daiichi Sankyo: Consultancy; Arog: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees. Sweet:Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Incyte: Research Funding; Bristol Myers Squibb: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Celgene: Speakers Bureau. Roboz:Novartis: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Janssen Pharmaceuticals: Consultancy; Argenx: Consultancy; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Jazz Pharmaceuticals: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Otsuka: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Janssen Pharmaceuticals: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy. Strickland:Astellas Pharma: Consultancy; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bonifacio:Novartis: Employment. Haines:Novartis: Employment. Barbera:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals Corporation: Employment.

Description: Background: Sickle cell disease (SCD) is the most common single-gene disorder in African Americans and can lead to complications, including acute pain and chronic organ damage. Approximately 40% of men with SCD experience priapism, a clinical disorder characterized by prolonged, painful penile erection in the absence of sexual stimulation. Vaso-occlusion-induced ischemia is generally thought to account for SCD-associated priapism. Crizanlizumab, a humanized monoclonal antibody that binds P-selectin and blocks interaction with its ligands (including leukocyte PSGL-1). Crizanlizumab significantly decreased vaso-occlusive crises (VOCs) leading to healthcare visit vs placebo, and was well tolerated in SUSTAIN, a phase 2 study in adults with SCD. This SPARTAN study aims to evaluate the clinical efficacy of intravenous (IV) crizanlizumab 5 mg/kg in reducing priapic events in patients with SCD and a history of priapism utilizing a modern electronic reporting system. Electronic reporting tools have advantages over the paper format in regards to accuracy of and compliance in recording PROs (Stone et al, 2003). The study design and details of PRO collection methods are presented here. Study Design and Methods: This is a Phase 2, multicenter, open-label, single arm study of crizanlizumab in male patients aged ≥16 years with SCD-related priapism. The study will consist of 14 weeks prescreening, 12 weeks screening, and 52 weeks of treatment. The primary endpoint is percent reduction from baseline of priapic events frequency (unwanted/painful erection lasting 〉60 minutes) by 26 weeks. It is expected that crizanlizumab treatment reduces priapic events by ≥ 25% in SCD patients with priapism by 26 weeks. Demonstration of significant percent reduction from baseline in priapic events will be evaluated statistically. Priapic events will be self-reported in real time via a restricted and secure study-issued smart watch and smart phone with a study-specific digital application (app). The patient records the start of a priapic event using a button on the pin code-protected app, which triggers a report in a database, creates a date/time stamp, and records the patient's identification. The patient is then prompted to complete an event reporting survey in one of three ways: using the app on the watch/phone, by a personal call with an operator, or by paper diary. Event reporting surveys will record priapic event occurrences, time and length of events, how the event was relieved, if there was a trigger, and the patient-reported pain at its worst during the event (scale of 0-10). Paper diaries are available as a back-up. Secondary endpoints include safety, as well as the following outcomes at 26 and 52 weeks: rate of priapic events, percent reduction in ≥4-hour erections requiring an ER visit, rate of VOC at 26 and 52 weeks, rate of uncomplicated VOC events, and rate of complicated crises. Approximately 56 patients are planned to be enrolled across 28 sites. Eligible patients must be ≥ 16 years old, have ≥4 events during prescreening, ≥3 during screening with 1 event occurring within 4 weeks prior to first treatment. Patients will be treated with IV crizanlizumab 5 mg/kg on the first day of Week 1, Week 3 (loading dose), Week 7, and then every 4 weeks until final treatment at Week 51. Primary analysis will be conducted after patients receive 26 weeks of treatment. Mandatory safety follow-ups will be conducted until 15 weeks after last dose. Patient feedback was considered and incorporated into the trial design. Results: This Phase 2 study (ClinicalTrials.gov Identifier: NCT03938454) has been successfully designed and approved by the institutional review board. Trial is ongoing. Conclusions: This study, which incorporates electronic PRO collection methods, has been designed to address the unmet treatment need in male patients 〉16 years old with SCD-related priapism. Figure 1. SPARTAN Study Design Disclosures Darbari: Novartis: Membership on an entity's Board of Directors or advisory committees; Hilton Publishing: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: one day advisory board meeting . Paulose:Novartis Pharmaceuticals Corporation: Employment. Laine:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals: Employment. Kato:Novartis, Global Blood Therapeutics: Consultancy, Research Funding; Bayer: Research Funding.

Description: Introduction: Midostaurin, a multitargeted tyrosine kinase inhibitor (TKI), plus induction and consolidation chemotherapy followed by single-agent midostaurin maintenance therapy resulted in significant benefits in event-free and overall survival (OS) in adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) compared with placebo (RATIFY study; Stone et al, N Engl J Med, 2017). In RATIFY, patients who received allogeneic hematopoietic stem cell transplant (alloSCT) did not receive midostaurin maintenance. Despite alloSCT providing the highest likelihood of sustained remission, relapse rates remain high (30%-59%; Schiller et al, Biol Blood Marrow Transplant, 2016), especially in patients with FLT3-internal tandem duplication-positive (ITD+) AML. Posttransplant maintenance therapy may improve this outcome. Here, we report the primary results from RADIUS, a randomized, open-label, phase 2 exploratory trial (NCT01883362) that investigated whether the addition of midostaurin to standard of care (SOC) after alloSCT could reduce the risk of relapse in patients with FLT3-ITD+ AML. Methods: Adults (aged 18-70 y) who had undergone myeloablative alloSCT in first complete remission (CR1), had achieved hematologic recovery, and were transfusion independent were eligible. Patients enrolled postengraftment and were randomized to receive SOC with or without midostaurin 50 mg twice daily continuously (4-week cycles) for up to 12 cycles. Study treatment started 28 to 60 days post-alloSCT and patients were followed for ≥24 months post-alloSCT. The primary endpoint was relapse-free survival (RFS) at 18 months post-alloSCT. Secondary endpoints included safety and disease-free survival (DFS), OS, and RFS at 24 months post-alloSCT. The study was not adequately powered to detect a statistical difference between the 2 arms; a sample size of 60 was calculated to detect a 50% reduction in the risk of relapse. Results: 60 patients were randomized (30 per arm). Baseline characteristics were generally balanced between the 2 arms. Overall, 30 patients completed 12 cycles of study treatment (14 with SOC; 16 with midostaurin). The median exposure to midostaurin was 10.5 months (range, 0.2 to 12.0 months) and the median dose intensity was 93 mg/day (range, 15-100 mg/day). Early treatment discontinuations were similar between arms (15 in the SOC arm; 13 in the midostaurin arm), frequently due to adverse events (AEs; 3% vs 23%) and consent withdrawal (20% vs 7%). Among 6 patients who withdrew consent in the SOC arm, 2 did so to pursue other TKI therapies. Midostaurin dose modifications occurred in 19 patients (63%), mostly due to AEs (84%); 1 instance was due to receiving a concomitant CYP3A4 inhibitor. With an estimated 18-month RFS (95% CI) of 76% (54%-88%) in the SOC arm and 89% (69%-96%) in the midostaurin arm, estimated relapse rates were 24% and 11%, respectively, which is a 46% relative reduction in the risk of relapse with the addition of midostaurin (Figure 1). At 18 months, the median RFS was not reached in either arm. Longer follow-up at 24 months (data not yet matured) will be presented, including RFS, OS, and DFS. In the SOC and midostaurin arms, AEs were reported in 87% and 100% of patients, respectively (the most common any-grade AE was vomiting: 23% vs 73%; Figure 2); serious AEs were reported in 57% and 30% of patients, respectively, with diarrhea (7% vs 13%), nausea (10% vs 3%), vomiting (10% vs 3%), and pyrexia (7% vs 7%) being the most common. Overall, 8 patients discontinued midostaurin therapy due to AEs (mostly gastrointestinal related) and 12 died on study (all during the follow-up phase; 8 in the SOC arm and 4 in the midostaurin arm [n=4 vs n=2 due to AML disease progression]). Rates of graft-vs-host disease (GVHD) were generally similar between the SOC and midostaurin arms (overall, 70% vs 73%; acute GVHD, 53% vs 57% [grade 2/3 events: 37% vs 30%; no grade 4 events]; chronic GVHD, 47% vs 37% [most events were mild or moderate; severe events: 1 with SOC and 2 with midostaurin]). Conclusions: Adding midostaurin to SOC reduced the risk of relapse at 18 months post-alloSCT by 46% (vs SOC). The safety profile of single-agent midostaurin was consistent with previous reports; no major safety concerns were identified when adding midostaurin to SOC following alloSCT. These data suggest that midostaurin monotherapy can be safely administered for ≤1 year and may improve outcomes in patients who undergo alloSCT in CR1. Disclosures Maziarz: Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc.: Patents & Royalties. Scott:Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy, Research Funding; Alexion: Consultancy. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy. Kim:Novartis: Consultancy, Honoraria, Research Funding; Briston-Meyers Squibb: Consultancy, Honoraria, Research Funding; Paladin: Consultancy; Pfizer: Consultancy. Haines:Novartis: Employment. Bonifacio:Novartis: Employment. Rine:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals Corporation: Employment.

Description: INTRODUCTION SUSTAIN was a randomized, double-blind, placebo-controlled, phase 2, 52-week study that compared the effect of crizanlizumab, a P-selectin inhibitor, versus placebo on the frequency of sickle cell pain crises (SCPCs, or vaso-occlusive crises [VOCs] leading to a health care visit) in patients with any genotype of sickle cell disease (SCD). Crizanlizumab 5.0 mg/kg significantly reduced the annual frequency of VOCs versus placebo (1.6 vs 3.0, P=0.01) and increased the time to first on-treatment VOC (4.1 vs 1.4 months, P=0.001). The current study, SUCCESSOR (SUSTAIN Chart-review of Crizanlizumab to Evaluate Sickle-cell Study One-year Retrospective), reviewed medical records of patients who completed the SUSTAIN study at US sites to assess additional cases of significant pain crisis events, and to generate real-world data on treatment patterns and health care resource utilization upon completion of treatment with crizanlizumab. METHODS SUCCESSOR is a retrospective cohort study of adult patients (≥18 years old) who participated in the SUSTAIN study in the United States to evaluate outcomes related to SCD up to 52 weeks following their completion of the trial. SUCCESSOR included the per protocol population from SUSTAIN, which included the intent-to-treat patients who received at least 12 of the 14 planned study drug doses, completed a visit at least 14 days after the final dose of study drug, and had no major protocol violations that impacted the efficacy assessments. The overall study period for the retrospective study was from September 2015 to March 2017 and patient data were obtained from medical records. Crizanlizumab was not administered post-SUSTAIN. Patient consent was obtained prior to data collection if required by local and/or central research ethics review. RESULTS In this preliminary analysis, a total of 6 patient data sets were extracted. These patients had been randomized to the following treatment arms in the SUSTAIN study: 1 placebo, 1 crizanlizumab 2.5 mg/kg, and 4 crizanlizumab 5.0 mg/kg. The patient who had received placebo during SUSTAIN was a 27-year-old male with HbS/β0-thalassemia SCD. The patient who had received crizanlizumab 2.5 mg/kg was a 42-year-old female with HbSC SCD. The patients who had received crizanlizumab 5.0 mg/kg were: a 28-year-old male with HbSS SCD; a 32-year-old female with HbSS SCD; a 56-year-old female with HbSC SCD; and a 65-year-old female with HbSS SCD. All patients were Black or African-American. In the 52 weeks following completion of the SUSTAIN study, patients who had received placebo or crizanlizumab 2.5 mg/kg reported 4 and 5 VOC events, respectively, while crizanlizumab 5.0 mg/kg patients reported 0-2 VOC events (Table). Four patients (3 crizanlizumab 5.0 mg/kg, 1 placebo) reported hydroxyurea (HU) usage during and after SUSTAIN. One patient who had received crizanlizumab 5.0 mg/kg and did not report HU usage during SUSTAIN reported HU usage post-SUSTAIN. All patients reported opioid usage after SUSTAIN. Transfusions were not allowed during SUSTAIN; 2 patients, 1 who had received crizanlizumab 5.0 mg/kg and 1 who had received placebo, reported transfusions post-SUSTAIN. Five of the 6 patients reported utilizing health care resources (eg, clinic visits, emergency department visits, or hospitalizations) post-SUSTAIN. One patient who received crizanlizumab 5.0 mg/kg did not report utilizing any health care resources post-SUSTAIN and did not report any VOC events in the 52 weeks after SUSTAIN. CONCLUSIONS We report our initial results from a limited number of patients from SUCCESSOR and therefore summarized post-SUSTAIN outcomes without analysis. In 5 of the 6 patients, the annual frequency of VOC events remained the same or increased in the post-SUSTAIN period compared to that during the SUSTAIN study. Data collection is ongoing in additional eligible patients. Disclosures Shah: Novartis: Consultancy, Research Funding, Speakers Bureau. Boccia:Amgen: Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau. Hardesty:Biomarin: Research Funding; Bioverativ: Research Funding; Global Blood Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Prometic: Research Funding; Sangamo: Research Funding; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paulose:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Laine:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Purkayastha:Novartis Pharmaceuticals Corporation: Employment. Nandal:Novartis Pharmaceuticals Corporation: Employment. Kutlar:Sancilio: Other: DSMB Chair; Bluebird Bio: Other: DSMB Member; Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding.

Description: Background: Achieving sustained DMR (variably described as ≥ MR4 or ≥ MR4.5) is an emerging treatment goal for patients with CML. DMR is associated with excellent long-term clinical outcomes and a higher likelihood of successful treatment-free remission (TFR) upon discontinuation of tyrosine kinase inhibitor (TKI) therapy. Biological predictors of patients likely to achieve DMR are unknown. Here, we present an exploratory analysis of gene expression signatures in order to predict DMR to TKI therapy, as well as understand the biological underpinnings that allow a DMR, based on patients treated with imatinib or nilotinib in the ENESTnd study (NCT00471497). Methods: ENESTnd is a phase 3, randomized, open-label study comparing nilotinib 300 mg twice daily (BID), nilotinib 400 mg BID and imatinib 400 mg once daily (QD) in patients with newly-diagnosed CML. To maximize the likelihood of defining predictive and biologically relevant gene signatures, samples from a group of poor responders (BCR-ABL1IS 〉 10% by 3 months of therapy) and good responders (BCR-ABL1IS 〈 0.01% by 12 months of therapy) were selected across all treatment arms. Whole blood samples collected prior to study treatment initiation were available from 112 such patients from the total 846 patients enrolled in ENESTnd, and were subjected to RNA sequencing. DMR was assessed using quantitative polymerase chain reaction transcript ratios standardized to the international scale (IS) and was defined as BCR-ABLIS ≤ 0.01% (MR4) or ≤ 0.0032% (MR4.5). For statistical analysis, responders were defined as patients having achieved DMR by 5 years, whereas non-responders were in the trial for ≥ 5 years without achieving DMR. Five years was selected to ensure that patients on both imatinib and nilotinib arms had adequate time to reach MR4.5. The association of clinical variables with responder status (good or poor) was assessed via a multivariate logistic regression model. Results: We correlated clinical variables (eg, Sokal risk score, TKI, age, sex) with responder status for 112 ENESTnd study patients who received 400 mg imatinib QD (n = 47), 300 mg nilotinib BID (n = 33), or 400 mg nilotinib BID (n = 32). Of the 112 patient samples, 70 were included in the analysis using MR4.5 as an endpoint, with 47 patients characterized as responders (imatinib: 16; nilotinib: 31), and 23 as non-responders (imatinib: 13; nilotinib: 10). Of the 112 samples, 42 were excluded from analysis because the patients discontinued the trial before 5 years and did not achieve MR4.5 (imatinib: 18; nilotinib: 24). Younger age (〈 35 years) was associated with good response (p 〈 0.02) in a multivariate analysis. We developed a predictive model of responder status by applying penalized regression to clinical variables and gene expression (13569 genes) in independent (clinical or gene expression) and combined gene and clinical models. The best performing model used patients with MR4.5 vs poor responders, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.87 (Figure; Table). Including clinical variables did not result in markedly different performance (AUC = 0.85). Significantly, both models outperformed a model that included clinical variables only (AUC = 0.65). Relaxing the definition of good responders to include patients with MR4 yielded similar results (Table). Detailed biomarker/pathway analysis to explore the biological pathways that separate good and poor response are underway. Conclusions: We present a gene expression model that distinguishes patients who achieved a DMR from those with a poor response to treatment at 5 years. The approach for sample selection optimized the chances of finding a biological and clinical signal and may be applicable to all CML patients initiating TKI therapy. This work could yield new therapeutic targets that could potentially turn a patient biologically determined to be a poor responder into a good responder who might even achieve a TFR. Disclosures Radich: Novartis: Other: RNA Sequencing; TwinStrand Biosciences: Research Funding. Larson:Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy; Agios: Consultancy. Kantarjian:Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Takeda: Honoraria; Astex: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Jazz Pharma: Research Funding. Deininger:Blueprint: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Ascentage Pharma: Consultancy, Honoraria; TRM: Consultancy; Sangoma: Consultancy; Fusion Pharma: Consultancy; Adelphi: Consultancy; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Humana: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Sangamo: Consultancy. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy; TG Therapeutics: Consultancy; Bayer: Speakers Bureau; Sanofi: Speakers Bureau. DeAngelo:Abbvie: Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; GlycoMimetics: Research Funding; Celgene: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Blueprint: Consultancy, Research Funding; Shire: Consultancy. Branford:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Qiagen: Consultancy, Honoraria; Cepheid: Consultancy, Honoraria. Sadek:Novartis: Employment. Chaturvedi:Novartis Pharmaceuticals: Employment. Sondhi:Novartis: Employment, Other: Stock; Sanofi: Other: Stock. Mishra:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals: Employment. Shrestha:Novartis: Employment. Obourn:Novartis: Employment. Druker:Cepheid: Consultancy, Honoraria; Burroughs Wellcome Fund: Membership on an entity's Board of Directors or advisory committees; GRAIL: Equity Ownership, Other: former member of Scientific Advisory Board; CureOne: Membership on an entity's Board of Directors or advisory committees; Beat AML LLC: Other: Service on joint steering committee; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Pfizer: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Aptose Biosciences: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Aileron Therapeutics: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees , Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Patents & Royalties, Research Funding; OHSU (licensing fees): Patents & Royalties: #2573, Constructs and cell lines harboring various mutations in TNK2 and PTPN11, licensing fees ; Celgene: Consultancy; Merck & Co: Patents & Royalties: Dana-Farber Cancer Institute license #2063, Monoclonal antiphosphotyrosine antibody 4G10, exclusive commercial license to Merck & Co; Dana-Farber Cancer Institute (antibody royalty): Patents & Royalties: #2524, antibody royalty; Beta Cat: Membership on an entity's Board of Directors or advisory committees, Other: Stock options; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Research Funding; Gilead Sciences: Other: former member of Scientific Advisory Board; ICON: Other: Scientific Founder of Molecular MD, which was acquired by ICON in Feb. 2019; Monojul: Other: former consultant; Novartis: Other: PI or co-investigator on clinical trial(s) funded via contract with OHSU., Patents & Royalties: Patent 6958335, Treatment of Gastrointestinal Stromal Tumors, exclusively licensed to Novartis, Research Funding.

Description: Background: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy approved for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma. The ELIANA trial showed efficacy (81% overall remission rate [ORR]; 60% complete remission [CR]) and safety of tisagenlecleucel in r/r B-ALL (Maude et al. N Engl J Med. 2018). In the ELIANA trial, sustained remissions were associated with B-cell aplasia, an expected on-target effect of tisagenlecleucel and a pharmacodynamic marker for tisagenlecleucel persistence. In some patients who demonstrated short CAR-T cell persistence, reinfusion with 1 or more additional doses of tisagenlecleucel has restored B-cell aplasia and produced a 60% CR rate in patients who were reinfused with humanized CD19-targeted CAR-T cell therapy (Maude et al. J Clin Oncol. 2016). This prolongs the period of tisagenlecleucel activity and immunosurveillance and may therefore prolong durable remission. We introduce a trial in progress investigating the efficacy and safety of tisagenlecleucel reinfusion in pediatric and young adult patients with B-ALL experiencing a loss of B-cell aplasia. Study Design and Methods: HESTER (NCT04225676) is a phase II, open-label, multicenter trial to determine the efficacy and safety of tisagenlecleucel reinfusion in pediatric and young adult patients with B-ALL experiencing loss of B-cell aplasia. Eligible patients must be ≤25 years of age with a confirmed diagnosis of CD19(+) leukemia. Patients must have been previously infused with commercial tisagenlecleucel and have at least 1 additional dose of commercial tisagenlecleucel prescribed to them in the course of medical practice. Commercial tisagenlecleucel must be given for reinfusion within 9 months of the initial manufacturing date. Patients must have loss of B-cell aplasia defined as peripheral blood (PB) absolute B lymphocyte count ≥50/μL or PB B lymphocyte ≥10% of the total lymphocytes; patients are not required to be minimal residual disease negative (MRD)(-). Karnofsky (age ≥16 years) or Lansky (age