ALBERT

Description: Abstract 4439 Background: Several reports have recently been published documenting the experience of patients with Philadelphia chromosome positive chronic myeloid leukemia in the chronic phase (CML-CP) who were switched from Glivec (IM), the β-crystalline form of imatinib mesylate, to non-identical alternate copies of imatinib mesylate (IMac) including those composed of the α-crystalline form. As a result of pre-clinical tests performed during the early development of IM, the β-crystalline form of imatinib mesylate was selected for further development due to its superior stability. In one case report evaluation, 126 Iraqi patients with CML-CP were switched from IM to an IMac that was the α-crystalline form of imatinib mesylate. At the time of switch to IMac, patients had previously received 400mg IM once-daily for an average of 50 months and were at least in complete hematologic response (CHR). Post-switch, patients were initially placed on the same IMac dose and followed-up on a monthly basis; more frequently in cases of poor response or adverse events. By 3 months post-switch, 22 (17%) patients had lost hematologic response and of these patients 18 (14%) and 4 (3%) had progressed to accelerated phase (AP) and blast crisis (BC), respectively. By 6 months post-switch, an additional 20 patients (16%; 33% total) had lost hematologic response. Safety assessment for IMac in this cohort has not been previously published. Objective: To assess the clinical safety and to estimate the survival of Iraqi CML patients switched from IM to IMac. Methods: Patient case records were retrospectively reviewed for safety findings as assessed by the treating physician. A previously published Markov transition-state model was used to compare projected life-years (LYs), progression-free life-years (PFLY), and quality-adjusted life-years (QALYs) of IM patients switched to IMac vs. patients not switched. Patients entered the model after a mean 50 months of IM therapy. At that time, based on the IRIS trial results, patients were considered to have CHR (4.7%), partial (6.5%) or complete (88.9%) cytogenetic response. Patients remaining on IM transitioned within these 3 responses levels and no hematologic response, AP, BC, and death according to the original model probabilities. For patients switched to IMac, transition rates were based exclusively on response rates observed in the Iraqi study (Scenario 1) or on the Iraqi study for the first 6 months, and thereafter based on the transition rates originally in the Markov model (Scenario 2). Utilities were from the original model. Results: Non-hematologic adverse event (AE) rates observed in patients who were switched to IMac are reported (Table). Patients remaining on IM were predicted to experience 15.7 LYs, 14.5 PFLYs, and 13.4 QALYs. Corresponding numbers for patients switched to IMac were 2.4 LYs, 1.1 PFLYs, 1.4 QALYs (in Scenario 1) and 11.4 LYs, 10.2 PFLYs, and 9.6 QALYs (in Scenario 2). Results were also sensitive to response distribution at model entry. Conclusions: The clinical safety, efficacy, and tolerability of IM have been established from more than 10 years of clinical experience. Recent introduction of generic versions of imatinib (including α-crystalline form) allows assessment of whether patients switching from IM to a generic version are able to achieve the same clinical outcomes as with the branded drug. The Iraqi case report is the largest cohort currently available for such review. This case report suggests that switching from IM to an IMac that does not have the safety and/or efficacy may result in substantial loss of LYs, PFLYs, and QALYs. Robust pharmacovigilance programs may need to be established to differentiate safety findings for originator drugs vs. substandard generic versions. Disclosures: Botteman: Novartis: Consultancy. Magestro:Novartis: Employment, Equity Ownership. Manley:Novartis Pharma AG: Employment. Zernovak:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Woodman:Novaris Pharmaceuticals Corp: Employment, Equity Ownership.

Description: Background:MDM2, a negative regulator of the tumor suppressor p53, is overexpressed in a number of cancers including hematological malignancies. Disrupting the MDM2-p53 interaction represents an attractive approach to treat cancers expressing wild-type functional p53, and the inhibition of MDM2 and antitumor activity with the small molecule DS3032b has been demonstrated in preclinical studies and in patients with solid tumors. Here, we report the initial results of the Phase I trial aimed at characterizing the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles and preliminary efficacy of DS3032b in in patients with hematological malignancies. Methods:This study (NCT02319369) is a dose escalation study of DS-3032b as an oral single agent with a starting dose of 60 mg and escalating through 90 mg, 120 mg, 160 mg and 210 mg dose levels guided by a modified continuous reassessment method using a Bayesian logistic regression model following escalation with overdose control principle. The drug was administered orally once daily (QD) in 21 of 28 days per cycle (QD 21/28). The patient population included relapsed/refractory AML and high-risk MDS. Results:Thirty eight subjects with relapsed/refractory AML or high-risk MDS were enrolled in the study in 5 dose levels; 60 mg (7 pts), 90 mg (6 pts), 120 mg (12 pts), 160 mg (8 pts) and 210 mg (5 pts). Twenty four (63%) subjects were males. The median age was 68.5 (range 30-88) years, with approximately two-thirds over 65 years. Thirty-seven of 38 patients were p53 wild type, and one subject had known pathogenic insertion mutation with an allele frequency of about 20%. DS-3032b was tolerated up to 160 mg QD in the 21/28 days schedule that was determined to be the maximum tolerated dose. All subjects experienced at least one treatment emergent adverse event (TEAE) of any grade, and 93% subjects experienced a grade ≥3 TEAE at a data cut off on May 2, 2016. The most common (≥20%) TEAEs of any grade regardless of attribution were nausea (73%), diarrhea (57%) vomiting (33%), fatigue (37%), anemia (33%), thrombocytopenia (33%), neutropenia (20%) hypotension (30%), hypokalemia (23%) and hypomagnesemia (20%). A total of 5 subjects experienced dose limiting toxicities; two subjects in the 160 mg cohort due to grade 3 hypokalemia and grade 3 diarrhea, and three subjects in the 210 mg cohort due to grade 3 nausea and vomiting, grade 2 creatinine elevation/ renal insufficiency, and grade 3 anorexia and fatigue.. Preliminary PK results showed plasma exposure (Cmax and AUClast) increased with dose; and approximately 2-fold drug accumulation was observed on Day 15 following the daily oral dosing. Increase in the serum levels of macrophage inhibitory cytokine (MIC-1) as a p53 target gene was used as a circulating pharmacodynamic biomarker, where magnitude of MIC-1 serum level increase corresponded with DS3032 plasma exposure. Clinical activity of single agent DS-3032b was observed from the reduction in bone marrow blasts by the end of cycle 1 (4 weeks) in 15 of 38 patients. Complete remission was observed in 2 subjects with AML; 1 subject each at 120 mg and at 160 mg, with a remission duration of 〉4 and 〉10 months, respectively. One subject with MDS achieved marrow CR with platelet improvement, of 4 months duration, at the 120 mg dose level. Of note, each of these three subjects developed a TP53 mutation while on treatment, two at the time of disease progression and one subject who remains in an ongoing response. Further evaluation of DS-3032b in rational combinations such as with hypomethylating agents is being planned. Conclusions: Disruption of MDM2-p53 interaction by DS-3032b appears to be a promising approach to treat haematological malignancies. MDM2 expression/amplification in leukemic blasts is being investigated as a potential predictor of response. Rational combinations with agents targeting different mechanistic pathways may offer the most promise for further development. Disclosures DiNardo: Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Zernovak:Daiichi Sankyo: Employment. Kumar:Daiichi Sankyo: Employment. Gajee:Daiichi Sankyo: Employment. Chen:Daiichi Sankyo: Employment. Rosen:Daiichi Sankyo: Employment. Song:Daiichi Sankyo: Employment. Kochan:Daiichi Sankyo: Employment. Limsakun:Daiichi Sankyo: Employment.

Description: Background: MDM2, a negative regulator of the tumor suppressor p53, is overexpressed in several cancers including hematological malignancies. Disrupting the MDM2-p53 interaction represents an attractive approach to treat cancers expressing wild-type functional p53. Anticancer activity of small molecule MDM2 inhibitor milademetan (DS-3032b) has been demonstrated in preclinical studies and in a phase 1 trial in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome. Quizartinib is a highly selective and potent FLT3 inhibitor that has demonstrated single-agent activity and improvement in overall survival in a phase 3 clinical study in relapsed/refractory AML with FLT3-internal tandem duplication (FLT3-ITD) mutations. We present here the preclinical studies exploring the rationale and molecular basis for the combination of quizartinib and milademetan for the treatment of FLT3-ITD mutant/TP53 wild-type AML. Methods: We investigated the effect of quizartinib and milademetan combination on cell viability and apoptosis in established AML cell lines, including MV-4-11, MOLM-13 and MOLM-14, which harbor FLT3-ITD mutations and wild type TP53. Cells were treated with quizartinib and milademetan at specified concentrations; cell viability and caspase activation were determined by chemiluminescent assays, and annexin V positive fractions were determined by flow cytometry. We further investigated the effect of the combination of quizartinib and the murine specific MDM2 inhibitor DS-5272 in murine leukemia cell lines Ba/F3-FLT3-ITD, Ba/F3-FLT3-ITD+F691L and Ba/F3-FLT3-ITD+D835Y, which harbor FLT3-ITD, ITD plus F691L and ITD plus D835Y mutations, respectively. F691L or D835Y mutations are associated with resistance to FLT3-targeted AML therapy. In vivo efficacy of combination treatment was investigated in subcutaneous and intravenous xenograft models generated in male NOD/SCID mice inoculated with MOLM-13 and MV-4-11 human AML cells. Results: Combination treatment with milademetan (or DS-5272) and quizartinib demonstrated synergistic anti-leukemic activity compared to the respective single-agent treatments in FLT3 mutated and TP53 wild type cells. Combination indices (CIs) were 0.25 ± 0.06, 0.61 ± 0.03, 0.62 ± 0.06, 0.29 ± 0.004 and 0.50 ± 0.03, respectively, in MV-4-11, MOLM-13, MOLM-14, Ba/F3-FLT3-ITD+F691L and D835Y cell lines, all of which harbor FLT3-ITD or ITD plus TKD point mutations. The combination regimen triggered synergistic pro-apoptotic effect in a p53-dependent manner as shown by annexin-V staining and caspase 3/7 assays. Mechanistically, the combination treatment resulted in significant suppression of phospho-FLT3, phospho-ERK and phospho-AKT and anti-apoptotic Bcl2 family proteins (eg, Mcl-1), as well as up-regulation of p53, p21 and pro-apoptotic protein PUMA, compared to single agent treatments. Of note, the combination regimen also exerted a synergistic pro-apoptotic effect on venetoclax (BCL-2 inhibitor)-resistant MOLM-13 cells (CI: 0.39 ± 0.04) through profound suppression of Mcl-1. In an in vivo study using the MOLM-13 subcutaneous mouse xenograft model, quizartinib at 0.5 and 1 mg/kg and milademetan at 25 and 50 mg/kg demonstrated a significant tumor growth inhibition compared with vehicle treatment or respective single-agent treatments. In MV-4-11 intravenous mouse xenograft model, the combination of quizartinib plus milademetan showed a significantly prolonged survival, with no animal death in the combination group during the study period, compared to respective single agent treatments and untreated control (Figure). Conclusion: Synergistic anti-leukemic activity was observed for quizartinib plus milademetan combination treatment in preclinical AML models. A phase I clinical trial of quizartinib/milademetan combination therapy in patients with FLT3-ITD mutant AML is underway. Figure. Effects of quizartinib, milademetan and their combination on survival of mice intravenously inoculated with human MV-4-11 AML cells Disclosures Andreeff: Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Oncolyze: Equity Ownership; Astra Zeneca: Research Funding; Reata: Equity Ownership; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; SentiBio: Equity Ownership. Kumar:Daiichi Sankyo: Employment, Equity Ownership. Zernovak:Daiichi Sankyo: Employment, Equity Ownership. Daver:Pfizer: Research Funding; ImmunoGen: Consultancy; Otsuka: Consultancy; Karyopharm: Research Funding; Alexion: Consultancy; ARIAD: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Karyopharm: Consultancy; Novartis: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Kiromic: Research Funding; Sunesis: Research Funding; Incyte: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy. Isoyama:Daiichi SANKYO CO., LTD.: Employment. Iwanaga:Daiichi Sankyo Co., Ltd.: Employment. Togashi:Daiichi SANKYO CO., LTD.: Employment. Seki:Daiichi Sankyo Co., Ltd.: Employment.

Description: Abstract 394 Background: The advent and approval of TKIs has dramatically improved the life expectancy of patients with CML. As treatment innovation has transformed CML into a chronically managed disease, we examined the impact of these changes on patients with CML in order to offer recommendations for healthcare providers (HCPs) to better support patients with CML. Method: 50 patients with CML from Brazil, France, Germany, Russia and Spain were included in this ethnographic investigation including: patients within 18 months of diagnosis and on frontline imatinib therapy (n = 20), patients with ongoing frontline treatment (〉 18 months to 7 years, n = 20), and patients who were switched to second- or third-line TKI therapies (n = 10). Patients in all 5 countries participated in a 2.5-hour in-home interview, and patients in Brazil and France completed 7-day photo journals and an optional telephone debrief interview. Patients were asked to discuss and write about their perceptions and experiences regarding such issues as adherence, disease knowledge, disease management, and their relationship with HCPs. Result: This global ethnographic investigation generated a 5-stage, patient-centered model emphasizing emotions and experiences throughout the diagnosis, treatment and management of their disease: crisis, hope, adaption, normalcy, and uncertainty. Depending upon their circumstances, these experiential stages were found to be abbreviated or prolonged and influenced by patients having differentiating levels of knowledge about their disease, comfort levels with the treatment and/or their HCPs, as well as different degrees of optimism about their treatment and long-term prognosis. In addition, the study results showed that patients cycle through the various stages of the model throughout the course of their disease. The crisis phase occurred at diagnosis and tended to resolve upon HCP reassurance of the availability of successful treatments. Hope followed crisis when patients were educated about their disease and its treatments and responded to initial therapy. Adaption involved patients adjusting to any physical changes wrought by the disease, treatments, and associated adverse events. As well, they began to psychologically come to terms with the long-term nature of their disease and develop their drug-taking routines and compliance pattern. As patients attained stability in their disease and adapted to changes, a ‘new’ normal returned and patients began to refocus their life away from the disease back to social, work, and family matters. The uncertainty stage was found to be associated with drug resistance, disease progression, newly occurring adverse events, or due to limitations around access to therapy because of public health regulations or personal financial issues. While uncertainty arose for multiple reasons and could occur at any time after patients had advanced through the 4 preceding phases, patients who went through stages of uncertainty most often cycled back to phases of adaption or normalcy once the issues were resolved. Conclusions: Here, we have identified 5 common patient experience stages and we provide recommendations based on patient research for the management of CML. This investigation suggests that HCPs can help patients move through the early stages of crisis and hope by providing reassurance, along with information and resources regarding drug efficacy and product differentiation, while explaining the importance of speed and depth of responses. Once in the adaption/normalcy stages, HCPs should set expectations for the risk/benefits of long-term chronic drug therapy and long-term disease monitoring and continue to support patient compliance and adherence programs while helping patients achieve and maintain a normal lifestyle. Disclosures: Guilhot: Novartis: Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Coombs:Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Zernovak:Novartis: Employment, Equity Ownership. Macdonald:Novartis: Consultancy. Shapiro:Novartis: Consultancy.

Description: Abstract 1514 Background: TKIs have proven to be highly effective in the treatment of CML. Several studies have demonstrated that adherence to TKI therapy is a predictor of achieving optimal outcomes. Since chronic phase CML is now becoming more of a long-term disease state in many patients, it is critical that patients understand the importance of adhering to their prescribed drug regimen to maximize and sustain efficacy over many years. This study aimed to establish the key determinants of adherence, and to establish a typical adherence rate to be used as a baseline for future comparison. Methods: Overall, 405 CML-treating physicians in Brazil, France, Italy, Spain and Russia participated in a quantitative online survey and 1,155 patient treatment histories and compliance records were retrospectively analyzed. Results: In this study, although the majority of physicians discussed adherence with patients at each appointment and agreed that evidence suggests there is a link between adherence and progression, only approximately half of the physicians prioritized adherence to therapy or viewed non-adherence as a major driver of disease progression. Overall, the survey of CML-treating physicians demonstrated that their perceptions of adherence closely matched the actual rates of adherence. Physicians believed that patient forgetfulness is the major reason behind non-adherence and it was found that physicians most frequently learn about non-compliance through conversations with their patients rather than through other means, such as the frequency of writing prescription refills. Physicians believe they take on an appropriate amount of responsibility on adherence education and that nurses and pharmacists could play a more active role in adherence management. The study also found that physicians tend to be more reactive at utilizing adherence interventions and perceived the use of blood level monitoring as an effective tool to evaluate non-adherence to therapy. Similarly, the patient record review showed patients are significantly (P = .014) more likely to be adherent to TKI therapy if physicians have a proactive and focused approach to utilizing adherence interventions and enroll patients in a program. Data from the patient records within the European region (France, Italy and Spain) closely matched a previously published US healthcare claims data analysis addressing adherence to imatinib. Across the five countries studied, 43%-53% of the patients were fully adherent to therapy. However, overall, 〉 10% of patients missed ≥ 10% of their prescribed daily dose, with Russia having the highest percentage of patients (23%) and Brazil the lowest percentage of patients (8%) regularly non-adherent to therapy. Of patients in the European region with a known response (n = 363), greater adherence to therapy was significantly correlated with achievement of better therapeutic milestones (P = .04); however, this factor was not significant across all five countries (P = .082). Additionally in the subset of patients from the European region, adherence correlated (P = .027) with the use of individual patient counseling on adherence performed by a nurse and/or hematologist, or if the institution had established adherence protocols (P = .012). Factors not found to significantly influence adherence in all five countries were patient co-morbidities (P = .344), patient age (P = .533), or concomitant non-CML prescription medications (P = .519). Conclusions: Information from this study demonstrated that adherence can be improved through greater patient-physician interactions and provides strong support for the implementation of early, proactive, and focused interventions in combating non-adherence to maximize patient outcomes. Disclosures: Guilhot: Novartis: Equity Ownership, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Coombs:Novartis: Employment, Equity Ownership. Zernovak:Novartis: Employment, Equity Ownership. Szczudlo:Novartis: Employment, Equity Ownership. Rosti:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

Description: Abstract 1695 Background: A global, prospective registry was established to document the frequency of diagnostic testing, management (mgmt) strategies, and outcomes of patients (pts) with CML. Here, we summarize the reported deviations from published disease mgmt recommendations and the overall efficacy achieved by pts. Methods: 1853 pts (≥ 16 years of age) within 6 months (mo) + 2 weeks of CML diagnosis were enrolled from Latin America (LA; n = 497), United States (US; n = 379), Asia Pacific (AP; n = 465), Middle East and Africa (MEA; n = 209), and Russia and Turkey (RT; n = 303). Baseline demographics and medical history were collected at enrollment; current disease status and mgmt information were collected at approximately 6-mo intervals or with a change in disease status or mgmt. Results: From February 2008 to June 2011, data were available for 1831 (99%) pts. Across all regions, nearly all (93.8%) screened pts were in chronic phase CML. Regardless of the time of evaluation (eval), disease burden was mostly assessed through the use of hematologic counts (Table 1). Cytogenetic testing and molecular monitoring were used in a minority of pts at any timepoint. Hydroxyurea (HU) and imatinib were the first agents used in 61.9% and 29.5% of pts, respectively (Table 2). Overall, 81.1% of pts received imatinib therapy at some time and it was the most common second agent (48.1%) pts received. Among the 49% of pts who had response assessments, subsequent treatment changes occurred most frequently (23.9% of pts) at the 3-mo timepoint (Table 1). The median time from disease eval to dose/regimen modification was 3 days. Of those who received imatinib, 32% had dose modifications primarily for: lack of efficacy (20%), physician request (20%), and adverse events (19%). Of the pts with a corresponding eval at 12 mo after diagnosis, 88% had a CHR, 65.4% had a CCyR, and 42.5% had a MMR (BCR-ABLIS ≤.1%). These data are preliminary; response assessments by treatment, as well as further efficacy analyses, are ongoing. Conclusions: Overall, the majority of pts did not have cytogenetic or BCR-ABL transcript level testing performed per the European LeukemiaNet recommendations. Furthermore, despite availability of more effective therapies for the treatment of CML, HU is still used as a primary therapy in a substantial proportion of pts. Based on this analysis, pts outside the US primarily receive HU as initial therapy rather than tyrosine kinase inhibitors (TKIs). Overall, second-generation TKIs, such as nilotinib and dasatinib, are infrequently used. These results illustrate the need for continuing education on the mgmt of CML in order to improve outcomes for all pts. Disclosures: Pasquini: Bristol Myers Squibb: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cortes:Bristol Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuitcals: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding. Zernovak:Novartis: Employment, Equity Ownership. Sivarathinasami:Novartis: Employment. Collins:Novartis: Employment. Hughes:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:BMS: 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, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 3750 Background: The WORLD CML Registry is a multinational, prospective registry established to longitudinally assess global patterns of current and evolving methods for diagnosis, treatment, and clinical outcome measures in pts with CML and to compare clinical practice patterns to management recommendations provided by the European LeukemiaNet (ELN; Baccarani M, et al. J Clin Oncol. 2009;27:6041–6051). Here, we report overall efficacy and safety data from this registry, as well as clinical monitoring practices and outcomes in the subgroup of pts with CML in chronic phase (CP) treated with first-line imatinib. Methods: Pts (≥ 16 y of age) with CML in CP, accelerated phase (AP), or blast crisis (BC) within 6 mo + 2 weeks of confirmed CML diagnosis were enrolled at sites in Latin America, Asia-Pacific, the United States, Russia, Turkey, the Middle East, and Africa. Baseline demographics and medical history were collected at enrollment; disease status and management information were collected at approximate 6-mo intervals or when there was a change in disease status/management. Adverse events (AEs) were collected only if they resulted in a dose/regimen change, nonadherence to treatment, or death. Results: A total of 1837 of the 1889 pts enrolled between February 2008 and December 31, 2010, were evaluable (ie, had confirmed informed consent forms and no protocol deviations) and are the basis for this analysis. Median age was 47 y (range, 16–92 y), and 58% of pts were male. CML diagnosis was established using hematologic (91% of pts), bone marrow (82%), cytogenetic (83%), and molecular (polymerase chain reaction [PCR]; 53%) assessments. Nearly all pts (94%) were initially diagnosed in CP (Table). As of the data cutoff (December 31, 2010), median overall survival (OS) and median event-free survival (EFS) in all pts were not reached. Estimated OS and EFS rates at 3 y were 90.4% and 74.8%, respectively. AEs reported in ≥ 1% of pts were thrombocytopenia (3%) and neutropenia (2%). In the CML-CP subgroup, imatinib (Glivec®/Gleevec®) was administered as first-line therapy (in clinical practice or in a clinical trial) to 63% of pts (n = 1083). Disease burden in CML-CP pts on imatinib over time was most commonly assessed via blood counts (Table). Cytogenetic and molecular assessments were used in a minority of CML-CP pts at most time points. Only 50% of pts had a disease assessment at 3 mo (hematologic, 49%; cytogenetic, 10%; molecular, 15%). Of the pts on first-line imatinib outside of a clinical trial setting (n = 1024), 95 (9%) had their dose increased, 77 (8%) had their dose decreased, and 82 (8%) were switched to nilotinib or dasatinib. In all CML-CP pts treated with first-line imatinib, estimated OS and EFS rates at 3 y were 92.1% and 76.6%, respectively (Table). Estimated OS and EFS rates at 3 y were higher in pts who had higher imatinib exposure (treatment received ≥ 85% of total days) vs pts who received imatinib treatment on 〈 85% of days. Conclusions: The majority of CML-CP pts treated with first-line imatinib did not have cytogenetic or molecular assessments in accordance with current ELN recommendations, particularly at early time points. Additionally, pts who had higher drug exposure to imatinib had higher estimated OS and EFS rates at 3 y than those who did not. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Piccolo:Novartis Pharma AG: Employment. Zernovak:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Sivarathinasami:Novartis Healthcare Pvt. Ltd,: Employment. Eng:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Kim:Novartis: Consultancy, Research Funding, Speakers Bureau; 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; ARIAD: Research Funding; II-Yang: Consultancy, Honoraria, Research Funding. Hughes:Novartis Pharmaceuticals Corp: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy; CSL: Research Funding.

Description: Abstract 2781 Background: The WORLD CML Registry, with sites in the US, Latin America, Asia-Pacific, the Middle East, Africa, Russia, and Turkey, is a multinational, prospective registry established to longitudinally assess global clinical practice patterns for the management of patients (pts) with CML. Here, we report updated results for the subgroup of pts at US sites and evaluate alignment of US practice patterns with current National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for CML (http://www.nccn.org). Methods: Pts (≥ 16 y of age) within 6 mo + 2 weeks of confirmed CML diagnosis were enrolled. Baseline demographics and medical history were collected at enrollment. Information on disease status and management was collected approximately every 6 mo or with a change in disease status or management. Adverse events (AEs) were collected only if they resulted in a dose/regimen change, nonadherence to treatment, or death. Results: This analysis includes 377 evaluable pts (those with confirmed informed consent forms and no protocol deviations) of 418 total pts enrolled in the US from February 2008 to December 31, 2010. Median age was 53 y (range, 18–91 y), with 26% ≥ 65 y of age. CML diagnosis was confirmed using hematologic (85%), bone marrow (84%), cytogenetic (82%), and molecular (polymerase chain reaction [PCR]; 52%) assessments. Nearly all pts (96%) were diagnosed in chronic phase (CP; Table). Most pts with CML-CP (73%) were treated with imatinib (Glivec®/Gleevec®) as first-line therapy (additional pts may have received first-line imatinib in a clinical trial). Median duration of imatinib treatment in CML-CP pts was 7.59 mo (range, 0.03–33.54 mo). In CML-CP pts (n = 363), imatinib dose was increased in 29 pts (8%; primary reasons included physician request [4%] and lack of efficacy [7%]), decreased in 32 pts (9%; primary reasons included AEs [5%] and physician request [3%]), and interrupted in 10 pts (3%; primary reasons included AEs [2%]). Regimen was switched from imatinib to nilotinib in 21 pts (6%; primary reasons included lack of efficacy [2%] and AEs [2%]) and to dasatinib in 20 pts (6%; primary reasons included AEs [2%], lack of efficacy [1%], and physician request [1%]). Disease burden over time on imatinib was most commonly assessed using blood counts (Table). Only 16% of pts had a molecular assessment at 3 mo; at later time points, 43%-64% of pts had molecular assessments. Cytogenetics was least common (done in 13% of pts at 3 mo and 25%-34% of pts at later time points). AEs reported in ≥ 1% of all pts in the analysis were nausea (3%), fatigue (2%), rash (2%), diarrhea (2%), headache (2%), thrombocytopenia (2%), neutropenia (1%), and dyspnea (1%). There were 17 deaths (5%) reported; 5 deaths were related to CML progression, 1 was related to CML treatment (necrotizing pneumonia), 7 were unrelated to CML treatment, and 4 had unknown causes. Conclusions: In the US, many pts treated with first-line imatinib did not have routine molecular or cytogenetic assessments, suggesting that many US physicians do not monitor their patients as recommended by the NCCN guidelines. These findings may reflect the lack of readily available molecular testing during part of the time period evaluated by this registry. Disclosures: Hermann: Novartis: Sponsor -paid expenses of reported trial Other. Miller:Novartis: Consultancy, Research Funding, Speakers Bureau, development of educational presentations Other; Incyte: development of educational presentations, development of educational presentations Other. Snyder:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ericson:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Zernovak:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Juma:Novartis Pharmaceuticals Corp: Employment. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Description: Introduction: UCART22 is a genetically modified T-cell product manufactured from non-HLA matched healthy donor cells. Donor derived T-cells are transduced using a lentiviral vector to express anti-CD22 CAR (anti-CD22 scFv-41BB-CD3ζ) and are further modified using Cellectis' TALEN® technology to disrupt the T-cell receptor alpha constant (TRAC) and CD52 genes. These modifications minimize the risk of graft versus host disease (GvHD) and allow the use of anti-CD52 directed drugs in the lymphodepletion (LD). UCART22 demonstrated antigen-specific cytotoxic activity against B-ALL cell lines and primary human samples in vitro. In a preclinical in vivo model, immune compromised mice engrafted with Daudi cells, a CD22(+) expressing Burkitt's lymphoma cell line, treated with UCART22 cells demonstrated extended survival in a dose-dependent fashion compared to controls (Wells et al, Blood 2017, abstr. 208). Methods: BALLI-01 (NCT04150497) is a Phase I open-label dose-escalation study designed to assess the safety, the maximum tolerated dose (MTD), and preliminary anti-leukemia activity of UCART22 in patients (pts) with R/R B-ALL. Additional endpoints include characterization of the expansion, trafficking and persistence of UCART22. Eligible pts include adults (18-65 years) with adequate organ function, ECOG PS ≤1, and B-ALL blast CD22 expression ≥ 90% by flow cytometry. Pts must have received at least one standard chemotherapy regimen and one salvage regimen. Protocol therapy includes LD regimens of cyclophosphamide and fludarabine (FC) or FC with alemtuzumab (FCA), followed by a single dose of UCART22 at 1 of 4 dose levels (DL). DLT is assessed at the end of the 28-day DLT observation period. Anti-leukemia activity is based on investigator assessment using NCCN ALL response criteria. UCART22 expansion and persistence are assessed in blood and bone marrow (BM) by flow cytometry, vector copy number and chimerism analysis by qPCR. Immune reconstitution is assessed by flow cytometry. Results: As of 01 July, 2020, 7 pts signed consent, 1 pt failed screening, and 6 pts (4 male; median age 24 [22-52]) were enrolled. Five pts received UCART22 infusion [DL1: 1X105 cells/kg (n=3), DL2: 1x106 cells/kg (n=2)] after FC LD (cyclophosphamide 1g/m2 x 3 days and fludarabine 30 mg/m2 x 4 days). 1 pt discontinued prior to UCART22 administration due to AE (hypoxia due to pneumonitis related to LD). Median number of prior therapies was 3 [2-4]. Median baseline BM blasts % prior to LD was 35% [5-78.4%]. Among 5 pts treated, 4 pts experienced 10 treatment-related treatment-emergent AEs (TEAEs): bilirubin increased (n=1, G4); ALP increased (n=1, G2); hypotension (n=1, G2); CRS (n=2, G2; n=1, G1); headache (n=1, G1); lymph node pain (n=1, G1); fever (n=1, G1); transaminitis (n=1, G1). Two pts experienced serious TEAEs: 1 pt had G3 febrile neutropenia and G3 peri-hepatic hematoma; 1 pt had G4 bleeding and G5 sepsis in the context of PD. No pts had treatment-related serious TEAE, GvHD, ICANS, protocol-defined DLT nor AE of special interest. 2 pts at DL1 achieved best response at day 28 of CR with incomplete hematologic recovery (CRi); and 1 pt at DL2 had initial significant reduction in BM blasts [40% (D -1) to 13% (D 28)] and then progressed. Host T cells recovery was observed in all pts within the DLT period (range D17-D28). Correlative analysis of UCART22 expansion and persistence is ongoing. Conclusion: UCART22 demonstrated no unexpected toxicities at doses of 1x105/kg and 1x106/kg with FC LD regimen. CRS was observed in 3 patients, all grade 1-2, and was manageable. No pts had DLT, GvHD nor ICANS. Two pts achieved CRi. As host immune recovery was observed early, the addition of alemtuzumab to FC LD is now being explored in ongoing treatment cohorts to potentially achieve a deeper and more sustained T-cell depletion and promote expansion and persistence of UCART22. Enrollment is ongoing. Disclosures Jain: Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; BMS: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Fate Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roboz:Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Agios: Consultancy; MEI Pharma: Consultancy; Abbvie: Consultancy; Array BioPharma: Consultancy; Bayer: Consultancy; Celltrion: Consultancy; Eisai: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy. Konopleva:Eli Lilly: Research Funding; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ablynx: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; Sanofi: Research Funding; Calithera: Research Funding; Kisoji: Consultancy; Cellectis: Research Funding; AbbVie: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding; Agios: Research Funding; Genentech: Consultancy, Research Funding. Liu:BMS: Research Funding; Karyopharm: Research Funding; Agios: Honoraria, Other: Regional Advisory board meeting. Jabbour:Pfizer: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding. Poirot:Cellectis SA: Current Employment. Schiffer-Manniou:Cellectis SA: Current Employment. Gouble:Cellectis SA: Current Employment, Current equity holder in publicly-traded company. Haider:Cellectis SA: Current Employment. Zernovak:Cellectis SA: Current Employment. Larson:Astellas, Celgene, Daiichi Sankyo, Novartis, Rafael Pharmaceuticals, Cellectis, Forty Seven: Research Funding; Novartis, Takeda, CVS/Caremark, Celgene, Amgen, Epizyme: Consultancy. OffLabel Disclosure: UCART22 is not FDA approved