1st Generation Tyrosine Kinase Inhibitors Research Articles

Impact of Tyrosine Kinase Inhibitors (TKIs) on Growth in Children and Adolescents with Chronic Myeloid Leukemia: A Systematic Review.

Chronic Myeloid Leukemia (CML) is a rare myeloproliferative disease in childhood. Treatment in CML includes Tyrosine Kinase Inhibitors (TKI's), which inhibit the cytoplasmic kinase BCR/ABL. Tyrosine kinases play a key role in the secretion of growth hormone and insulin-like growth factor1 (IGF-1). The aim of this systematic review was to study the effect of TKIs on the growth of children and adolescents with CML. English-language publications were searched in the PubMed/Cochrane library/Google Scholar databases (2002-2023), and retrieved studies were assessed according to PRISMA-Statement and Newcastle- Ottawa-scale. The search strategy yielded 1066 articles. After applying the inclusion/exclusion criteria, 941 were excluded based on title screening and 111 on abstract review. The systematic review included 14 articles (11 retrospective observational studies/3 clinical trials). Twelve studies reported data on the prevalence of growth disorders after the administration of 1st generation TKIs (imatinib). Two studies reported a negative effect of 2nd generation TKIs (dasatinib/nilotinib) on physical growth. Four studies recorded a decrease in height z-score after treatment compared to baseline. Two 1st-generation TKIs studies reported data on children's final height; one reported restoration of final height to normal after the onset of puberty, despite initial slowing, and the final height was lower than mid-parental target height. Serum IGF-1 levels were reported in 2 studies to be within normal range, while in 3 studies, a significant decrease was documented. Considerable study heterogeneity was observed related to dosage/duration of treatment/disease phase/stage of puberty/ethnicity. A negative effect of TKIs on the growth and final height of children was noted.

Tyrosine kinase inhibitors with and without upfront CNS radiation for brain metastases in oncogene-driven non-small cell lung cancer (TURBO-NSCLC).

2019 Background: Newer generation tyrosine kinase inhibitors (TKI) for NSCLC with EGFR mutations and ALK rearrangements have demonstrated encouraging central nervous system (CNS) activity with CNS objective response rates, greatly improved from 1st generation TKIs. In response to these data, guideline statements have acknowledged a strategy of CNS-penetrant TKI +/- upfront stereotactic radiosurgery (SRS) for the treatment of select patients with BM. However, optimal use of upfront SRS for BM in these patients is controversial since upfront CNS radiation has been the historical standard of care, and there are limited data guiding patient management with upfront TKI alone. Additionally, results from a large multi-institutional series reported inferior overall survival (OS) with the omission of SRS in patients with EGFR-mutated NSCLC treated with first-generation TKI. Methods: Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs +/- upfront SRS were retrospectively collected from 7 centers in the United States. Time to CNS progression (PD), local CNS PD, and OS were analyzed, with multivariable adjustment (MVA) in Fine and Gray and Cox proportional hazards models for baseline factors including age, sex, performance status, mutation, extracranial metastases, prior therapy, neurologic symptoms, and number and size of BM. Results: We identified 317 patients (200 TKI only and 117 TKI+SRS). 250 (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients who received TKI+SRS were more likely to have BM ≥1 cm (p<0.001) and neurologic symptoms (p<0.001) at baseline. The median follow-up from treatment of BM was 23 months and 26 months in the TKI and TKI+SRS groups, respectively. Median OS was similar between the TKI and TKI+SRS groups (median 41 months [95% CI: 35-NR] vs 40 months [95% CI: 40-NR], respectively; p=0.5). On MVA, TKI+SRS was associated with a significant improvement in time to CNS PD (HR 0.63; 95% CI: 0.42-0.96; p=0.033). Local CNS control was significantly improved with TKI+SRS (HR 0.30, 95% CI: 0.16-0.55; p<0.001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated greater CNS control benefits with TKI+SRS in patients with BM ≥1 cm. Conclusions: This is the largest multi-institutional study comparing strategies of CNS-penetrant TKIs +/- upfront SRS in TKI-naïve patients with oncogene-driven NSCLC. The addition of SRS improved time to CNS PD and local CNS control but not OS. Patients with BM ≥1 cm may benefit the most from upfront integration of SRS. [Table: see text]

Abstract 3346: BBT-207, a novel, 4th generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with broad-spectrum activity to both treatment-emergent and drug-naïve mutants for the treatment of NSCLC

Abstract Background: Activating mutations in EGFR, e.g., L858R (L) and Del19 (D), are observed in 14.1-32.3% of NSCLC worldwide and defines a druggable entity. Single agent EGFR TKI treatment was established in clinical trials. However, a treatment-emergent mutation of T790M (T) was identified as a major source of drug resistance. Irreversible 2nd and 3rd generation EGFR TKIs were shown effective. Mutant-specific inhibition by 3rd generation EGFR TKIs reduced adverse events such as skin toxicities. The emergence of a missense mutation at C797 (C), to which irreversible TKIs covalently bind, limited their efficacy. Patients harboring treatment-emergent C mutations are left with few therapeutic options. Despite anecdotal reports of efficacy from 1st generation TKIs, these complex molecular variants involving C797 are an increasing clinical concern. To prevent the emergence of drug-resistant subclones, a broad-spectrum EGFR TKI against both treatment-emergent and drug-naïve mutants is required. Such a 4th generation EGFR TKI must also enable monotherapy, allowing precise dose adjustment in case of toxicity. Method: Derived from BBT-176 which is under clinical evaluation (NCT04820023), we synthesized BBT-207 and other related molecules. Using Promega ADP-Glo™ kinase assay, we tested compounds against wild-type (WT) and mutated EGFR proteins. Ba/F3 cells harboring WT and mutated EGFR genes were created and cell viability was measured by CellTiter-Glo® and SpectraMax iD3®. In vivo anti-tumor activity was evaluated in Ba/F3 cell-derived xenograft models and an Osimertinib-resistant patient-derived xenograft model. Single dose pharmacokinetic (PK) study was performed in animals. Results: BBT-207 showed IC50 values < 10 nM against EGFR triple mutants (DTC and LTC) and comparable IC50 values against double mutants (DC and LC), while Osimertinib was ineffective in both groups. BBT-207 was also as active as Gefitinib to single mutants (D and L). Double mutants containing T790M (DT and LT) were inhibited effectively by BBT-207 and Osimertinib at similar concentrations, while not by Gefitinib. In in vivo models to which Osimertinib was inactive (LC and DTC), significant tumor growth inhibition was observed from BBT-207 alone, which was enhanced by the addition of Osimertinib. PK studies in mouse, rat, dog and monkey were consistent with high exposure and sustained drug concentrations above the IC50 values, with evidence of penetration into the central nervous system. Conclusion: BBT-207 is a reversible, mutant-specific, broad-spectrum TKI, active to clinically observed mutations of EGFR and is expected to be compatible with monotherapy of QD schedule in humans. BBT-207 is well-positioned to augment the treatment of EGFR mutated NSCLC, either for acquired drug resistance or in earlier line. Citation Format: Taiguang Jimmy Jin, Sang-Uk Kang, Chulwon Kim, Jehrod Brenneman, Mihee Song, Pavel Printsev, Bo-Bae Seo, Yong-Hee Lee, Sang-Yoon Lee. BBT-207, a novel, 4th generation, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with broad-spectrum activity to both treatment-emergent and drug-naïve mutants for the treatment of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3346.

Treatment Outcomes of Nilotinib as Second Line Therapy for Chronic Myeloid Leukemia Patients in Karbala Province of Iraq

Background: Second line treatment of chronic myeloid leukemia (CML) is crucial after imatinib therapy failure. In Iraq, nilotinib is the only available second line tyrosine kinase inhibitors (TKIs), making management of CML patients with failure response to 1st generation TKIs as a great challenge to the health system. Objectives: Our study tries to evaluate nilotinib safety and efficacy among CML patients in Karbala province of Iraq as the only drug available as second line treatment for CML patients post imatinib failure. Materials & Methods: This research was carried out in Al-Hussein cancer center in Karbala province of Iraq between January 2012 & December 2020. Nilotinib was used as a second-line treatment for 30 CML patients and their response were assessed by the level of BCR-ABL1 transcription in peripheral blood at 3 months, 6 months and 12 months from starting treatments. Results: The median age was 42.5 years, included 16 males and 14 females with male to female ratio 1.14. According to Sokal score 15 patients were high risk, 11 patients were intermediate risk and 4 patients were low risk. More than 66% of our patients achieved major molecular response (MMR) after starting nilotinib as second line. The BCR- ABL transcription level had a significant reduction from baseline at 3 months, 6 months and 12 months respectively (P value <0.05). Male patients and those who received imatinib for ≥ 24 months were better survival. Conclusion: Nilotinib is effective and safe drugs as second line treatment among Iraqi patients.

Long-Term Outcome of Philadelphia Chromosome Positive Leukemia From Eastern Indian Subcontinent: An Experience in the Era of Tyrosine Kinase Inhibitor (TKI) Therapy

IntroductionPhiladelphia chromosome (Ph) marks a group of leukemia with almost all cases of chronic myeloid leukemia (CML), a subset of acute lymphoid leukemia (ALL) and rare cases of acute myeloid leukemia (AML). In the era of precision medicine, such cases are successfully managed with tyrosine kinase inhibitor (TKI) drugs. This study examined the features and long-term outcome of Ph+ve cases from a tertiary cancer care center from Eastern Indian subcontinent. Materials and MethodsReviewing retrospective case-records registered between 2005 and 2015, cases of CML and ALL were documented under Ph+ve category; while no instance of Ph+ve AML was found. ResultsIn CML cohort, adult and juvenile incidences were 95.2% and 4.8% respectively; in ALL cohort, the same was found for 66.67% and 33.33% cases. Among the CML cases, 10-year overall survival (OS) and progression-free survival (PFS) were significantly affected upon the phase of disease at time of detection. Furthermore, both OS and PFS significantly dropped whenever non-TKI-based treatment was applied prior to TKI-commencement. Long-term (10-year) sensitivity to 1st generation TKI, imatinib, was noted 88.51% and 83.33% for adult and juvenile CML cohorts, respectively. For Ph+ ALL cohort, the OS was benefitted upon combinatorial TKI and chemotherapy. However, large fractions of affected individual from CML as well as ALL cohorts were found to discontinue follow-up. ConclusionTogether with differences in outcome on the basis of drug-use from onset, age (juvenile versus adult) and stage at diagnosis, our analyses bring forward the real-world scenario of Ph+ve leukemia managed with precision medicine.

Dasatinib-Induced Lymphocyte Elevation and Imbalance of T Cell Receptor V Beta Gene Expression in Chronic Phase Chronic Myelogenous Leukemia Patients

Introduction: Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasms caused by a reciprocal translocation of chromosomes 9 and 22 [t(9;22)], producing the BCR-ABL fusion gene. Imatinib (Ima), the 1st generation tyrosine kinase inhibitor (TKI), has drastically improved the prognosis of CML compared to previous therapies. Imatinib and the 2nd-generation TKIs dasatinib (Dasa) and nilotinib (Nilo) are generally used for chronic phase CML (CP-CML) as induction chemotherapy. Lymphocyte proliferation and increased large granular lymphocytes (LGLs) are sometimes observed in patients treated with Dasa. These LGLs have been reported to be mainly natural killer (NK) cells. However, there is insufficient data about T-lymphocytes, including CD8 T cells, in CML patients treated with TKIs. We analyzed lymphocyte counts and percentages in CP-CML patients treated with Dasa and other TKIs. We also examined T cell receptor (TCR) V beta gene repertoire in some patients.Methods: The patients in this study were CP-CML patients diagnosed at our hospital from August 2006 to June 2016 and treated with TKIs. The main aims were to examine (1) lymphocyte rates and (2) cytotoxic T lymphocytes (CTLs) and TCR V beta gene repertoire. These analyses were conducted using flow cytometry. All statistical analyses were performed using GraphPad Prism 6 software.Results: Table 1 summarizes data comparing patients treated with Dasa and those treated with other TKIs. Six patients were treated with Dasa only. Seven and 2 patients, respectively, were treated with Ima or Nilo only. Eleven patients were treated with multiple TKIs including Dasa, and 2 patients were treated with multiple TKIs not including Dasa. The median age at first TKI administration was 60 years in patients treated with Dasa and 72 years in patients treated with other TKIs. No significant statistical difference was observed in age at first TKI administration. The median follow-up period of patients treated with TKIs without Dasa was significantly longer than that of patients treated with TKIs including Dasa. This was due to the difference in the timing of approval of Ima (1st generation TKI) and Dasa (2nd generation TKI). There was no significant difference in the best response between the Dasa and non-Dasa groups. There was also no significant difference in overall survival between the 2 groups (Log-rank, P = 0.7283). Pleural effusion was observed in 5 patients in the Dasa group and 1 in the non-Dasa group, without statistical significance. Figure 1 shows lymphocyte elevation in the Dasa group compared to the non-Dasa group with regard to both lymphocyte counts and percentages. Figure 2 shows the time courses of lymphocyte percentages. Counts from 1, 3, 6 and 12 months from the initiation of Dasa (A) and non-Dasa TKIs (B) are indicated. The lymphocyte rates in the non-Dasa group showed no significant change (Figure 2B). However, gradual lymphocyte elevation was clearly seen with the passage of time in Dasa group patients, with statistical significance (Figure 2A). The time courses of lymphocyte counts in 2 cases are shown in Figure 3. Lymphocyte elevations were clearly observed after changing to Dasa from Nilo (Figure 3A) and Ima (Figure 3B). We also analyzed the detailed lymphocyte fraction in some patients. Representative data of a patient treated with Dasa only are shown in Table 2 and Figure 4. NK cells were found in the peripheral blood, as have been seen in previous reports, and, interestingly, CTLs were also detected at all time points (Table 2). It is notable that about 20% of the peripheral blood consisted of CTLs 35 months after the first administration, which was the same percentage as that of NK cells. TCR V beta gene repertoire in the same patient is shown in Figure 4. Oligoclonal CD8 T cell expansion was observed using V beta 13.1, V beta 7.1, and V beta 2 expression. These results suggest that not only NK cells but also CTLs may play an important role in attacking CML blasts in patients treated with Dasa.Conclusions: In CP-CML patients treated with TKIs, lymphocyte elevation was obviously observed only in patients treated with Dasa. CTL analyses and TCR V beta gene analyses suggest that CTLs can be induced along with NK cells in patients treated with Dasa. These results show that Dasa can work in a different way than other TKIs. Clarifying the tumor antigens recognized by these CTLs may bring new insights and connect to new cellular therapies for refractory CML cases. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 6304: Decrypting EGFR signaling with BRET biosensors: A novel approach to study RTK mutations and the effects of inhibitors

Abstract Receptor tyrosine kinases (RTKs) comprise nodes at the center of complex signaling networks regulating various aspects of cell growth, differentiation and survival. Dysregulated RTK activity can alter many cellular processes, often culminating in cancer. Consequently, RTKs are prime targets for new anti-cancer agents. Yet, the efficacy of these drugs is limited by the development of drug-induced adverse events and acquired resistance. Discovery of novel therapeutics devoid of such limitations requires a deeper understanding of often overlooked determinants of therapeutic efficacy, including kinetics, subcellular localization, signaling bias and drug target mutations. In this study, we present a live-cell BRET-based biosensor platform applicable to studying such key elements, which allows for real-time spatiotemporal monitoring of RTK signaling across more than 10 effector proteins/pathways. Using EGFR and two of its ligands (EGF and Epiregulin) as a model system, we used our platform to highlight spatiotemporal signaling bias. Indeed, Epiregulin-induced engagement of effector protein Grb2 was more efficacious (25%) and displayed faster kinetics relative to that observed with EGF. Interestingly, EGF, but not Epiregulin, promoted a gradual increase in Grb2 levels at early endosomes. These data highlight opportunities for the identification of biased ligands displaying improved therapeutic efficacy. The impact of various glioblastoma-related EGFR mutations on receptor signaling were also profiled. The EGFR(vI) mutant showed constitutive activity on the PLCG1 effector pathway while the EGFR(vV) mutant was uniquely constitutive on SHIP1 and SHIP2 pathways. Further, EGFR(vIII) was devoid of constitutive activity on some effector proteins (PLCG1, Grb2) and highly constitutive on others (PI3K, SHIP1/2). The G598V mutant showed constitutive activity on all pathways except Grb2. This data shows how oncogenic mutations can rewire an RTK's signaling network. Identification and targeting of common signaling nodes exploited by various mutants could enhance drug efficacy and minimize mutation-related drug resistance. Finally, RTK biosensors were used to screen for tyrosine kinase inhibitor (TKI) activity on EGFR kinase domain mutants found in NSCLC (T790M and C797S). 1st generation TKI Gefitinib and 4th generation TKI Osimertinib reversed EGF activation of WT EGFR. However, only Osimertinib could reverse EGF-mediated activation of EGFR(T790M) but was ineffective at inhibiting EGFR(C797S). The platform could thus serve as a tool to assess anti-cancer treatment efficacy against various RTK mutants. These data position our biosensor platform as a versatile technology to study multiple facets of RTK biology and pharmacology. Access to real-time, spatiotemporal readouts across multiple signaling pathways will enable the development of novel RTK-based anti-cancer agents. Citation Format: Florence Gross, Guilhem Dugast, Arturo D. Mancini, Stephan Schann, Xavier Leroy. Decrypting EGFR signaling with BRET biosensors: A novel approach to study RTK mutations and the effects of inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6304.

Rechute d’une leucémie aigüe lymphoblastique révélée par une fissure anale

Proctological damage is very frequently encountered in acute leukemia (AL), it can be indicative of the disease and occur latter. We report the observation of a 65-year-old patient with no known comorbidities, followed for 2 years for lymphoblastic leukemia Phenotype B with PH positive, treated by GRAAPH protocol associated with a 1st generation tyrosine kinase inhibitor (TKI). She relapsed a year after the end of chemotherapy and presented with severe terminal constipation with proctalgia progressing in a context of fever, deterioration of general condition and anorexia. The clinical examination found intense paleness, performans status at 3, without organomegaly or hemorrhagic signs, the proctological examination found a large posterior anal fissure very painful with hypertonic sphincter. The biological exam shows normochromic normocytic anemia at 5g/L and thrombocytopenia at 3000 element/mm3 and blast hyperleukocytosis at 70,000 element/mm3. The bone marrow aspiration coupled with immunophenotyping confirms relapse of ALL phenotype B, and karyotype and FISH demonstrate the presence of t (9.22) and the Bcr-Abl rearrangement. A medical treatment of the fissure was instituted based on laxatives and healing ointment, associated with salvage chemotherapy and 2nd generation TKI. Proctologically, the outcome was favorable with the disappearance of proctalgia and the onset of healing of the anal fissure. On the other hand, on the hematological level, the patient was refractory to chemotherapy and died due to the evolution of her disease.

P3110Tyrosine kinase inhibitor nilotinib increases atherosclerosis burden in ApoE knock-out mice

Abstract Background In 2001, imatinib, the 1st generation tyrosine kinase inhibitor (TKI), dramatically improved the treatment and survival of the patients with chronic myeloid leukemia (CML). However, the emergence of imatinib-resistant patients led to the development of 2nd generation TKIs. Nilotinib demonstrated increased efficacy to control CML disease over imatinib and is now recommended as first-line therapy. But arterial occlusive adverse events (AOE) occurs in patients treated with nilotinib and not with imatinib. Mechanisms leading to AOE with nilotinib is not well understood. AOE are dominated by ischemic heart disease and lower extremity arterial disease. Moreover, we demonstrated that CML patients with cardiovascular risk factors are at high risk to rapidly develop AOE with nilotinib. Purpose To evaluate the impact of nilotinib in a pre-clinical model of atherosclerosis. Methods ApoE Knock-Out mice (8-week-old) were treated with either placebo (N=10), imatinib (IMA) 200mg/kg/day (N=10) or nilotinib (NILO) 100mg/kg/day (N=10) by daily feeding and a high-fat diet for 12 weeks. Heart and aorta were harvested after sacrifice, for histology staining and immunochemistry. Splenocytes were cultured from collected spleens, and Interleukin (IL) 12p70 and IL10 measured by ELISA. Results Mice treated with nilotinib showed an increase of atherosclerotic plaque size at the aortic sinus level: 462.1x103 μm2 vs. 344.4x103 μm2 with imatinib or 394.9x103 μm2 with placebo (p<0.05) and at the thoracoabdominal aorta level (p<0.05). Plaques had greater infiltration of macrophages: 33.0±3.4% with nilotinib vs. 7.3±1.3% with imatinib and 12.6±1.1% with placebo (p<0.001) and a larger necrotic nucleus 33.0±3.4% with nilotinib vs. 7.3±1.3% with imatinib or 12.6±1.1% with placebo (p<0.001). Nilotinib modulated the systemic immune response by increasing IL-12p70 and by decreasing IL-10 production by splenocytes after stimulation by LPS-IFNγ whereas IL10 increase was observed with imatinib. Plaque size (aortic sinus) Conclusion Nilotinib has a pro-atherogenic effect in a pre-clinical model of atherosclerosis and increases the monocyte/macrophage pro-inflammatory response. Further experiments are required to identify pathways activated by nilotinib.

CLINICAL CASE OF TREATMENT OF A PATIENT WITH CHRONIC MYELOID LEUKEMIA WITH A MUTATION BCR-ABL Y253H AND COMORBIDITIES

The article presents information on the methods of diagnosis and targeted therapy of chronic myeloid leukemia (CML). A clinical case of CML with the development of resistance to therapy with 1st generation tyrosine kinase inhibitors (ITK), the appointment of 2nd generation ITK (dasatinib) with regard to comorbidity, the development of adverse events in the form of fibrosing alveolitis and severe pleurisy, translation of nilotitis in the form of fibrosis of the alveolitis and severe pleurisy is considered, but the lack of effect of treatment. The study of the mutational status revealed a BCR-ABL Y253H mutation, which made it possible to individualize the patient’s therapy, obtain a large molecular response, and overcome undesirable phenomena. The development of resistance or the loss of response to the treatment of ITK in CML with comorbidity requires the timely identification of mutations in the kinase domain of BCR-ABL and contributes to the selection of early personalized therapy for a particular patient.

ABL Tyrosine Kinase Inhibitors (TKIs) Are Associated with Increased Rho-Associated Kinase (ROCK) Activity That May Contribute to Vascular Toxicity in Patients with Chronic Myeloid Leukemia (CML)

IntroductionThe use of 2nd or 3rd generation ABL TKIs in patients with CML is associated with vascular toxicity, including peripheral arterial occlusive disease and cardiovascular and cerebrovascular events. However, Imatinib, a 1st generation TKI, has not been shown to increase risk of cardiovascular events (Douxfils J et al. JAMA Oncol 2016;2:625). Therefore, there is a need to identify risk factors and predictors of vascular toxicity for patients receiving these TKIs. In mice, inhibition of the Abl kinases results in activation of Rho and its downstream target Rho kinase (ROCK) (Zandy et al. Proc Natl Acad Sci USA 2007;104:17686). Growing evidence suggests that elevated ROCK activity plays a central role in the pathogenesis of cardiovascular disease and stroke in both animal and clinical studies. TKIs used in CML are potent inhibitors of ABL1 and ABL2 kinases. We hypothesized that CML patients receiving 2nd or 3rd generation BCR/ABL1 TKIs have higher ROCK activity than patients not receiving these TKIs, providing a putative mechanism for the vascular toxicity observed in clinical studies.MethodsWe measured leukocyte ROCK activity in CML patients and analyzed results based on their last TKI dose. We isolated fresh peripheral blood leukocytes from 38 patients (17 females, 21 males) with a median age of 53 years (range, 24-90 years). 4 patients had newly diagnosed untreated CML at the start of the study. One male was receiving Dasatinib for Ph+ ALL and was also included. ROCK activity was assessed in leukocytes by measuring the ratio of phospho-myosin-binding subunit (p-MBS) on myosin light-chain phosphatase, a downstream target of ROCK, to total MBS using an automated Western blotting system (Wes, ProteinSimple, San Jose, CA) (Hata T et al. Atherosclerosis 2011; 214:117). Each patient had 1-6 measurements of leukocyte ROCK activity over 1 - 18 months (n=78 measurements). Information about cardiovascular risk factors, concomitant medications, CML status, and total duration of TKI therapy was collected. For patients with multiple samples over time, ROCK activity was calculated as the mean of all samples taken while receiving the same TKI. Patients in treatment-free remission (TFR) were considered off-TKI, but those in TFR < 1 month were excluded from the analysis to reduce potential confounding effects.ResultsWe analyzed blood samples from 4 untreated CML patients, 8 while in TFR, and 31 who were actively receiving one of the 5 TKIs (7 Imatinib, 12 Dasatinib, 9 Nilotinib, 2 Ponatinib, 1 Bosutinib). 3 patients developed acute coronary syndrome during the study and required coronary revascularization for myocardial infarction. We found no significant difference in ROCK activity when comparing all patients receiving TKIs to those not receiving TKIs. However, we found higher leukocyte ROCK activity when comparing all patients receiving 2nd and 3rd generation TKIs to those not receiving any TKI (Welch's t test, mean leukocyte ROCK activity 1.00 ± 0.06 vs 0.80 ± 0.06; p=0.03). We also found higher leukocyte ROCK activity when comparing patients receiving Dasatinib to patients receiving Imatinib (mean leukocyte ROCK activity 1.05 ± 0.09 vs 0.75 ± 0.10; p=0.04). The comparison of Imatinib to all 2nd and 3rd generation TKIs was not significant (p=0.06).ConclusionsWe found that patients on 2nd and 3rd generation TKIs have higher leukocyte ROCK activity compared to those not receiving TKIs, and higher leukocyte ROCK activity in patients on Dasatinib compared with patients receiving Imatinib. These results are consistent with the known lower-risk of cardiovascular side-effects observed with Imatinib in comparison to the next generation ABL TKIs. Limitations include small sample size and heterogeneity in the patient population in terms of age, cardiovascular risk factors, specific TKI used, and total duration and sequencing of TKI agents. The study continues to accrue CML subjects in order to follow individual patients over time on TKI therapy. DisclosuresLarson:Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Cytotoxic Immune Response Can be Obtained Earlier in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Dasatinib Than with Other Tyrosine Kinase Inhibitors

Introduction: Generation of BCR-ABL fusion gene by reciprocal translocation of chromosomes 9 and 22 immortalizes hematopoietic stem cells by mechanisms such as activation of the JAK-STAT pathway, translational activation of BCL-XL, and inhibition of DNA repair, thereby leading to chronic myeloid leukemia (CML). Amazing improvement in the prognosis of CML has been achieved since the introduction of tyrosine kinase inhibitors (TKIs). Imatinib, a 1st-generation TKI, and dasatinib and nilotinib, 2nd-generation TKIs, are generally used for chronic phase (CP) CML as induction therapy. However, to date, no consensus about the cessation of TKIs in CP-CML patients has been obtained. We recently reported the case of a CP-CML patient with long-term complete molecular response (MR) after cessation of dasatinib, who has been maintaining memory CTLs with T cell receptor (TCR) clonality (Jo et al. Oncology Letters 15: 2935-2938, 2018). Here, we show that up-regulation of memory CTLs occurs early in dasatinib-treated patients compared with those treated with other TKIs.Methods: We examined the TCR V beta gene repertoire to analyze TCR clonality of CD8-positive T cells in TKI-treated CP-CML patients using flow cytometry.Results: Table 1 summarizes the data comparing patients treated with TKIs including dasatinib (Dasa group) and those treated with TKIs without dasatinib (non-Dasa group). Seven patients were treated with dasatinib only; 7, with imatinib only; 8, with multiple TKIs, including dasatinib; and 1, with multiple TKIs without dasatinib. The median age at first TKI administration was 57 years in the Dasa group and 69 years in the non-Dasa group. No significant statistical difference was observed in age at first TKI administration. The time of TCR clonality assay was significantly earlier in the Dasa group than in the non-Dasa group (P = 0.0013). There was no significant difference in the MR at the time of TCR clonality assay between the 2 groups. Figure 1 shows representative data of the TCR clonality assay of the patients in the non-Dasa group. We defined a TCR V beta gene percentage of 10% and above as being positive for monoclonality in this study. The time of analysis was at 116th month (Mo) after the 1st imatinib administration, and NK cell percentage was 30.2% at that time. TCR monoclonality was observed in neither effector CTLs (upper panel) nor memory CTLs (lower panel), although the patient had gained MR5. Figure 2 shows representative time-course data of the patients in the Dasa group. MR levels were MR4.5 (13th Mo), MR5 (16th Mo), and MR5 (19th Mo). Interestingly, memory CTL clonality with the TCR V beta 20 gene had already been observed in the 13th Mo, and it had been continuously observed in the 16th and 19th Mo. NK cell percentages were less than 24% throughout the observation period. Table 2 summarizes the CTL clonality assay results and NK cell percentages. There was no significant change in the NK cell percentages between the 2 groups. Although no statistical significance was observed in both effector and memory CTL clonality between the 2 groups, it is notable that approximately 73% and 87% positivity of effector and memory CTL clonality was observed in the Dasa group. Approximately 38% and 50% positivity of effector and memory CTL clonality was observed in the non-Dasa group, although the TKI exposure time for this group was significantly longer. Notably, the positive percentages of effector and memory CTL clonality in the non-Dasa group are quite similar to the overall probabilities of maintenance of deep MR reported in various imatinib-stop studies such as the STIM study (Mahon et al. Lancet Oncol 11: 1029-1035, 2010) and the TWISTER study (Ross et al. Blood 122: 515-522, 2013). These results suggest that acquisition of CTL clonality may correlate with treatment-free remission (TFR) in CP-CML patients treated with TKIs.Conclusions: Effector and memory CTL clonality was attained more rapidly and frequently in dasatinib-treated CP-CML patients than in patients treated with TKIs without dasatinib. There was no significant difference in the NK cell percentages. The positive percentages of CTL clonality resembled the percentages of TFR in various TKI-stop studies. These results suggest that the acquisition of CTL clonality may provide long-term remission and TFR to CP-CML patients and that cessation of TKIs should be considered in patients with clonal expansion of memory CTLs, irrespective of NK cells. [Display omitted] DisclosuresJo:Bristol-Myers Squibb: Honoraria.

P3.02-002 Liquid and Solid Rebiopsies in EGFR-Mutated NSCLC Patients

Treatment of EGFR-mutated NSCLC patients with acquired resistance to EGFR tyrosine kinase inhibitors (TKI) relies on identification of the mechanism of resistance. We performed a retrospective multicentric study in order to investigate use and results of liquid (circulating free DNA) and solid rebiopsies in routine practice. We included 95 EGFR-mutated NSCLC patients with at least one rebiopsy after treatment with EGFR TKI (mostly 1st generation TKI). 87 solid rebiopsies and 71 liquid rebiopsies were performed. The number of liquid biopsies increased over time, from 1/y (6,6% of all rebiopsies in 2014) to 53/y (70,6% of all rebiopsies in 2016). The proportion of liquid biopsies increased with the number of rebiopsies per patient, from 35,5% for the first rebiopsy to 83,3% for the third rebiopsy. The rebiopsy identified a mechanism of acquired resistance in 48 patients (50,5%), including 43 patients with a T790M mutation (45,2%), 2 patients (2,1%) with MET amplification, 1 patient (1%) with small cell lung cancer transformation, 1 patient (1%) with a C797S mutation and 1 patient (1%) with a KRAS mutation. The initial EGFR mutation was found in 74 solid rebiopsies (85%) and 43 liquid rebiopsies (60%). The T790M mutation was found in 32 solid rebiopsies (36,8%) and 18 liquid rebiopsies (25,3%). Among 44 patients having both liquid and solid rebiopsies performed at the same time, an EGFR mutation was found by both techniques in 26 cases (59,1%) and the overall concordance was 88,6%. Analysis of cerebrospinal fluid was positive in 10 patients (100%) for the initial EGFR mutation and 1 patient (10%) for the T790M mutation. A T790M mutation was identified in 37,3% of all first rebiopsies. Repeated rebiopsies when the first biopsy was negative identified the T790M mutation in 29,6% of cases. In our series representative of daily practice, rebiopsies of EGFR-mutated NSCLC patients with acquired resistance to EGFR TKI identified a mechanism of resistance in half of the cases. Repeating rebiopsies increased the chance of detecting a T790M mutation.

Abstract 2061: Non-covalent EGFR T790M targeting TKIs inhibit AZD9291 resistant EGFR C797S mutants

Abstract Approximately 10-15% of non-small-cell lung cancers (NSCLC) have epidermal growth factor receptor (EGFR) mutations resulting in increased sensitivity to 1st generation tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. For common mutations in EGFR, treatment with 1st generation TKIs results in approximately 70% overall response rate, increased progression free survival, and increased quality of life compared to chemotherapy alone. However, resistance to 1st generation TKIs typically develops within ~12 months, and approximately 55% of patients acquire a secondary mutation in EGFR Exon 20, T790M. To overcome resistance, 2nd and 3rd generation covalently binding TKIs targeting T790M mutations have been developed. Recent studies show that approximately 40% of acquired resistance to 2nd and 3rd generation TKIs can also occur via a third acquired EGFR mutation at the site of covalent binding, C797S. To date, there are no standard approved targeted therapies for treating EGFR C797S mutant NSCLC. Moreover, with proposed increased use of covalent inhibitors in the first line setting, C797S mutations are expected to become more prevalent and new strategies to overcome therapeutic resistance will be required. To this end, we have generated stable Ba/F3 and HCC827 NSCLC cell lines expressing C797S mutant EGF receptors with common mutations in EGFR including, L858R/T790M/C797S, and Ex19del/T790M/C797S. EGFR mutant cell lines expressing C797S were screened against 1st, 2nd, and 3rd generation EGFR TKIs and cell viability was determined using Cell Titer Glo. Triple mutant cell lines containing T790M and C797S mutations were not sensitive to any 1st, 2nd, or 3rd generation inhibitors with IC50 values of &amp;gt;10µM, 7.0µM, and 7.6µM, respectively. However Ba/F3 and HCC827 cell lines transfected with EGFR triple mutants were inhibited by non-covalent inhibitors: CUDC-101, an EGFR, HER2 and HDAC inhibitor, and PKC412, a FLT3 inhibitor. In triple mutant Ba/F3 cells, CUDC-101 and PKC412 had IC50 values of 470nM and 250nM in Ex19del/T790M/C797S EGFR mutants, respectively, and IC50 values of 690nM and 270nM in L858R/T790M/C797S EGFR mutants. In HCC827 cells, PKC412 had IC50 values of 610nM and 520nM in L858R/T790M/C797S and Ex19del/T790M/C797S triple mutants, respectively. In addition, western blot analysis of triple mutant Ba/F3 cells showed decreased phosphorylation of EGFR in presence of 50nM PKC412 and 500nM of CUDC-101. Moreover, PKC412 partially decreased p-EGFR expression at 50nM in HCC827 triple mutant cell lines. In conclusion, unlike other EGFR TKIs, the non-covalent EGFR inhibitors CUDC-101 and PKC412 inhibit both T790M and C797S EGFR mutants at low concentrations. Currently, we are establishing additional osimertinib resistant HCC827, H1975, PC9 and H4006 cell lines for further in vitro and in vivo studies. Citation Format: Jacqulyne P. Robichaux, Monique Nilsson, John V. Heymach. Non-covalent EGFR T790M targeting TKIs inhibit AZD9291 resistant EGFR C797S mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2061. doi:10.1158/1538-7445.AM2017-2061

Patient reported outcome of tyrosine kinase inhibitor related side effects and their impact on daily life in Chinese patients with chronic myeloid leukemia in the chronic phase

目的评估中国慢性髓性白血病（CML）慢性期（CP）患者报告的酪氨酸激酶抑制剂（TKI）相关不良反应及其对日常生活的影响。方法2014年5月至11月在全国范围内向正在接受TKI治疗的成年CML患者发放无记名调查问卷。TKI不良反应对患者日常生活的影响程度采用自我报告的形式，以1分（没有影响）至5分（严重影响）进行评估。结果731例CML-CP受访者报告了TKI相关不良反应影响其日常生活评分，中位年龄41 (18~88）岁，男性407例（56%），560例（77%）确诊至TKI治疗时间< 1年。中位TKI治疗时间为3（<1~13）年，549例（75%）获得完全细胞遗传学反应，301例（41%）获得完全分子学反应。TKI最多见的不良反应依次为水肿（44%）、乏力（38%）、胃肠道不适（32%）、面部颜色改变（19%）、肌肉痉挛（19%）、皮疹（14%）、肝功能异常（12%）、体重增加（12%）和血细胞计数降低（8%）。多因素分析显示，TKI服药时间<4年是乏力的独立影响因素；女性、年龄≥40岁、服用一代TKI者容易发生水肿；服用一代TKI容易发生胃肠道不适；服用二代TKI容易出现皮疹及肝功能异常；女性容易出现体重增加；确诊至TKI治疗时间≥1年、服用一代TKI者较易出现肌肉痉挛；服用仿制品是血细胞计数降低的独立影响因素。患者自我报告TKI相关不良反应影响日常生活的评分显示218例（30%）没有影响（1分），375例（51%）受轻中度影响（2~3分），138例（19%）受严重影响（4~5分）。多因素分析显示，仅将人口学特征纳入分析时，女性、年龄≥40岁、服用仿制品、TKI服药时间<4年与受访者较高的日常生活受影响程度显著相关；将不良反应也纳入多因素分析后，未接受高等教育、TKI服药时间<4年、服用仿制品以及以下不良反应：水肿、乏力、胃肠道不适、面部颜色改变、皮疹和肝功能异常与较高的日常生活受影响程度相关。结论服用TKI的中国CML-CP患者中，水肿、乏力、胃肠道不适、皮疹、面部颜色改变和肝功能异常是最常见的、影响其日常生活的药物不良反应。女性、年龄≥40岁、未接受高等教育、服用仿制品和TKI治疗时间较短与患者日常生活受影响显著相关。

Variations in EGFR ctDNA Correlates to the Clinical Efficacy of Afatinib in Non Small Cell Lung Cancer with Acquired Resistance.

Monitoring of non small cell lung cancer (NSCLC) patients on afatinib after acquired resistance to 1st generation tyrosine kinase inhibitors is important. Circulating tumor DNA (ctDNA) offers an attractive means other than conventional tissue biopsy to characterize real time dynamic changes of the disease. In our study, we aim to ascertain the clinical value for ctDNA monitoring of NSCLC patients with acquired resistance for afatinib treatment. 200 patients positive for the activating epithermal growth factor receptor (EGFR) mutations were recruited for the study. Baseline molecular profiling for L858R, Exon 19 deletion and T790M were performed. Thereafter, serial blood samples were taken and patients were assessed by overall survival (OS) to determine the usefulness of ctDNA monitoring. At baseline, matched tumor biopsy and ctDNA analysis had a concordance agreement of 93.5% for L858R and exon 19 deletion. We also determined that a large proportion of patients had the drug resistance mutation T790M prior to starting afatinib and these patients were linked to a worse survival outcome. For patients that registered a drop in ctDNA levels after afatinib was administered, we observed that their survival outcome was more favorable (hazard ratio 1.56, (95% CI 1.04 to 2.43). ctDNA levels were mostly elevated after the 3rd sampling cycle. Our results suggest that ctDNA can be used to predict the clinical benefits of afatinib treatment. Pre and post blood sampling aids to identify patient groups that may benefit most from the treatment and ctDNA is relatively sensitive to address the dynamic changes of the disease at the molecular level.

Clinical Features and Treatment Outcomes of 51 Patients with Chronic Myeloid Leukemia Treated with a Tyrosine Kinase Inhibitor at a Single Institution from 2002 to 2014.

Although clinical trials of first- and second-generation tyrosine kinase inhibitors (TKIs) have been shown to improve the prognosis of chronic myeloid leukemia (CML), there is still uncertainty about the clinical features, treatment outcomes, adverse effects, and other possible problems of their use in the clinical setting. We retrospectively analyzed 51 CML patients treated with TKIs at a single institution between 2002 and 2014. The patients (median age: 53.8 years) were classified as having chronic (n = 48), accelerated (n = 2), or blastic phase (n = 1) CML. Our treatments included both 1st generation TKIs (60.8%) and 2nd generation TKIs (39.2%). We found that the overall response rates of complete cytogenetic response (CCyR), major molecular response (MMR), and MR4 (molecular response 4) were 90.2%, 78.4%, and 64.7%, respectively. Second line 2nd generation TKIs had response rates equivalent to those of 1st line 1st generation TKIs. Moreover, 1st line 2nd generation TKIs tended to achieve an early response rate. Overall survival (OS) at 5 years was 93.2%. Sudden blastic crisis (BC) occurred in 2 CML patients receiving TKI with CCyR status. Hematopoietic stem cell transplantation was performed for BC (n = 1) and sudden BC (n = 2). Side effects of all grades (1-3) and grade 3 alone were 64.7% and 11.8%, respectively. Dose reduction, replacement with another TKI, or low dose TKI treatment may be useful methods to control side effects. Further reasons of TKI discontinuation were economic problems (n = 3) and pregnancy (n = 1). Consequently, our treatment strategy for CML demonstrated good response rate and OS. Currently, treatment discontinuation due to intolerance, resistance, economic problems, pregnancy, and sudden BC remains a concern in clinical practice.

Comparison of the Efficacy of the First and Second-Generation Tyrosine Kinase Inhibitors in the First-Line Treatment of Ph-Positive Acute Lymphoblastic Leukemia

It is reported that compared with the the good efficacy of imatinib as the first-line treatment of Ph-positive acute lymphoblastic leukemia (Ph+ ALL), 2nd-generation tyrosine kinase inhibitor (TKI) cannot get higher rate of complete remision (CR) and overall survival (OS). It is also reported that the patients treated with dasatinib have higher incidence of pleural effusions and hemorrhage and BCR-ABL mutant of T315I. Whether 2nd-generation TKI can be the first-line treatment of Ph+ ALL needs more clinical research. Aim of this retrospective study is to compare the efficacy and safety of 1st and 2nd-generation TKI in the first line treatment of Ph+ ALL.50 patients with newly diagnosed Ph+ ALL and first-line treated by TKI combined with chemotherapy and / or allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Nanfang hospital between January, 2010 and May, 2014 were enrolled and their clinical data were retrospectively analyzed in this study. Among these patients, 33 cases were treated with 1st-generation TKI, 17 with 2nd-generation TKIs, all of which started from the diagnosis and lasted to the time of allo-HSCT or the end of follow-up. Besides TKIs, VILP / VCDLP were the routine induction regimens, and hyper-CVAD-A ± L-asp/B were the consolidation regimens, furthermore 36/50 cases received allo-HSCT. Quantitative detection of BCR-ABL level as minimal residual disease (MRD) monitoring in bone marrow after every cycle of chemotherapy with RTQ-PCR methold.Compared with the group treated with 1st-generation TKI, there were more male patients (P=0.017), older median age of onset (P=0.041), higher incidence of additional karyotype (P=0.022) and BCR-ABL(P210) transcript (P=0.001) and ABL1 gene mutations (P=0.022) in the group treated with 2nd-generation TKIs, while no significant differrnce in white blood cell count, incidence of central nervous system leukemia, EGIL classification, IGH gene rearrangement and P16 gene deletion. With respect to early response, no statistical difference was observed between the two groups, such as the first and second-cycle cumulative rate of CR and >3-log reduction in MRD level (19/33 vs 7/17, P=0.272.; 28/33 vs 12/17, P= 0.232; 12/33 vs 4/17, P=0.357; 21/33 vs 7/17, P=0.130, respectively), totle CR rate (29/33 vs 16/17, P=0.486), median time to achieve CR [40(15-113) vs 30(12-80) days, P=0.364], MRD negative rate (27/33 vs 11/17, P=0.180) and median time to achieve MRD negative [78(28-189) vs 88(29-155) days, P=0.316]. Median age of onset ≥35y, BCR-ABL(P210) transcript and ABL1 gene mutations were analyzed to be the risk factors for early molecular response. With median follow-up of 403(30-1880) days, both OS and disease-free survival (DFS) were not significantly different between the two groups, either in all patients or in those received allo-HSCT. No statistical difference in pleural effusion and hemorrhage except BCR-ABL mutant of T315I (0/10 vs 3/5) in was observed between the two groups.To sum up, in the first-line treatment of Ph+ ALL, 2nd-generation TKI is equivalent to 1st-generation TKI, but might take therapeutic advantage in the patients with older age, BCR-ABL(P210) transcript and ABL1 gene mutation, and BCR-ABL mutant of T315I in failed cases treated with 2nd-generation TKI needs more attention. DisclosuresNo relevant conflicts of interest to declare.

Outcomes and Treatment Patterns of Patients with CML in an Inner-City, Underserved, Multi-Ethnic Patient Cohort Reveals Good Overall Survival with Both First and Second Generation TKIs As Initial Therapy

Introduction:Recent approval of second generation tyrosine kinase inhibitors (TKI) in chronic myelogenous leukemia (CML) has raised issues about their efficacy and pharmaco-economic utility in front line therapy of CML. We aimed to study these issues as well as reasons for switching TKIs in a real world setting of inner-city, multi-ethnic, underserved patient populations.Methods:We conducted an analysis of CML treatment and outcomes in an inner city cohort in the Bronx, NY. We identified 149 confirmed cases of CML that were treated over the last 17 years. All chart review was conducted by one of the study authors and discrepancies were reviewed by at least two of the authors. Data were analyzed using Chi-squared, t-testing for unpaired samples, and analysis of variance (ANOVA) to determine significance. Mortality was analyzed using Kaplan-Meir curves.Results:Demographics and Presentation:The mean age at time of presentation was 50 years (range 10 - 89 years, n=124). Average follow-up time was 5.1 (± 3.9) years. The cohort was minority rich and included 38.9% Hispanic, 32.9% African American, 18.8% Caucasian, 6.7% Asian and 2.7% multi-ethnic. The majority of the patients had private insurance or Medicare (62.4%), followed by Medicaid (30.9%) and emergency Medicaid (6.7%). The majority of evaluable patients presented in chronic phase (96.1%).Treatment Patterns: Front-line therapy was a 1st generation TKI (imatinib) in the majority of evaluable patients (83.9%) followed by a 2nd generation TKI (dasatinib or nilotinib) (11%). Rates of imatinib use as first line therapy were similar for both Private/Medicare (82.1%) and Medicare (88.1%) patients. Interestingly, a higher percentage of patients with Emergency Medicaid were started on a 2nd generation TKI (22.2%) as opposed to Private/Medicare and Medicaid (9.0% and 11.9% respectively). This was due to the availability of patient assistance programs to pay for TKIs. After the approval of dasatinib and nilotinib in 2008, there was increased use of the 2nd generation TKIs as first line though a majority of patients were still treated with imatinib as first line (72.2%, 80.0%, and 66.7% for Private/Medicare, Medicaid and Emergency Medicaid respectively).Outcomes:At the time of conclusion of the study, a total of 31 patients had expired. Twenty patients were evaluable for therapy at the time of death, percentages of patients on 1st, 2nd and 3rd line therapy were 10%, 50%, and 25% respectively. Allogeneic stem cell transplant was performed in 15% of expired patients.Of evaluable live patients (n=109), 45.9% were receiving the original front line therapy, whereas 37.6% and 16.5% were receiving second and third line therapies respectively. Regarding reasons for switch from a one TKI to another, we noted 34 patients who had been switched from a 1st to a 2nd generation TKI. Progression of disease was the cause in 53.0% of cases, followed by lack of response (17.6%), adverse events (14.7%), cytopenias (8.8%) and intolerance (5.9%). Two patients were switched from a 2nd generation TKI to a 1st generation, and both cases were due to intolerance.Overall survival of the cohort at 2 and 5 years was 94% and 82% respectively. No differences in survival were detected between different ethnicities, gender and age groups. Emergency Medicaid patients had a poorer overall survival compared to other insurance types though this did not reach statistical significance (p=0.0928). Interestingly, overall survival was similar for patients treated with 1st of 2nd generation TKIs as first line therapy (Median survival not reached, Log rank P value =0.4).Discussion:We analyzed CML outcomes and treatment patterns in a large inner city underserved multiethnic cohort in the Bronx. The CML population reflected the ethnic composition of the borough which is predominantly Hispanic and African American. The majority of patients presented in chronic phase CML which is in agreement with other studies. Majority of patients were started on imatinib as first line therapy and had similar overall survival to those that were started on Dasatinib or Nilotinib. The majority of patients who were switched from a first generation TKI to a second generation TKI were due to relapse or lack of adequate response. Our results suggest that TKIs are successfully used in real world populations and are leading to high overall survival even with use of imatinib as first line therapy. DisclosuresNo relevant conflicts of interest to declare.

Potential Economic Consequences of Genetic Mutations and Restricted Access to Tyrosine Kinase Inhibitor Treatments Among Patients with Chronic Myelogenous Leukemia in the USA

Introduction: The 1st generation tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of chronic myelogenous leukemia (CML). The 2nd generation TKIs (2G-TKI), dasatinib and nilotinib, further improved the outcomes among CML patients. Which of the 2G-TKIs is effective for an individual patient depends, among other factors, on genetic mutations that the patient may have. The National Comprehensive Cancer Network (NCCN) guidelines provide recommendations for management of cytogenetic/hematologic resistance to TKIs. The objective of this study was to assess potential economic consequences of limiting access to therapies, while taking into account frequencies of the genetic mutations that make patients insensitive to 2G-TKIs.Methods: A decision analytics economic model was developed to examine clinical and economic outcomes among patients treated with 2G-TKIs from a US payer perspective. The model was based on a hypothetical cohort of 1,000 CML patients, who are treated with dasatinib or nilotinib following treatment failure with imatinib. BCR-ABL1 genetic mutation frequencies among the patients and impact of mutations on treatment responses to 2G-TKIs were obtained from published literature. Clinical outcomes were estimated after 12 months of treatment and included complete hematologic response (CHR) and major cytogenetic response (MCyR). The annual total TKI drug costs (2014 Wholesale Acquisition Costs) per CHR and MyCR were estimated. Three hypothetical TKI access scenarios were compared: 1) open access to both 2G-TKIs; 2) access to 2G-TKIs restricted to dasatinib only (DASA-Only); and 3) access to 2G-TKIs restricted to nilotinib only (NILO-Only).Results: The model showed that among the hypothetical cohort of 1,000 TKI treated CML patients, the percentage of patients with CHR was greatest in the open access (92.6%), followed by DASA-Only (88.2%) and NILO-Only (66.7%). Similarly, the percentage of CML patients with MCyR was greatest in the open access (56.4%), followed by DASA-Only (53.4%) and NILO-Only (46.9%). These findings were primarily due to the incidence of mutations with insensitivity or resistance to dasatinib (12.4%) and to nilotinib (19.1%) (Table). Compared to the TKI costs per CHR in open access ($120,706/CHR), the costs were 5% higher ($126,753/CHR) in DASA-Only, and,40.8% higher ($169,990/CHR) in NILO-Only. Likewise, compared to the TKI costs per MCyR in open access ($198,284/MCyR), the cost were a 5.5% higher ($209,259/MCyR) in DASA-Only, and,21.8% higher ($241,515/MCyR) in NILO-Only.Conclusions: Open access to TKIs in a managed care setting is important in order to enable clinicians to choose the most appropriate TKI treatment for a CML patient. Open access to both 2G-TKIs is likely associated with greater rates of positive clinical outcomes, including CHR and MCyR, and lower costs compared to restricted access.TableBCR-ABL1 Mutation Frequencies Among CML PatientsMutation NamePercentage of Patients with MutationMutation Class for 2G-TKI Response*DasatinibNilotinibT315I3.3DDM351T7.3AAG250E5.3AAF359V4.3ACM244V5.0AAY253H3.0ACE255K3.1BCH396R3.3AAF317L2.7CAE355G2.3AAQ252H1.7BBE255V1.6BCE459K1.6AAF486S1.5AAL248V1.2AAD276G1.2AAE279K1.2AAY253F0.7ABF359C0.7ACF359I0.7AB*Class A: mutation may confer same response as normal genotype to 2G-TKI. Class B: mutation may confer intermediate insensitivity/resistance to the 2G-TKI. Class C: mutation may confer substantial insensitivity/resistance to the 2G-TKI. Class D: mutation may confer non-response to the 2G-TKI. DisclosuresJabbour:Ariad, Novartis, BMS, Pfizer, and Teva : Consultancy. Dinara:Bristol-Myers Squibb: Employment, Equity Ownership. Melissa:Bristol-Myers Squibb: Consultancy, Research Funding. Jay:Bristol-Myers Squibb: Consultancy, Research Funding.