Start Of Tyrosine Kinase Inhibitors Research Articles

Abstract 5145: Association of a ctDNA biomarker of treatment response with clinical outcomes in a real-world pan-cancer cohort treated with tyrosine kinase inhibitors

Abstract Clinical evidence suggests that early changes in circulating tumor DNA tumor fraction (ctDNA TF) is predictive of patient response to immune checkpoint inhibitors, but the extent to which this approach can be used for patients on Tyrosine Kinase Inhibitors (TKIs) is not known. Here, we use xF Monitor to estimate ctDNA TF in patients that received TKIs and show that changes in circulating TF correlate with outcomes in a real-world pan-cancer cohort. Tempus xF Monitor is a ctDNA assay that measures quantitative molecular changes in ctDNA TF by utilizing diverse genomic events, dynamically weighting somatic variant allele frequencies and copy number variants, while using germline information to inform these estimates and providing single nucleotide variant (SNV) results on 105 genes. Molecular responders (MR) were defined as patients with ≥50% reduction in ctDNA TF between baseline and on-treatment time points, consistent with our previously established threshold. Deidentified patient records from the Tempus multimodal database were analyzed if patients had an xF test ≤ 15 weeks prior to the start of their first TKI regimen and an xF test 15 -180 days post-TKI initiation. Patients received TKI agents as classified in the Tempus Medical Ontology, which assigns a unique ID to key clinical concepts, validated and harmonized across industry standard terminologies. The TKI list was further validated using the NCI Metathesaurus (https://ncim.nci.nih.gov/ncimbrowser/) TKI concept (NCI Code C1967). Clinical endpoints were defined from TKI start to the first progression event or death (rwPFS) or death (rwOS), both censored on the last follow-up in event-free patients. Kaplan Meier analysis and Cox proportional hazard models were fitted to compare MR status and survival outcomes on TKI. The evaluable pan-cancer cohort N=69, median age = 61.5 yo, advanced/metastatic disease = 72%, 65% were female, consisted of > 10 cancer diagnoses (35% NSCLC, 26% BC), 41% 1L. In this cohort, 49% of patients received a TKI combination regimen, 21% with CT, 18% with ICI. 68% of patients with NGS testing received matched targeted mutation therapies based on NCCN guidelines. Patients classified as MR based on xF Monitor results had improved survival outcomes with a median rwOS of 951 days (vs 439 days for non-MRs). MR patients had significantly longer rwPFS (HR = 0.383, p = 0.005, CI = 0.12 - 0.75) and rwOS (HR = 0.205, p = 0.004, CI = 0.07 - 0.61) than non-MRs. xF Monitor is a novel tumor naive serial quantitative ctDNA TF algorithm off the Tempus xF assay that has the potential to be used clinically as a monitoring biomarker to stratify patients who are likely to benefit from TKI therapy. xF monitor can be used as a strategy to identify patients at a high risk of progression who could benefit from early switch or intensifying therapy. Results need to be prospectively validated in a larger cohort. Citation Format: Akash Mitra, John Guittar, Regina Schwind, Terri Driessen, Matthew Berginski, Christine Lo, Michelle M. Stein, Jonathan Freaney, Seung Won Hyun, Chithra Sangli, Kate Sasser, Halla Nimeiri, Aadel Chaudhuri. Association of a ctDNA biomarker of treatment response with clinical outcomes in a real-world pan-cancer cohort treated with tyrosine kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5145.

Prospective Assessment of Co-Morbidities and Framingham Risk Score in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients and Its Impact on Clinical Outcomes Following Frontline TKI Therapy: Toronto CML Genomic Alliance in Greater Toronto Area & Ontario (TCGA-GTA)

Introduction Front-line (1L) tyrosine kinase inhibitor (TKI) drug selection is a pearl of clinical practice in CML. It requires consideration of multiple aspects including the goal of therapy, potency of the drug as well as comorbidity of the patient (pt). Contemporary CML practice emphasizes the importance of comorbidity for TKI selection. However, such data is scarce particularly the prevalence of comorbidity and its impact on 1L drug selection. We are developing a shared care model with community hematologists in Greater Toronto Area (TCGA-GTA). Newly diagnosed CML pts in the community will be referred to the study core center for prospective enrolment into the CML registry, informed consenting for genetic testing/future research, and evaluation of baseline comorbidity. Pt will return to referring hematologists for management of CML, including 1L TKI treatment as per standard of care, and is scheduled to visit the study center at 6 and 12 months, then annually for 10 years. It gives us a unique opportunity to evaluate the impact of comorbidity on 1L TKI drug selection. Patients and method Adult pts with newly diagnosed CML of any phase within 2 months of diagnosis are eligible for the study unless they are not able to visit study core center. Comorbidities and Framingham risk score (FRS) were assessed at the time of initial evaluation. Mutation profile testing is done by a bar-coded error-corrected sequencing platform for 40 genes developed at the Ontario Institute for Cancer Research. Cumulative incidence of molecular response with 2 log (MR2), 3 log (MR3), 4 log reduction or deeper (MR4), and treatment failure (TF) were calculated using cumulative incidence method considering competing risk. Event-free survival (EFS) was defined as time from start of TKI until TKI stop/switch, TF or death. Failure-free survival (FFS) was defined as time from start of TKI to TF [primary resistance, loss of complete cytogenetic response, new additional cytogenetic abnormalities (ACAs), and progression to accelerated or blasts phase (AP/BP)] or death. Results From November 2020 until June 31, 2023 (data cutoff), a total of 77 pts were enrolled in the study. The median follow-up time was 12 months. The frequency of 1L TKI selection was as follows: IMATINIB (IM) (n=23, 30%), DASATINIB (n=25, 32%), NILOTINIB (n=22, 29%), BOSUTINIB (n=1, 1%), ASCIMINIB (n=6, 8%). Majority of the pts were male (n=51, 66%). Ninety-three percent of pts were in chronic phase at diagnosis, while 4% and 3% were in AP and BP, respectively. Presence of ACAs was detected in 18 pts (23%), 10 of which were high risk, while 6% (n=5) were not evaluable. The baseline clinical and disease characteristics of pts on 1L IM vs other TKIs (2G-TKI) are summarised in Table 1. Of note, pts on IM were significantly older with higher FRS and comorbidities, including coronary artery disease, diabetes mellitus, and hypertension. The OS of all pts at 1 year was 98.5% (95% confidence interval 90%-99.8%). At 1 year, pts with intermediate to high risk FRS had lower FFS (73.2% vs 86.5%, p=0.037) while history of hyperlipidemia was associated with lower EFS (59.3% vs 81.5%, p=0.023) and 6 times more likely to stop or switch therapy due to intolerance or resistance (HR 5.9, p=0.002). Baseline comorbidities did not demonstrate signifincant impact on MR2 and MR3 at 1 year but pts with low FRS were more likely to achieve MR4 within 1 year (22.3% vs 0%, p=0.023). Age did not affect any of the clinical and molecular endpoints. Compared to 2G-TKI, IM had worse EFS (HR 3.93, p=0.003), FFS (HR 5.66, p=0.011), and MR2 (47.3% vs 84.4%, p=0.003) at 1 year. Further, IM pts experienced higher rate of any side effects compared to those on 2G-TKI (69.6% vs 31.5%, p=0.003). Conclusion The TCGA-GTA study provides valuable insights into the impact of comorbidity on selection of 1L TKI and its outcome in a real-world setting. Pts who are older and with higher FRS and comorbidities tend to receive 1L IM. However, pts on 1L 2G TKIs are more likely to reach treatment goals faster with lower probability of TF. The present study did not reach a clear conclusion whether the worse outcomes in the pts receiving IM are from IM treatment or concurrent risk factors such as age and comorbidities, thus further study with an expanded cohort and longer follow-up is required. Elderly pts or those with comorbidities would need alternative treatment with better efficacy and tolerability, such as Asciminib, that can overcome comorbidity issues in the future.

Toxicities Associated with Tyrosine Kinase Inhibitor Maintenance Following Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background Use of tyrosine kinase inhibitor (TKI) maintenance following allogeneic hematopoietic cell transplantation (HCT) in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia may help to prevent post HCT relapse but is difficult to administer due to toxicity. However, these toxicities and their impact on maintenance is not fully characterized. Herein, we report our experience at a single, large transplant center to describe toxicities encountered with post HCT TKI maintenance in Ph+ ALL. Methods Ph+ ALL patients (pts) who underwent 1st allogeneic HCT at City of Hope between 2003-2021 and received at least one dose of TKI maintenance were included in this retrospective analysis. Baseline characteristics and toxicities were summarized via descriptive analysis, and groups were compared via Fischer test. Survival analyses were calculated from the time of TKI initiation. Results Baseline characteristics are described in Table 1. Of the 186 pts studied, 50 (26.8%) received imatinib and 136 (73.2%) received a newer generation TKI (NG-TKI: 112 dasatinib, 6 nilotinib, 1 bosutinib, 17 ponatinib) at a median time of 78 days (IQR, 41-134) and 91 days (IQR, 58-129), respectively. A total of 96 patients (51.6%) began TKI maintenance within 90 days of HCT. Post HCT TKI was started prophylactically in 149 patients (80.1%) while 37 patients (19.9%) received TKI preemptively for positive MRD. The MRD status at time of HCT differed between the imatinib group and NG-TKI group. In the imatinib group MRD was negative in 33 of 50 patients (66.0%) compared with 78 of 136 patients (57.4%) in the NG-TKI group (P<0.01). There were 12 (24.0%) vs 18 (13.2%) with an unknown MRD-status at HCT in the imatinib vs NG-TKI groups, respectively ( P<0.01). The median follow-up duration for surviving patients in the entire cohort was 5.5 years (range, 1.0-17.5). The median cumulative TKI exposure was 413.5 days (range, 4-2740). The median cumulative imatinib exposure in patients initially receiving imatinib was 328 days (range, 3-2216), while the median cumulative NG-TKI exposure in patients initially receiving NG-TKI was 268.5 days (range, 3-2740), respectively. The median cumulative exposure of dasatinib, nilotinib, bosutinib and ponatinib were 249 days (range, 3-2740), 222 days (range, 114-839), 371 days, and 576 days (range, 72-921), respectively. Twenty-seven (54.0%) vs 75 (55.2%) patients completed >12 months of initial imatinib and NG-TKI maintenance (P=1.0), respectively. Of the treated patients, 78 pts (41.9%) required at least one dose reduction of their initial TKI due to toxicity; 19 of them (10.2%) required ≥2 dose reductions. When imatinib maintenance was used as the initial TKI, a dose reduction due to toxicity was required in 18 patients (36.0%), of whom 7 patients (14.0%) required ≥2 dose reductions. Initial NG-TKI maintenance required a dose reduction due to toxicity in 60 (44.1%), of whom 12 (8.8%) required ≥2 dose reductions. One hundred and thirty-nine patients (74.7%) had their maintenance TKI therapy interrupted, 122 (65.6%) due to toxicity. Sixty-seven patients (36.0%) did not complete their pre-determined maintenance period owing to toxicity; 70 pts (37.6%) discontinued one TKI, and 11 (5.9%) discontinued two TKIs, due to toxicity. The most common reasons for discontinuing the initial TKI are listed in Table 2, including 45.2% of patients due to toxicity, and 12.9% due to progressive disease. Toxicity-related discontinuations occurred within 6 months on that TKI in 63.0% of patients, and 75.3% within the first 12 months. Five-year overall survival and progression-free survival from the start of TKI were similar between the imatinib and NG-TKI group; 83.1% vs 76.9% (P=0.74) and 72.8% vs 70.5% (P=0.63), respectively (Figure 1). Conclusion Toxicities resulting in dose reductions, interruptions, and discontinuation are common in TKI maintenance post HCT. The toxicity profile (mainly GI and blood count related), frequency, and severity of TKIs in the post HCT setting appears to be different than what has been previously reported in the pre-HCT setting, making it a formidable challenge to meet the recommended cumulative TKI maintenance exposure (2 years) per the NCCN guidelines. While the choice of TKI did not appear to impact on long-term outcomes and relapse rates were not excessive in our analysis, further studies are needed to develop tolerable and personalized TKI maintenance strategies.

Incidence, Interpretation and Management of Liver Function Abnormalities in Patients with Chronic Myeloid Leukemia (CML) Treated with Tyrosine Kinase Inhibitors (TKI)

Background: Hepatotoxicity is a well-recognised side effect of tyrosine kinase inhibitors (TKI) and in some patients it can be a challenge to find a well-tolerated and effective drug. Isolated hyperbilirubinemia is common but, particularly in the case of nilotinib, is generally attributed to concomitant Gilbert's syndrome, characterized by the reduced expression of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We have previously reported hyperbilirubinemia in association with the homozygous Gilbert genotype in patients treated with imatinib, dasatinib and nilotinib and have now extended our studies to more recent TKI. In addition we have analysed the incidence of TKI-associated transaminitis and attempted to identify safer alternative TKI. Methods: From our database of >900 patients presenting with CML CP1 from 2000-2022 and treated with a TKI, we identified 467 individuals who had received only TKI (prior interferon, combination experimental therapy, auto- and allografted patients all excluded), had normal liver function tests (LFT) at TKI start and for whom serial consecutive LFT were available. Variations in dinucleotide repeats in the UGT1A1 promoter region were analyzed by PCR with genotypes: 6/6 (homozygous for (TA) 6 allele; wild-type), 7/7 (homozygous for (TA) 7 allele) and 6/7 (heterozygous). Because individual patients could receive more than one TKI, we defined the period on treatment with each TKI as an ‘episode’ so as to attribute abnormal LFT to a specific drug. Abnormal LFT were graded according to the CTCAE version 4.0 and any occurrence of abnormalities was cross-checked to exclude a confounding reason (e.g. antibiotics, cholecystitis). Patients were censored at last LFT. Results: 229 females and 238 males (median age at diagnosis 47 yrs (range 11-90) had 955 separate TKI episodes: imatinib 406, dasatinib 222, nilotinib 189, bosutinib 87, ponatinib 28 and asciminib 23. The median number of LFT per patient was 47 (range 3-264). 7 UGT1A1 genotypes were identified, of which 45%, 41% and 13% were wild type 6/6, heterozygous 6/7 and homozygous 7/7 respectively (6 patients with other genotypes excluded). With the exception of asciminib, hyperbilirubinemia was more frequent in homozygous patients for all TKI. It was also common in all patients treated with nilotinib but in wild type and heterozygous patients, was frequently associated with concomitant transaminitis. A close temporal relationship between start of TKI and raised bilirubin suggests causality (Fig 1a-d). The incidences of transaminitis of any grade were 44%, 47%, 65%, 66%, 43% and 39%, and of >grade 1 were 7%, 8%, 17%, 32%, 18% and 13% for imatinib, dasatinib, nilotinib, bosutinib, ponatinib and asciminib respectively. Of 202 patients with a transaminitis on first line TKI, 94 were subsequently switched to a 2 nd line TKI, and 27 of those to a 3 rd line TKI. Irrespective of the TKI used, recurrent transaminitis of any grade was common occurring in 60/94 (64%) on 2 nd line and 19/27 (71%) on 3 rd line, although abnormalities >grade 2 were unusual (<1% on 2 nd line, <5% on 3 rd line). 179 patients developed transaminitis on imatinib, 46 and 29 switched (rarely for transaminitis) to dasatinib and nilotinib respectively. 28 (61%) on dasatinib and 23 (79%) on nilotinib had a second transaminitis (dasatinib - 14% >grade 1, nilotinib - 22% >grade 1)). Of 227 patients without transaminitis on imatinib, 63 and 67 switched to dasatinib or nilotinib. 28 (44%) on dasatinib and 38 (57%) on nilotinib developed further transaminitis (dasatinib - 0% >grade 1, nilotinib 19% >grade1). With respect to identifying a ‘safer’ drug we studied in detail 15 patients with grades 3-4 transaminitis on 1 st line therapy; imatininb-10, dasatinib-1, nilotinib-3, bosutinib -1. Four settled on dose reduction, and of the remaining 11, 7 returned to normal or maximum grade 1 on dasatinib. Conclusion: With the exception of asciminib the previous association of TKI, homozygous Gilbert and hyperbilirubinemia was confirmed. Grade 1 transaminitis is common on all TKIs, with higher grades of severity most frequent on bosutinib. Patients experiencing abnormal transaminases on 1 st line TKI are likely to have similar problems on 2 nd and 3 rd line agents, with a trend to higher incidence/severity on nilotinib compared to dasatinib.

Outcomes of Adolescents and Young Adult Patients with Chronic Myeloid Leukemia in the Era of Second-Generation TKIs and Treatment-Free Remission

Background: While chronic myeloid leukemia (CML) is most often diagnosed in older adults, it is frequently diagnosed in adolescents and young adults (AYA). Defined by the NCI as individuals between the ages of 15-39 years old, AYA CML patients have been understudied by comparison to their older counterparts, with little known about their outcomes in the United States (US) in the era of second-generation tyrosine kinase inhibitors (TKIs) and treatment-free remission (TFR). We sought to determine the clinical outcomes of AYA patients with CML at our institution, a CML specialty center. Methods: We performed a single-center, retrospective cohort study of patients with CML who were diagnosed between the ages of 15-39 years old and seen in our adult hematology clinic between January 2012 and December 2022. Patients were identified by ICD-9 and ICD-10 codes from the electronic medical record and chart review. Descriptive statistics were used to summarize the data. Outcomes evaluating second-generation TKIs (2G-TKIs) started with patients diagnosed in June 2010. Outcomes evaluating molecular response included BCR-ABL1 PCR testing conducted after implementation of the International Scale (IS) in 2012. Molecular treatment milestones were defined per the 2023 NCCN guidelines for CML. Results: Of 396 CML patients evaluated at our institution, 136 (34.3%) were diagnosed as AYA at a median age of 31 years (range 15-39). The majority were male (62.5%; n=85/136) and English speaking (94.1%; n=128/136). The most frequently cited race/ethnicities were Caucasian (40.4%; n=55/136), Asian (20.6%; n=28/136), and Hispanic (19.1%; n=26/136). At time of diagnosis, 91.2% (n=124/136) were in chronic phase (CP), followed by 4.4% (n=6/136) in accelerated phase (AP) and 4.4% (n=6/136) in blast phase (BP). Of those diagnosed in advanced phase, 91.7% (n=11/12) were male and 66.7% (n=8/12) were Asian or Hispanic. Of CP patients evaluated, 75.8% (n=94/124) started treatment in the 2G-TKI era. Most CP patients were first prescribed dasatinib (61.7%; n=58/94), followed by imatinib (28.7%; n=27/94), and nilotinib (8.5%; n=8/94). Of 62 patients in CP with available molecular data after 2012, 64.5% (n=40/62) met a transcript level <10% at 3-months and 80.6% (n=50/62) met a transcript level <1% at 12-months. Major molecular response (MMR) was achieved and maintained in 59.7% (n=37/62) of these patients, with 25.8% (n=16/62) losing MMR and 14.5% (n=9/62) never achieving MMR. Reasons for loss of MMR included TFR attempts (31.3%; n=5/16), non-adherence from side effects (25%; n=4/16), lack of health insurance/inability to afford medication (18.8%; n=3/16), lack of response (18.8%; n=3/16), and pregnancy attempts (6.3%; n=1/16). Fertility was a notable issue for AYA patients, with 16 females (31.4%; n=16/51) and 18 patients overall (13.2%; n=18/136) interrupting or delaying start of TKI because of pregnancy/fertility. For patients who attempted TFR, 48.1% (n=13/27) remained off TKI in MMR at time of last follow-up. Of 130 AYA patients with CP or AP CML at diagnosis, 7.7% (n=10/130) experienced disease transformation, including 3.2% (n=3/94) of CP patients in the 2G-TKI era. Of 14 patients who presented or transformed into BP, 42.8% (n=6/14) underwent allogeneic stem cell transplantation and 64.3% (n=9/14) died. Of the entire cohort, 9.56% (n=13/136) patients died at a median age of 35 years old, including 5.4% who presented in CP (n=7/124) and 50% (n=6/12) of those who presented in AP/BP. Of the 13 who died, 11 (84.6%) died from CML-related complications. Conclusions: This represents the largest analysis of NCI-defined AYA CML patients in the US in the 2G-TKI era. Molecular response, progression and successful TFR rates in AYA CP CML patients appear to approximate those reported in prior large clinical trials that compared 2G-TKIs with imatinib. AYA patients can experience unique challenges that impact their management, including pregnancy/fertility and adherence, which can affect clinical outcomes. Patients may also present with aggressive advanced phase disease leading to mortality despite transplantation. Further study is warranted to better support the needs of this patient population. Evaluation of CML patients ≥ 40 years old at diagnosis at our institution is ongoing. A formal comparison between these groups will be presented.

Phase 2 Study of Dasatinib with and without Venetoclax in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECP-CML)

Background Treatment-free remission (TFR) is a therapeutic goal for patients with ECP-CML once patients maintain a deep molecular remission (DMR) on tyrosine kinase inhibitors (TKIs). Only a fraction of patients (pts) achieved sustained (3+ years) molecular remission with 4.0- to 4.5-log reduction (MR4.5). Preclinical studies showed that BCL-2 is a key survival factor for CML stem/progenitor cells. Therefore, the combination of TKIs and venetoclax, targeting BCR::ABL1 and BCL-2, has the potential to significantly improve DMR and subsequently the rates of TFR. The aim of this study is to evaluate the safety and efficacy of the combination. Methods Patients with ECP-CML or accelerated phase (AP; defined by clonal evolution only) were eligible; pts with < 1 month of prior TKI therapy were eligible. Pts received single-agent dasatinib 50 mg/d for the first 3 months. From Month 4 and onwards, venetoclax was administered from Days 1 to 14 each month concomitantly with dasatinib for a total of 3 years. The first 16 patients received venetoclax 200 mg/d, with a rapid ramp-up starting 50 mg on Day 1, then 100 mg on Day 2, then 200 mg daily on Day 3 and onwards. Due to neutropenia observed with continuous dose of venetoclax 200 mg/d, the protocol was ameded: from patient #17 and onwards, venetoclax was administered at 200 mg/d for 14 days per month and upon achievement of MR4.5, venetoclax was reduced to 100 mg/d for 7 days per month. After 3 years of combination, patients received single-agent dasatinib. TFR was offered after ≥ 3 years of DMR. The primary endpoint was the rate of major molecular response (MMR) by 12 months of the combination. The secondary endpoints were the 12-month rate of MR4.5 and the cumulative overall rate of MR4.5; the rates of MR4.5 at 6-, 12-, 18-, 24, and 36-months of the combination; the proportion of patients with sustained MR4.5 of 3 years and more; the TFR rate; overall survival; and the safety of the combination. Cumulative response rates were calculated with treatment failure as a competing event. Failure-free survival (FFS) was calculated from the initiation of therapy to loss of major cytogenetic response (MCyR), transformation to AP or blast phase, discontinuation of therapy for any reason except of TFR, or death. Results Sixty-five pts were enrolled and treated between April 2018 and August 2021. The median age at treatment initation was 46 years (range, 23-73) and 57% of the pts were females. Twenty-one (32%) pts had splenomegaly, 46 (71%) had low Sokal risk disease and 3 (5%) had high Sokal risk disease (Table 1). By 12 months of the combination, 85% of the pts had achieved MMR or deeper response. The median time to MMR, MR4, and MR4.5 were 6.2 months, 13 months, and 23.9 months from the time of TKI start, respectively. After a median follow-up of 25.7 months (range, 8.7-48.1), two pts discontinued therapy due to adverse events (GI intolerance, and pleural effusion); the 2 -year FFS was 96%. One pt switched TKI therapy due to the lack of 18-month complete cytogenetic response (CCyR); no loss of CCyR, transformation, or death was observed. We then compared the outcomes with the combination to the outcomes of 85 pts treated with single-agent dasatinib. From the start of TKI therapy, the 12-month cumulative MMR rates were 78% and 79% in the dasatinib single-agent and dasatinib + venetoclax groups, respectively. The cumulative 24-month rates of CCyR, MMR, MR4, and MR4.5 are summarized in Table 2. In the dasatinib single-agent group, 3 pts switched TKI therapy due to the lack of 12-month MCyR, 18-month CCyR, and the acquisition of ABL1 mutation (1 each); 3 pts switched TKI therapy due to loss of CCyR; 2 pts died during therapy (deaths unrelated to CML). Within one year of therapy, the incidence of grade 1/2 neutropenia (absolute neutrophil count, below lower range of normal to 1,000 x10 9/L) was 21% and 52% in the dasatinib single agent and dasatinib + venetoclax groups, respectively ( P<0.001); the incidence of grade 3/4 neutropenia (absolute neutrophil count, below 1,000 x10 9/L) was 8% and 17%, respectively ( P<0.001). There was no incidence of neutropenic fever in the dasatinib + venetoclax. Conclusion The combination of dasatinib 50 mg/d and venetoclax is safe and effective in pts with ECP-CML. With a median follow-up of 2 years, the cumulative resposne of dasatinib + venetoclax is similar to that of dasatinib single-agent without adding significant toxicities. Further follow-up is needed for the evaluation of TFR.

Radio-iodine refractory thyroid cancer patients: a tailored follow-up based on clinicopathological features

ObjectiveTo report the experience of a single center for the selection of radioiodine-refractory (RAIR) thyroid cancer patients (RAIR-TC) who needed tyrosine kinase inhibitor (TKIs) treatment.Patients and methodsWe evaluated all features of 279 RAIR-TC patients both at the time of diagnosis and at the RAIR diagnosis.ResultsNinety-nine patients received indication to TKIs (Group A), while 180 remained under active surveillance (Group B). Group A had greater tumor size, more aggressive histotype, more frequent macroscopic extrathyroidal extension, distant metastases, advanced AJCC stage, and higher ATA risk of recurrence. After RAIR diagnosis, 93.9% of Group A had progression of disease (PD) after which TKIs’ therapy was started. The remaining 6.1% of patients had a so severe disease at the time of RAIR diagnosis that TKIs’ therapy was immediately started. Among Group B, 42.7% had up to 5 PD, but the majority underwent local treatments. The mean time from RAIR diagnosis to the first PD was shorter in Group A, and the evidence of PD within 25 months from RAIR diagnosis was associated with the decision to start TKIs.ConclusionsAccording to our results, a more tailored follow-up should be applied to RAIR-TC patients. A too strict monitoring and too many imaging evaluations might be avoided in those with less-aggressive features and low rate of progression. Conversely, RAIR-TC with an advanced stage at diagnosis and a first PD occurring within 25 months from RAIR diagnosis would require a more stringent follow-up to avoid a late start of TKIs.

The role of mean corpuscular volume and red cell distribution width in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors: the MARECAP retrospective study.

Tyrosine-kinase inhibitors (TKIs) and immunotherapy represent the backbone treatment for metastatic renal cell carcinoma (mRCC) patients. The aim of the present study was to describe mean corpuscular volume (MCV) and red cell distribution width (RDW) in mRCC patients treated with pazopanib or cabozantinib, and to explore their potential impact on oncological outcomes. We conducted a multicenter retrospective observational study in mRCC patients treated with pazopanib or cabozantinib between January 2012 and December 2020 in nine Italian centers. Descriptive statistics, univariate, and multivariate analyses were performed. The primary endpoints were the incidence and trend over time of anemia, macrocytosis (elevated MCV), and anisocytosis (elevated RDW). The secondary endpoints were the correlations of MCV and RDW with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A total of 301 patients were enrolled; mean Hb value was 12.5 g/dl, a mean increase of 1 g/dl was observed at day 15 and maintained at 3 months. Most patients had baseline macrocytosis (MCV levels > 87 fl), with a significant mean increase after 3 months of treatment. At univariate analysis patients with macrocytosis had better ORR, longer PFS, and OS. About one third of patients had baseline anisocytosis (RDW > 16%), with a significant mean increase after 3 months of treatment. At univariate analysis, patients with RDW values ⩽ 16% had higher ORR, longer PFS, and OS. At multivariate analysis, baseline macrocytosis was significantly associated with better PFS in patients treated with pazopanib and baseline anisocytosis with shorter OS in all patients. mRCC patients treated with pazopanib or cabozantinib may have baseline macrocytosis and anisocytosis. A significant increase of Hb, MCV, and RDW after TKIs start was observed. Baseline macrocytosis is positively correlated with PFS in patients treated with pazopanib and baseline anisocytosis affects survival of patients treated with TKIs.

Outcomes of Chronic Myeloid Leukemia with No Major Molecular Response within 2 Years of Tyrosine Kinase Inhibitor Therapy

Introduction: Achieving a major molecular response (MMR) defined as BCR::ABL1 ≤ 0.1% IS, is an important milestone for optimal response in patients with chronic myeloid leukemia (CML), and decreased risk of transformation to advanced CML. However, the long-term clinical impact of not achieving this milestone is unknown, especially whether it affects chances of survival in older patients. Therefore, we sought to examine responses and outcomes associated with BCR::ABL1 > 0.1% IS after 2 years of treatment with tyrosine kinase inhibitors (TKI). Methods: In a retrospective analysis, we screened our databases for CML patients treated at our institution between 2001 and 2020 and identified those who never achieved MMR within 2 years of TKI therapy. Overall survival (OS) was measured from treatment start date to death from any cause or censored at last follow-up, whereas CML-specific OS assessed only death due to CML complications as events. Progression-free survival (PFS) was measured from TKI start date to progression to either accelerated or blast phase or death. The role of various prognostic factors on survival was evaluated in a multivariate analysis Results: We identified 131 patients who never achieved MMR within 2 years (Table 1). Among them, 79 (60%) eventually achieved MMR at a median of 49.4 months from time of TKI start (range 27-187 months). 24 (30%) of these patients achieved MMR by continuing the same TKI, 48 (61%) by switching to a different therapy and 9 (11%) by undergoing stem cell transplant (Table 1). The remaining 52 patients had different levels of cytogenetic response as highlighted in (Table 1). The 10-year CML-specific OS of this cohort was 89%, with a 10-year OS of 76% and 10-year PFS of 74%. Patients who achieved only minor or no cytogenetic response (BCR::ABL1 > 10%) within the first two years had worse 10-year OS (64%) compared to those who achieved major cytogenetic response (BCR::ABL1 ≤ 10% - MCyR) (88%, P=0.01) or complete cytogenetic response (BCR::ABL1 ≤ 1% - CCyR) (85%, P=0.05) within the same period. These trends were similar when evaluating CML-specific OS (Figure 1). In patients aged ≥ 60 years at CML diagnosis, the 10-year OS was 55%; however, none of these deaths were attributed to CML complications (10-year CML-specific OS of 100%) and only 1 (4%) patient progressed to blast phase. In a multivariate analysis of patients included in this cohort, MCyR within 2 years was identified as the only independent prognostic factor associated with improved CML-specific OS with a hazard ratio of 0.19 (95% CI 0.04 - 0.89; P=0.04). Conclusion: CML related mortality remains low among patients who do not achieve MMR within the first 2 years of TKI therapy. Favorable outcomes were seen even among patients with BCR:ABL1 levels between 1% to 10% IS. This is particularly evident for those above the age of 60, where mortality is mainly due to CML-unrelated comorbidities. These findings may help the new considerations in European LeukemiaNet (ELN) recommendations and National Comprehensive Cancer Network (NCCN) guidelines. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

BCR::ABL1-Positive Acute Lymphoblastic Leukemia: Different Clinical Behavior and Relevance of Prognostic Features in Typical ALL and in CML-like Disease

Recently we showed that in 20-30% of children diagnosed as BCR::ABL1-positive (Ph+) acute lymphoblastic leukemia (ALL) the BCR::ABL1 fusion is present in a wider clone, involving myeloid cells, non-ALL B-cells and T-cells. This leads to discordant minimal residual disease (MRD) levels assessed by the quantification of two available MRD targets - immunoglobulin (IG)/T-cell receptor (TR) genes rearrangements and BCR::ABL1 fusion. As the cases with multilineage BCR::ABL1 involvement resemble lymphoid blast crisis (LBC) of chronic myeloid leukemia (CML) we named these leukemias "CML-like", as distinct from "typical Ph+ ALL". To reveal biological and clinical differences between the two subtypes, we retrospectively analyzed prognostic relevance of MRD and other features in 147 children with BCR::ABL1-positive ALL treated according to EsPhALL (n = 133) or other (n = 14) protocols. MRD was assessed by DNA-based monitoring of BCR::ABL1 genomic breakpoint and of clonal IG/TR rearrangements. Although overall prognosis of CML-like (n = 48) and typical Ph+ ALL (n = 99) was similar (5-year EFS 60% and 49%; 5-year OS 75% and 73%, respectively), typical Ph+ ALL presented more relapses (12/48 vs. 42/99; p = 0.046) while CML-like patients more often died in the first remission (6/48 vs. 3/99; p = 0.059 for CR1 deaths in total and p = 0.01 for CR1 deaths out of the total deaths). Prognostic role of MRD measured at standard treatment timepoints (TP1 - end of induction IA, day 33; TP2 - end of consolidation IB, week 12) was highly significant in the typical Ph+ ALL (p = 0.0005 for EFS). In contrast, in CML-like patients prognostic impact of MRD was not significant and thus inapplicable for therapy adjustment. Similarly, although diagnostic white blood cell counts were similar in the two subgroups, impact of the hyperleukocytosis ≥ 50 x 109/l on outcome was highly significant in the typical Ph+ ALL (and remained significant in multivariate analyses, being apparent even in patients with fast MRD response), but no prognostic impact was found in CML-like patients. While in the typical Ph+ ALL the NCI risk tended to impact 5-year OS (89% vs. 67%; p = 0.03), there was no impact on prognosis in the CML-like patients. The BCR::ABL1 transcript type (minor/p190 vs. Major/p210), IKZF1 deletion, sex, or the age at diagnosis (< 10 vs. ≥ 10 years) did not show any prognostic relevance. Earlier start of continuous tyrosine kinase inhibitors (TKI) treatment (day 15 vs. day 33) was associated with lower MRD levels in the typical Ph+ ALL but not in CML-like patients. However, earlier TKI start tended to result in better 5-year OS in both subtypes (78% vs. 67%; p = 0.082 and 83% vs. 60%; p = 0.066 for typical Ph+ ALL and CML-like, respectively). To shed more light on the nature of the two subtypes, we now collect additional data (including transcriptome profiles, single cell characteristics, genomic breakpoint features) in order to reveal biological background, cell of origin and further potential differences between the subtypes. Such data could help to find optimal treatment strategies, and also to answer the attractive question whether CML-like disease is in fact a regular CML in LBC or whether there is a wider spectrum of BCR::ABL1-positive leukemias. If these studies lead to a conclusion that CML-like is indeed indistinguishable from LBC-CML, it will be necessary to re-define CML as a disease manifesting - at least in childhood - very often in LBC and with the minor-BCR::ABL1/p190 fusion variant. In conclusion, our data unequivocally confirm that although clinically presenting at diagnosis as one entity, there are two biologically distinct subtypes of BCR::ABL1-positive ALL - typical Ph+ ALL and CML-like disease. The different biology is reflected in treatment response and although the overall survival rates of both subtypes are similar on current protocol, the key reasons of treatment failure are different - toxicity of intensive ALL treatment in CML-like patients and relapses in typical Ph+ ALL. Thus, early distinguishing of the two subtypes is essential to enable optimal treatment approach and therapy adjustments in upcoming trials. For the typical Ph+ ALL, TKI and concurrent chemotherapy with risk-directed intensity should be recommended; in the CML-like disease, representing one-fourth to one-third of childhood patients diagnosed as BCR::ABL1-positive ALL, no relevant risk factor applicable for therapy tailoring was found so far.

Treatment patterns and outcomes in ALK or ROS1 altered NSCLC: An ATOMIC Registry Study.

9077 Background: New tyrosine kinase inhibitors (TKIs) targeting ALK and ROS1 alterations in non-small cell lung cancer (NSCLC) have emerged over the last decade. Given the rarity of these genetic changes in NSCLC, data on long term outcomes with sequential therapies are limited. Methods: We conducted a multicenter retrospective cohort study of patients with metastatic NSCLC and ALK or ROS1 alterations across 12 Academic Thoracic Oncology Medical Investigators Consortium (ATOMIC) sites between 1/29/2007 and 3/31/2021. Data were abstracted from the electronic medical record. Median time to treatment discontinuation (TTD) of 1st TKI, overall survival (OS), and time to brain metastases were estimated using Kaplan-Meier methodology from start date of 1st TKI. Results: 566 patients with ALK (n = 464) or ROS1 (n = 102) were included. The majority (ALK: 426/464, 92%; ROS1: 88/102, 86%) received a TKI at some point during therapy (1st line TKI n = 262 ALK, 48 ROS1). Crizotinib was the most common 1st TKI (ALK: 57%; ROS1: 88%). Following crizotinib, alectinib (64%) and lorlatinib (41%) were the most common subsequent TKIs for ALK and ROS1, respectively. Alectinib (38%) and entrectinib (10.2%) were the 2nd most common initial TKIs used in ALK and ROS1, respectively. Additional treatment patterns presented in table. With a median follow up time of 31.1 (ALK, 95% CI, 27.6-35.0) and 32.6 (ROS1, 95% CI, 25.7-39.6) months, median OS from start of 1st TKI was 53.3 (ALK, 95% CI, 40.0-68.9) and 42.0 (ROS1, 95% CI, 31.8-NA) months. Out of the 321 patients with brain imaging prior to 1st line therapy, 40% (105/262, ALK) and 39% (23/59, ROS1) had CNS disease. Median time to development of brain metastases from start of 1st TKI in those without previous CNS disease (ALK: 278; ROS1: 58) was 30.0 (ALK, 95% CI, 25.3-39.1) and 27.0 (ROS1, 95% CI, 18.2-NA) months. Median TTD of 1st TKI was 11.2 (ALK) and 10.8 (ROS1) months. Conclusions: This is the largest retrospective cohort of NSCLC patients with ALK or ROS1 rearrangements treated in the real world setting. CNS metastases are common and subset analyses by agent and by year of diagnosis will be presented. Median time to CNS metastasis of &gt; 2 years supports revision of the NCCN guidelines to include regular surveillance brain MRIs in this population. [Table: see text]

Real-world experience of tyrosine kinase inhibitors in patients (pt) with recurrent bone tumours (BT): A CanSaRCC study.

11530 Background: Survival after relapse in osteosarcoma (OST), Ewing Sarcoma (ES) and chondrosarcoma (CS) remains dismal. Recent reports suggest a role of tyrosine kinase inhibitors (TKI) including regorafenib (R) and cabozantinib (C). We conducted a retrospective multi-centre pan-Canadian study to assess real-word outcomes with these novel treatments in recurrent BT. Methods: After ethics approval, data from pts treated in 7 different institutions was extracted from the CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) Database. Pt characteristics, treatment and outcomes were analyzed. Response was assessed per RECIST 1.1. PFS, OS were estimated using Kaplan-Meier. TTP was defined as time from TKI start to progression. Results: From June 2018-Dec 2021, 44 pts received R or C and best response by histology are listed in Table, with an overall clinical benefit rate of 63.6%. Median time to best response was 2.3 mo (range 1 – 17). 15 pts (34.1%) required dose reduction; most common reasons were hand-foot syndrome (13.6%), mucositis (9.1%) and hypertension (9.1%). At median FU of 6.4 mo (range 1.6 – 29), 25 pts (56.8%) died, 19 (43.2%) were alive with disease (AWD). Median PFS was 4.1 mo (95%CI 2.9 – 5.7), for OST was 5.0 (N = 25, 95%CI 2.6 – 10.6), for ES was 4.1 (N = 10, 95%CI 2-5.9), and for CS 4.0 (N = 9, 1 Progressed). Median OS was 10.5 mo (95%CI 7 – 14). By univariate analysis, age, line of therapy, gender, location of primary, or R vs. C did not correlate with PFS. Conclusions: Consistent with previous published studies, our pan-country real-world analysis shows that TKI have meaningful activity in the setting of recurrent BT with acceptable toxicities. Inclusion in earlier lines of treatment and/or maintenance therapy could be questions for future research. [Table: see text]

Growth Disturbances in Pediatric Patients Receiving Long-Term Tyrosine Kinase Inhibitor Therapy

Background:Since their approval in 2003, Tyrosine Kinase Inhibitors (TKIs) targeting bcr-abl1 kinase activity have changed the treatment paradigm for children with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). However, off-target inhibition of kinases, such as src and c-kit, can result in impaired osteoblast function, cause an imbalance in calcium and phosphate metabolism, and result in growth impairment in children. The aim of our study was to examine growth over time in pediatric patients receiving TKIs for CML or Ph+ ALL.Description: This is a single institutional retrospective longitudinal cohort study of patients (≤ 21 years of age) diagnosed with CML or Ph+ ALL between January 2000 and December 2015 who received a TKI and had ≥ 1 year of growth data available as of May 31, 2016. Patient demographics, treatment details including the type and duration of TKI therapy and details of concomitant conventional therapy (chemotherapy and radiation) were abstracted. Growth data was abstracted from the start of TKI at yearly intervals up to a maximum of five years or age 20 and from their last available appointment. Specific variables for growth included height, height percentile, height-SDS (height - standard deviation score or z score) and BMI-SDS (body mass index - standard deviation score). Height-SDS and BMI-SDS were determined using the CDC growth chart by age and gender. Age at diagnosis was used as a surrogate for expected pubertal status: pre-pubertal (3 - 8.9 years), pubertal/peri-pubertal (9 - 15.9 years), post-pubertal (16+ years). Overall change in height-SDS / BMI-SDS from baseline to 1-year and last follow-up were compared by diagnosis, gender, and pubertal age using ANOVA. Statistical analysis was performed using SAS® v9.3 (Cary, NC). For all analyses, a p-value of <0.05 was considered to be statistically significant.Results: Our cohort included 48 patients who received a TKI (n=29 CML, n=19 Ph+ ALL) - 46% were male and 38% were non-Hispanic white. The mean age at diagnosis was 12.1 ± 3.7 years for CML and 9.0 ± 4.6 years for Ph+ ALL patients (p=0.01). As expected, mean duration of TKI treatment was longer in CML (4.3 ± 2.8 years) versus Ph+ ALL (2.7 ± 1.7 years). The average duration of follow-up was similar in both groups (CML 4.6 ± 3.54 years vs Ph+ ALL 4.1 ± 2.9 years, p=0.60). At time of diagnosis, the mean Height-SDS for the entire cohort was 0.13 ± 1.28 with no difference between patients by diagnosis (p=0.92). At one year following treatment with TKI a decrease in mean height-SDS was noted, with a more significant difference in Ph+ ALL patients (-0.54 ± 0.21) compared to CML patients (-0.18 ± 0.39) (p=0.002). This difference remained significant at last follow-up (Ph+ ALL -0.96 ± 0.70, CML -0.52 ± 0.74, p=0.05) (Figure 1). There was no significant difference in mean change in height-SDS at 1 year or last follow-up by gender. Overall, the decrease in height-SDS at 1 year was most significant in the pre-pubertal age group (-0.51 ± 0.27) as compared to pubertal/peri-pubertal and post-pubertal groups (-0.26 ± 0.46 and -0.10 ± 0.24 respectively; p=0.04). BMI-SDS at baseline did not differ by diagnosis but did show a significant decrease at one year in Ph+ ALL versus CML patients (-0.18 ± 0.65 and 0.39 ± 0.54 respectively, p=0.003); this stabilized at the time of last follow up (-0.01 ± 0.75 and 0.38 ± 0.80 respectively, p=0.11).Conclusions: Our data underscores the concern of growth disturbances following prolonged TKI exposure in children, the role of exposure relative to pubertal change in bone growth, and the need for understanding off-target mechanisms in childhood survivors. Stabilization of BMI-SDS at the end of follow up with accompanying drop in mean height-SDS points to a mechanism of growth disturbance beyond nutritional deficiencies. This large pediatric cohort treated with TKIs is the first to include Ph+ ALL patients who were younger at onset of TKI treatment, and more likely to be pre/peripubertal at the start TKI exposure. Future directions will focus on a prospective study of musculoskeletal and other organ toxicities in patients treated with TKIs in childhood. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cytogenetic and Molecular Responses after 2 Years of Tyrosine Kinase Inhibitor (TKI) Treatment in Simplicity, an Observational Study of Chronic-Phase Chronic Myeloid Leukemia (CP-CML) Patients (Pts) in Routine Clinical Practice

Abstract Introduction: Data on clinical response and factors associated with response in CP-CML outside clinical trials are limited.SIMPLICITY (NCT01244750) is an ongoing observational study of CP-CML pts in routine clinical practice receiving first-line (1L) imatinib (IM), dasatinib (DAS) or nilotinib (NIL) in the US and Europe. This analysis aims to describe the factors associated with achievement of complete CyR (CCyR) and major MR (MMR). Methods: Clinical response after start of 1L TKI was assessed by CyR (karyotype or FISH) and MR (only tests by PCR on the international scale were included) as determined by the treating physician. Proportions of patients achieving CCyR and MMR between 30 days and either 12 or 24 months (mos) are presented; data at specified time points will be provided at presentation. Logistic regression models were used to identify factors associated with CCyR and MMR by 12 and 24 mos after 1L TKI initiation. Results: By March 03 2017, 1242 pts were enrolled prospectively in SIMPLICITY, receiving IM (n=416), DAS (n=418) or NIL (n=408); 55% were male. The median (interquartile range; min-max) age of pts at initiation of 1L TKI was 57 (46-68; 18-91) years; 35% of pts were treated in Europe, 65% in the US; 53% at academic centers and 47% at community practices. Numbers of pts followed by 3, 6, 12 and 24 months were 1233, 1224, 1195 and 1121, respectively. Of pts followed 12% (n=151), 31% (n=384), 44% (n=522) and 51% (n=567) had documented CyR testing by 3, 6, 12 and 24 mos; 23% (n=285), 55% (n=672), 72% (n=857) and 84% (n=937) of pts had documented MR testing by 3, 6, 12 and 24 mos; and 7% (n=82), 19% (n=231), 32% (n=379) and 42% (n=475) of pts had documented testing by both CyR and MR by 3, 6, 12 and 24 mos. Proportions of pts remaining on their 1L TKI declined with duration of follow-up. Of pts with documented CyR testing, 93% (n=141), 93% (n=356), 89% (n=464) and 85% (n=484) had remained on their 1L TKI by 3, 6, 12 and 24 mos, respectively. Of pts with documented MR testing, 93% (n=266), 91% (n=610), 85% (n=728) and 78% (n=730) had remained on their 1L TKI by 3, 6, 12 and 24 mos, respectively. In this non-controlled study, proportions of pts achieving CCyR were similar for pts tested by 12 and by 24 mos. For both periods, the proportion of pts achieving CCyR was highest for pts on 1L DAS, lower for 1L NIL, and lowest for 1L IM. Proportions of pts achieving MMR were higher for pts tested by 24 mos than by 12 mos. For both periods, the proportion of pts achieving MMR was highest for pts on 1L NIL, lower for 1L DAS, and lowest for 1L IM. Proportions were lower when calculated among pts followed through the period but not necessarily tested (intention-to-treat). Multivariate logistic regression analysis identified factors associated with MMR or CCyR by 12 and 24 mos after 1L TKI initiation. Receiving a second-generation (2G) TKI (i.e. DAS or NIL) as 1L therapy was associated with CCyR by 12 mos (odds ratio [OR]=2.6; p Conclusions: Response monitoring observed in clinical practice is not aligned with ELN/NCCN guidelines, so outcomes for the full SIMPLICITY cohort may differ from presented data on monitored patients. The lack of correlation between a 2G TKI as 1L therapy and achievement of MMR is unexpected, but may result from switches to 2L TKI in IM suboptimal responders or from differences in testing patterns in the individual cohorts; the uncontrolled nature of this study may have also contributed. Early switching of TKI treatment (previously found to be driven by toxicity, not response, and often from IM to 2G TKI) was associated with achieving MMR or CCyR by 12 mos. Not switching TKI, potentially a marker of better tolerance and adherence, was associated with achieving MMR or CCyR by 12 mos and 24 mos. Download : Download high-res image (116KB) Download : Download full-size image Figure . Disclosures Cortes: Teva: Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Goldberg: Bristol Myers Squibb: Research Funding, Speakers Bureau; Pfizer: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Ariad: Speakers Bureau; Celgene: Speakers Bureau; COTA: Employment, Equity Ownership. Hehlmann: Novartis: Research Funding; BMS: Consultancy. Mauro: Bristol-Myers Squibb: Consultancy. Zyczynski: Bristol-Myers Squibb: Employment. Sen: ICON Clinical Research: Employment. Foreman: ICON Clinical Research: Employment. Gajavelli: Bristol-Myers Squibb: Employment. Gambacorti-Passerini: BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding.

Echocardiographic Findings in Patients (pts) Receiving Tyrosine Kinase Inhibitors (TKIs) for the Treatment of Chronic Myeloid Leukemia (CML)

INTRODUCTIONTKIs are standard therapy for pts with CML, with therapy continued over several years and in many instances indefinitely. Cardiac effects of TKIs have been described, including prolongation of QTc and arterio-thrombotic events. Echocardiographic manifestations have been reported including a reduction in left ventricular ejection fraction (EF) and an increase in right atrial pressure (RAP) and right ventricular systolic pressure (RVSP). However, no systematic description of these changes over the course of therapy has been presented. We retrospectively examined features and course of treatment of CML pts who had undergone echocardiogram during or following treatment with TKI therapy.METHODSWe interrogated medical records for pts with CML who had undergone echocardiogram (ECHO). Pts were grouped by TKI and analyzed their age, race, sex, line of therapy, duration of therapy, and change of TKIs. Variables were analyzed using general linear model (for continuous variables), or chi-square test or Fisher's exact test (for categorical variables). T-test was used to compare EF, RVSP, and RAP measure before vs. during and during vs. after index TKI for patients with sequential ECHOs. To compare echocardiograph findings by TKI we used separate repeated measures ANOVAs for EF, RVSP, and RAP for patients with sequential ECHOs. All statistical analyses were conducted using SAS v9.4.RESULTSA total of 146 ECHOs were performed on 111 pts. 11 pts had ECHO before, during, and after TKI treatment, 17 pts had ECHO before and during TKI treatment, and 20 had ECHO during and after TKI. Their median age was 53 yrs (range, 15-83), and 53.1% were male. 95 (86%) were in CP at the time of TKI start; 71 (64%) were receiving their 1st TKI. TKIs used included imatinib in 53 (400 mg n=19, 800 mg n=34), dasatinib in 39, and nilotinib in 19. Among patients with 3 sequential ECHOs, 9 were on dasatinib, 1 on imatinib (400 mg), and 1 on nilotinib. Among patients with ECHOs before and during treatment, 13 were on dasatinib, 2 on imatinib (800 mg), and 2 on nilotinib, while among patients with ECHOs during and after treatment, 16 were on dasatinib, 1 on nilotinib, 1 on imatinib (800 mg), and 1 on imatinib (400 mg). Pt characteristics are presented in Table 1.Considering all ECHOs in all pts, median EF was 62.5% before TKI, 60% during, and 60% after index TKI. Median RVSP was 30 mmHg before index TKI, 33 mmHg during, and 28 mmHg after TKI. Median RAP was stable at 5 mmHg throughout index TKI use. For patients with two sequential ECHOs, EF decreased significantly during TKI therapy (compared to baseline, difference=-3.1%, N=16, p=0.0186), and marginally after TKI (vs during, difference=-2.8%, N=20, p=0.091). There was a mild, non-statistically significant increase in RVSP from baseline to during TKI (difference=3.6 mmHg, N=16, p=0.30) and from during TKI to after TKI use (difference=1.9 mmHg, N=18, p=0.51). RAP did not differ from baseline to during TKI use (difference=1.1 mmHg, N=13, p=0.19), or during TKI to after TKI (difference=-0.71 mmHg, N=14, p=0.16). The results of these pairwise comparisons are presented in Figure 1. In repeated measures ANOVA of those patients with three sequential ECHOs, EF did not differ significantly among TKIs used (F=0.22, N=10, p=0.68), nor did RVSP (F=0.04, N=11, p=0.86). RAP was marginally different among TKIs used (F=9.53, N=11, p=0.054) (Figure 2). Full model results for these repeated measures ANOVAs are presented in Table 2.CONCLUSIONChronic administration of TKIs results in modest ECHO changes, particularly a slight decline in EF. There was also a modest increase in RAP with dasatinib and, to some extent, nilotinib but small sample size make these results preliminary. Still, monitoring of patients on TKIs with ECHOs at baseline and during therapy might be advisable. [Display omitted] DisclosuresKantarjian:ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding. Wierda:The University of Texas MD Anderson Cancer Center: Employment; GSK/Novartis: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Acerta: Research Funding; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Genentech/Roche: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Juno: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Emergent: Consultancy, Honoraria, Research Funding; Karyopharm: Research Funding; Kite: Research Funding; Sanofi: Consultancy, Honoraria. Jabbour:Bristol-Myers Squibb: Consultancy. Cortes:Pfizer: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; Teva: Research Funding.

Prevalence of the concurrent administration of contraindicated medications in patients with cancer treated with tyrosine kinase inhibitors (TKIs): A pilot study from the IU Simon Comprehensive Cancer Center.

e18714 Background: Polypharmacy may result in drug-drug interactions that reduce efficacy or increase toxicities to patients. Tyrosine kinase inhibitors (TKIs), which is standard therapy for many patients with cancer, have interactions with many commonly prescribed drugs (including proton pump inhibitors [PPIs] and cytochrome inhibitors/inducers) which alter their metabolism. Methods: Retrospective study of 100 consecutively chosen patients with advanced cancer treated with TKIs were identified. Patients &lt; 18 years of age, participating in clinical trials, or taking an investigational treatment for their cancer were excluded. TKI start date and concurrent medications were identified from chart reviews. Documentation was undertaken to record co-administration of drugs that could prolong QT interval, PPIs, and CYP3A inhibitors and inducers. QT prolonging medications were divided into those with known risk (KR), conditional risk (CR), and probable risk (PR). IUSM Clinical Pharmacology Flockhart table was utilized for cytochrome drug interactions. All three categories of cytochrome inhibitors (strong, moderate, and weak) were included in the analysis. The primary objective was to estimate the percentage of patients treated with TKIs co-administered these classes of drugs with a potential for harmful drug-drug interaction. Results: Median age of 100 pts was 57 and median duration of treatment with the TKI was 441 days. 85 of 100 pts receiving TKIs for their cancer were also prescribed at least 1 drug with the potential for drug-drug interaction, including 39 with a QT prolonging drug with known risk and 25 with a CYP3A inducer or inhibitor. 53% had documentation of EKG while on TKI treatment. Conclusions: Most patients in this chart review were co-administered TKIs with other agents with a potential for harmful drug-drug interactions. Continual monitoring of medications is necessary to optimize efficacy of TKIs and reduce the chance for harmful side effects.[Table: see text]

High Prevalence and Early Occurrence of Skeletal Complications in EGFR Mutated NSCLC Patients With Bone Metastases.

ObjectivesThe prevalence of Skeletal Related Adverse Events (SREs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with bone metastases, treated with modern tyrosine kinase inhibitors (TKIs), has been scarcely investigated.Materials and MethodsWe retrospectively evaluated the data of EGFR mutated NSCLC patients with bone metastases treated with TKIs in 12 Italian centers from 2014 to 2019, with the primary aim to explore type and frequency of SREs.ResultsSeventy-seven out of 274 patients enrolled (28%) developed at least one major SRE: 55/274 (20%) bone fractures, 30/274 (11%) spinal cord compression, 5/274 (2%) hypercalcemia. Median time to the onset of SRE was 3.63 months. Nine patients (3%) underwent bone surgery and 150 (55%) radiation therapy on bone. SREs were more frequently observed within the 12 months from TKI start than afterwards (71 vs 29%, p 0.000). Patient Performance Status and liver metastases where independently associated with the risk of developing SREs. Median TKI exposure and overall survival were 11 and 28 months, respectively. Bone resorption inhibitors were associated with a lower risk of death (HR 0.722, 95% CI: 0.504–1.033, p = 0.075) although not statistically significant at multivariate analysis.ConclusionBone metastatic NSCLC patients with EGFR mutated disease, treated with EGFR TKIs, have a relatively long survival expectancy and are at high risk to develop SREs. The early SRE occurrence after the TKI start provides the rationale to administer bone resorption inhibitors.

Determinants of Choice of Front-Line Tyrosine Kinase Inhibitor for Chronic Phase CML: A Study from the “Registro Italiano LMC & Campus CML”

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged &amp;lt;45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p&amp;lt;0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC &amp;gt;100,000/mm3 vs 38.2% if WBC &amp;lt;100,000/mm3; p&amp;lt;0.001), lower Hb (53.8% if Hb &amp;lt;10 g/dl vs 41.9 if Hb &amp;gt;10 g/dl; p=0.001) and bigger spleen (65.1% if spleen &amp;gt;5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p&amp;lt;0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for &amp;gt;5 drugs, respectively (p&amp;lt;0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p&amp;lt;0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age &amp;gt; 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.

Real-world (RW) outcomes for advanced non-small cell lung cancer (aNSCLC) patients (pts) with EGFR exon 19 deletions (x19del) stratified by deletion size.

9591 Background: EGFR x19dels are well-established targetable drivers in NSCLC. Historically x19dels have been treated as a single group, but it’s unclear whether responses vary for distinct subtypes. We compared demographic, clinical and genomic characteristics as well as outcomes to EGFR tyrosine kinase inhibitors (TKIs) for aNSCLC pts with x19dels of varying lengths using a RW Clinico-Genomic Database (CGDB). Methods: Eligible pts had a diagnosis of aNSCLC, received care within the Flatiron Health network between 1/2011-9/2019, and had comprehensive genomic profiling (CGP) by Foundation Medicine. Clinical characteristics, treatment history and RW progression were obtained via technology-enabled abstraction as previously described (Singal G, JAMA 2019). x19del length was evaluated for association with overall survival (OS) and RW progression-free survival (rwPFS) with Kaplan-Meier analysis and unadjusted/adjusted (practice type, gender, age at TKI start, EGFR TKI type, race) hazard ratios (HR/aHR) from Cox proportional hazards models adjusted for survival bias. Results: Among 6,577 aNSCLC pts, EGFR x19dels were detected in 336 cases (5%). E746_A750del was the most frequent (214; 64%) and generally 5 amino acid (aa) deletions (x19del-5) were the most common (241; 72%). Other deletions (x19del-other) of 6 (61; 18%), 3 (20; 6%), 4 (11; 3%) or 8 aa (3; 1%) were also observed. Among pts treated with 1st-line EGFR TKI monotherapy after CGP, the x19del-5 (n = 70) cohort was more frequently female compared to x19del-other (n = 27) (90% vs 59%, p = 0.001). No statistically significant differences in the frequency of co-occurring alterations were observed, specifically for genes associated with response to EGFR TKI response such as CTNNB1 (14% vs 19%) and PIK3CA (10% vs 15%). 1st line EGFR TKIs used were similar for x19del-5 vs x19del-other (43% vs 41% osimertinib, 30% vs 37% erlotinib, 24% vs 22% afatinib, 3% vs 0% gefitinib). x19del-5 pts had similar median rwPFS (10.6 vs 10.6 months, HR: 0.73 [0.41-1.28], aHR:0.78 [0.38-1.59]) and median OS (29.2 vs 24.9 months, HR: 0.64 [0.32- 1.29], aHR: 0.75 [0.32-1.75]) compared to x19del-other. Conclusions: In a RW CGDB of 336 aNSCLC pts with EGFR x19dels, 5 aa x19dels were most common (71%) and 29% of cases had 3, 4, 6 or 8 aa x19dels . For pts included in the treatment cohort, no significant differences in rwPFS or OS were observed. These results suggest that x19del length does not significantly impact clinical outcomes to 1st-line EGFR TKIs.

Cytogenetic and Molecular Response with First- and Second-Generation Tyrosine Kinase Inhibitor (TKI) Therapy in Simplicity: An Observational Study of Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML)

Introduction: SIMPLICITY (NCT01244750) is an ongoing observational study of patients (pts) with CP-CML receiving first-line (1L) imatinib (IM), dasatinib (DAS), or nilotinib (NIL) in routine clinical practice in Europe and the United States (US). The study aimed to assess the effectiveness and safety of TKIs for pts with CP-CML outside the clinical trial setting. Here, we analyze the clinical outcomes (complete cytogenetic response [CCyR] and major molecular response [MMR]) associated with the CML risk level in SIMPLICITY pts with CP-CML receiving first-generation (1G: IM) or second-generation (2G: DAS/NIL) TKI therapy. Methods: Clinical outcomes after 1L TKI initiation were assessed by CyR (karyotype analysis or fluorescence in situ hybridization) and polymerase chain reaction MR tests. Proportions of pts achieving CCyR and MMR are presented for those with at least one recorded response test during 1L TKI therapy. Outcomes were stratified by CML risk level (Hasford scoring; low [≤780] and intermediate/high risk [≥781]), and the differences between 1L 1G and 2G TKI cohorts analyzed. Statistical comparisons for continuous variables were made using t-tests and the Mann-Whitney U test, and chi-square test for categorical variables. Multivariate logistic regression models, adjusted for age, gender, region, risk level (low vs intermediate/high), and baseline (BL) comorbidities, were used to determine if generation of TKI therapy (1G/2G) was associated with clinical response (CCyR or MMR) after start of 1L TKI. Performance and timing of CyR and MR tests were at the discretion of oncologists, limiting the analysis of outcomes and comparisons of CCyR and MMR rates. Results: There were 1,241 pts (IM: n=416; DAS: n=417; NIL: n=408) at database lock (October 2018); only 391 (31.5%) pts with CP-CML receiving 1L TKI were identified to have the elements needed for a Hasford risk assessment documented at diagnosis (IM: n=140; DAS: n=119; NIL: n=132). CML risk assessment (Hasford score) was significantly more common in Europe (68.7% vs 11.7% in the US, p&lt;0.0001). No significant difference in risk score was observed across the different 1L TKI groups (p=0.7012). Of the 130 (33.2%) pts with recorded CyR test results, no significant differences in BL demographics were observed except for median age at start of 1L TKI and BL cardiovascular and gastrointestinal (GI) comorbidities (Table 1). A higher percentage of pts on 2G TKIs achieved CCyR compared with 1G TKI in both low (88.1% vs 79.2%) and intermediate/high (73.0% vs 44.4%) CML risk categories, with statistical significance reached in the intermediate/high-risk group (p=0.0209). Multivariate logistic regression analysis (Figure 1) showed that pts were approximately 3 times more likely to achieve CCyR if receiving 2G TKIs (odds ratio [95% confidence interval]: 2.93 [1.21, 7.13] vs 1G, p=0.0177). Other predictors of CCyR were low baseline CML risk (5.75 [2.00, 16.50] vs intermediate/high CML risk, p=0.0011) and treatment at European centers (2.72 [1.03, 7.18] vs US centers, p=0.0431). MR test results were recorded in 358 (91.6%) pts; median number of MR tests was significantly higher in Europe (8 vs 5 in the US, p&lt;0.0001). No significant differences in pt demographics were observed except for age at start of 1L TKI and BL GI comorbidities (Table 1). A higher percentage of pts on 2G TKIs achieved MMR compared with 1G TKI in the low (82.0%vs 74.6%) and intermediate/high (87.0% vs 72.4%) CML risk groups, with significance reached in the latter cohort (p=0.0185). Multivariate logistic regression analysis showed that TKI generation was the sole predictor of MMR achievement; pts were approximately twice as likely to achieve MMR with 2G TKIs as with 1G TKI (OR: 2.13 [1.23, 3.70], p=0.0070) (Figure 1). Conclusions: Despite treatment guidelines recommending 2G TKI therapy for pts with higher CML risk, our analysis of SIMPLICITY pts showed no differences in 2G versus 1G TKI use in low and intermediate/high risk groups. Here, the use of 2G TKIs, compared with 1G TKI, was a significant predictor for achieving either CCyR or MMR, thereby validating the clinical response benefits of 2G TKIs regardless of BL CML risk. These findings emphasize the importance of adhering to treatment guidelines when making decisions on the generation of TKI, first (IM) or second (DAS/NIL), to be used in the 1L treatment of pts with CP-CML, particularly in higher risk pts. Disclosures Cortes: Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; BiolineRx: Consultancy. Chen:Bristol-Myers Squibb: Employment. Davis:Bristol-Myers Squibb: Employment, Equity Ownership. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy. Mauro:Bristol-Myers Squibb: Consultancy; Novartis Oncology: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy.