Patients Receiving Tyrosine Kinase Inhibitors Research Articles

Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases

Central nervous system (CNS) metastases can be seen at a rate of 30% in advanced stages for patients with non-small cell lung cancer (NSCLC). Growing evidence indicates the predictive roles of driver gene mutations in the development of brain metastases (BM) in recent years, meaning that oncogene-driven NSCLC have a high incidence of BM at diagnosis. Today, 3rd generation targeted drugs with high intracranial efficacy, which can cross the blood–brain barrier, have made a positive contribution to survival for these patients with an increased propensity to BM. It is important to update the clinical and pathological factors reflected in the survival with real-life data. A multi-center, retrospective database of 306 patients diagnosed with driver mutant NSCLC and initially presented with BM between between November 2008 and September 2022 were analyzed. The median progression-free survival (mPFS) was 12.25 months (95% CI, 10–14.5). While 254 of the patients received tyrosine kinase inhibitor (TKI), 51 patients received chemotherapy as first line treatment. The median intracranial PFS (iPFS) was 18.5 months (95% CI, 14.8–22.2). The median overall survival (OS) was 29 months (95% CI, 25.2–33.0). It was found that having 3 or less BM and absence of extracranial metastases were significantly associated with better mOS and iPFS. The relationship between the size of BM and survival was found to be non-significant. Among patients with advanced NSCLC with de novo BM carrying a driver mutation, long-term progression-free and overall survival can be achieved with the advent of targeted agents with high CNS efficacy with more conservative and localized radiotherapy modalities.

An audit of medullary thyroid carcinoma from a tertiary care hospital in northwest India.

Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy originating from parafollicular C cells. It accounts for 5%-10% of all thyroid malignancies. An ambispective analysis of pathologically proven MTC presented in a tertiary care hospital in northwest India was performed after considering demography, clinical manifestation, RET mutation status, management, and outcome as denominators. Among 2,735 thyroid malignancy cases who presented to our institute in the last 10 years (2012-2022), 78 (3%) had MTC with a mean age of presentation of 43 ± 11 years; 60% of them were female. The median duration of symptoms was 23 months (IQR 12-36 months). The most common presenting complaint was goiter with lymphadenopathy (80.8%). Among the atypical presentations, one each had ectopic Cushing's syndrome, hypertensive crisis in pregnancy due to pheochromocytoma, synchronous chondrosarcoma, and Von Hippel-Lindau disease spectrum. Median calcitonin and carcinoembryonic antigen (CEA) levels at presentation were 1,274 pg/mL (n = 64) and 149 ng/mL (n = 39), respectively. Twenty-two patients were germline RET mutation-positive, and they presented at a younger age. Majority of the patients presented with stage IV disease. Surgery was the primary modality of therapy. Twenty-nine patients received radiotherapy and 25 patients received tyrosine kinase inhibitors (TKIs). Nine patients received peptide receptor radiotherapy (PRRT) with Lu-177 with neoadjuvant capecitabine. Median progression-free survival (PFS) was 60 months. Patients without structurally and biochemically residual disease and stable disease after the first modality of therapy (Log-rank 11.4; p = 0.004) had a better PFS. Female patients (Log-rank: 9.5; p = 0.002) had a better PFS than male patients. This study showed that MTC comprises 3% of thyroid malignancies with a female preponderance. RET mutation-positive patients had a younger age at presentation. Surgery was the first-line therapy. Radiotherapy, TKI, and PRRT were given as a part of second-line or third-line therapy due to persistent disease and/or disease recurrence. The median PFS was better in female patients and in patients who had no residual lesions and stable disease after the primary modality of therapy.

Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group

Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.

Clinical analysis of allogeneic hematopoietic stem cell transplantation for seven cases of acute myeloid leukemia with BCR::ABL1 fusion

Objective: To explore the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute myeloid leukemia (AML) patients with BCR::ABL1 fusion. Methods: The clinical data of seven AML patients with BCR::ABL1 fusion from November 2012 to January 2022 were retrospectively analyzed, and their survival status was followed up. Results: The median age of patients at the time of diagnosis was 35 years. Four cases (57.1%) were diagnosed with high leukocyte counts. All cases were assayed as BCR::ABL1 positive and accompanied by four types of gene mutations (NPM1, RUNX1, ASXL1, PHF6) . Seven patients received tyrosine kinase inhibitor (TKI) combined with induction chemotherapy and bridged to allo-HSCT, and six patients received maintenance therapy with TKI. Before allo-HSCT, six patients achieved complete remission, and four patients achieved complete molecular remission (CMR) . After allo-HSCT, the three remaining cases also achieved CMR. All patients were in remission post-allo-HSCT. One case died of infection, and the remaining cases survived without relapse. The 3-year cumulative overall survival rate was (80.0±17.9) %. Conclusions: TKI combined with traditional chemotherapy could achieve a high response rate in AML patients with BCR::ABL1 fusion. In addition, allo-HSCT could enhance the molecular response rate. Maintenance therapy post-HSCT with TKI could improve prognosis.

Clinicopathological Characteristics and Real-life Data of Patients Receiving Tyrosine Kinase Inhibitor in Metastatic EGFR Mutant Non-small Cell Lung Carcinoma

Clinicopathological Characteristics and Real-life Data of Patients Receiving Tyrosine Kinase Inhibitor in Metastatic EGFR Mutant Non-small Cell Lung Carcinoma

Risk of renal adverse effects in patients with advanced thyroid cancer who are undergoing radiological monitoring, with a particular focus on patients receiving tyrosine kinase inhibitors

Risk of renal adverse effects in patients with advanced thyroid cancer who are undergoing radiological monitoring, with a particular focus on patients receiving tyrosine kinase inhibitors

The efficacy and safety of eltrombopag in treating TKI-induced thrombocytopenia in patients with chronic myeloid leukemia

ABSTRACTThrombocytopenia is one of the most common hematological adverse reactions in chronic myeloid leukemia (CML) patients receiving tyrosine kinase inhibitors (TKI) therapy, causing life-threatening bleeding cases. However, there are fewer therapeutic drugs for TKI-induced thrombocytopenia. Eltrombopag is a non-peptide thrombopoietin receptor agonist used for the treatment of immune thrombocytopenia， aplastic anemia, and hepatitis C-associated thrombocytopenia. Nevertheless, studies of eltrombopag for TKI-induced thrombocytopenia are still lacking. This study retrospectively analyzed the clinical and test data of 21 CML patients with TKI-related thrombocytopenia. The results demonstrated that the median baseline value of thrombocytopenia in the 21 CML patients was 15.57 × 109/L [2–28 × 109/L]. Following treatment with eltrombopag, 16 patients had a significant increase in their platelet levels. The peak median for platelet increase in effective responders was 145.12 × 109/L (51–460 × 109/L). However, 5 patients failed to respond to eltrombopag. Moreover, 4 of the 21 patients enrolled had adverse reactions, including reversible liver function impairment, palpitation, headache, insomnia, and loss of appetite. Nonetheless, no cases of disease progression, thrombotic events, or myelofibrosis were observed. Hence, eltrombopag may be a useful adjunctive therapy for relieving TKI-related thrombocytopenia in patients with CML.

Analysis of outcomes of the first line systemic therapy in patients with solitary, single and multiple metastases of renal cell carcinoma

BACKGROUND: Currently there are practically no works in the literature to assess the outcomes of systemic therapy in patients with solitary, single and multiple metastases of renal cell carcinoma.
 AIM: The aim of the study was to analyze the outcomes of systemic drug therapy of the first line in patients with solitary, single and multiple metastases of renal cell carcinoma.
 MATERIALS AND METHODS: The data of 981 patients with metastatic renal cell carcinoma who underwent systemic therapy of the first line at the City Oncological Hospital No. 62 in Moscow and the City Oncological Dispensary in St. Petersburg from 2006 to 2022 were retrospectively analyzed. All patients underwent clinical, laboratory and pathomorphological examination. 90 (9.2%) patients had solitary metastases, 252 (25.7%) single metastases and 639 (65.1%) multiple metastases. An analysis was made of the outcomes of 1st line therapy, which were conditionally divided into favorable, including all cases of complete response, partial response and stabilization, and unfavorable progression during treatment, death or deregistration. Subsequently patients who had previously received chemotherapy or cytokine treatment were excluded from the analysis.
 RESULTS: Complete response (3.3%) and deregistration (5.56%) were more often observed in patients with solitary metastases, stabilization more often occurred in patients with single metastases (51.1%), partial response (9.4%) and death (6.2%) in patients with multiple metastases. In patients with multiple metastases treated with immune checkpoint inhibitors a partial response was observed in almost half of the cases. Stabilization and progression were observed in almost the same percentage of cases (about a quarter of cases), and only two patients had a fatal outcome, which is slightly lower than in patients receiving tyrosine kinase inhibitors. Frequent outcomes when using tyrosine kinase inhibitors were stabilization of the process (40.72% of cases) or progression (38.72%), a complete and partial response was rarely recorded. Significant differences in the occurrence of favorable and unfavorable outcomes were revealed in patients with multiple metastases, depending on the number of affected organs and the prescribed drug. When comparing the results of systemic therapy of the first line, a higher efficiency of tyrosine kinase inhibitors was observed in solitary metastases of tumors with a high and moderate degree of differentiation. Systemic therapy of G3 tumors with solitary metastases had low efficacy in the appointment of tyrosine kinase inhibitors in 27.27% of patients. Higher efficiency was noted in single and multiple metastases. The effectiveness of immune checkpoint inhibitors was revealed in 70.6% of patients with single and multiple metastases.
 CONCLUSIONS: When choosing systemic therapy for metastatic renal cell carcinoma in clinical practice, it is necessary to take into account such prognostic factors as histological variants, the degree of differentiation of the tumor and the number of affected organs.

PD43-04 MANAGEMENT OF RENAL MASS SOLITARY KIDNEY WITH HIGH TUMOR COMPLEXITY

You have accessJournal of UrologyCME1 Apr 2023PD43-04 MANAGEMENT OF RENAL MASS SOLITARY KIDNEY WITH HIGH TUMOR COMPLEXITY Worapat Attawettayanon, Yosuke Yasuda, JJ Zhang, Nityam Rathi, Carlos Munoz-Lopez, Kieran Lewis, Snehi Sha, Jianbo Li, Joao Accioly, Rebecca Campbell, Jihad Kaouk, Georges-Pascal Haber, Mohamad Eltemamy, Venkatesh Krishnamurthi, Robert Abouassaly, Christopher Weight, and Steven Campbell Worapat AttawettayanonWorapat Attawettayanon More articles by this author , Yosuke YasudaYosuke Yasuda More articles by this author , JJ ZhangJJ Zhang More articles by this author , Nityam RathiNityam Rathi More articles by this author , Carlos Munoz-LopezCarlos Munoz-Lopez More articles by this author , Kieran LewisKieran Lewis More articles by this author , Snehi ShaSnehi Sha More articles by this author , Jianbo LiJianbo Li More articles by this author , Joao AcciolyJoao Accioly More articles by this author , Rebecca CampbellRebecca Campbell More articles by this author , Jihad KaoukJihad Kaouk More articles by this author , Georges-Pascal HaberGeorges-Pascal Haber More articles by this author , Mohamad EltemamyMohamad Eltemamy More articles by this author , Venkatesh KrishnamurthiVenkatesh Krishnamurthi More articles by this author , Robert AbouassalyRobert Abouassaly More articles by this author , Christopher WeightChristopher Weight More articles by this author , and Steven CampbellSteven Campbell More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003353.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Partial nephrectomy (PN) is preferred for renal mass in solitary kidney (RMSK), although tumors with high complexity (R.E.N.A.L=10-12) can be very challenging. Our objective was to evaluate the evolution of management for such patients, with focus on the pre-TKI (1999-2008) vs TKI (2009-2022) eras. METHODS: 499 RMSK were managed from 1999-2022 at our center; 133 had high R.E.N.A.L., including 80/53 patients in the early/late timeframes, respectively. After 2009, 23 patients received tyrosine kinase inhibitor (TKI) before surgery, and 30 had immediate surgery. Achievement of PN was the primary outcome; other outcomes included adverse events and surgical complications related to TKI, and recurrence-free and overall survival (RFS/OS). RESULTS: Overall, median R.E.N.A.L. and tumor diameter were 10/5.2 cm, respectively. Demographics, tumor diameter, and R.E.N.A.L were all similar in the early vs late cohorts. Non-confined pathology was found in 51%/58% of the early/late cohorts, respectively. In the late cohort, 23/53(43%) patients were selected for pre-surgical TKI. These 23 patients were the most challenging with increased median tumor diameter (7.1 vs. 4.4cm, p=0.02) and increased median R.E.N.A.L.(11 vs. 10, p=0.07). After TKI, median tumor diameter and R.E.N.A.L. were reduced to 5.6 cm and 9, and median tumor volume was reduced 59%. PN was accomplished in 21/23 (91%) of this cohort, and PN was also accomplished in 27/30 (90%) of the immediate surgery cases. In contrast, PN was only accomplished in 52/80(65%) patients in the pre-TKI era. 5-year dialysis-free survival was 91% vs 59% in the late vs early cohorts, respectively. Grade 3 adverse events related to TKI were observed in 11 patients (49%), and in this cohort, 5 urine leaks and one post-op. bleed were all managed successfully with conservative measures. Median follow-up was 41months; 5-year OS was 66%/71% in the early/late cohorts, respectively (p=0.5), while 5-year RFS were 73%/56%, respectively (p=0.07). Most recurrences were metastatic reflecting aggressive tumor biology, rather than failure of local management. CONCLUSIONS: RMSK with high tumor complexity is often locally advanced and challenging. Selective use of TKI may reduce the need for RN and augment dialysis-free survival. RFS mostly reflected aggressive tumor biology rather than failure of local management. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1119 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Worapat Attawettayanon More articles by this author Yosuke Yasuda More articles by this author JJ Zhang More articles by this author Nityam Rathi More articles by this author Carlos Munoz-Lopez More articles by this author Kieran Lewis More articles by this author Snehi Sha More articles by this author Jianbo Li More articles by this author Joao Accioly More articles by this author Rebecca Campbell More articles by this author Jihad Kaouk More articles by this author Georges-Pascal Haber More articles by this author Mohamad Eltemamy More articles by this author Venkatesh Krishnamurthi More articles by this author Robert Abouassaly More articles by this author Christopher Weight More articles by this author Steven Campbell More articles by this author Expand All Advertisement PDF downloadLoading ...

Reactivation of Hepatitis B Virus in Lung Cancer Patients Receiving Tyrosine Kinase Inhibitor Treatment.

(1) Background: We aimed to evaluate the risk of hepatitis B virus (HBV) reactivation in lung cancer patients treated with tyrosine kinase inhibitor (TKI), particularly in those with resolved HBV infection. (2) Methods: In this retrospective hospital-based cohort study, we screened all lung cancer patients with positive hepatitis B core antibodies (anti-HBc) receiving systemic antineoplastic treatment during the period from January 2011 to December 2020. Cumulative incidences of HBV reactivation, and their hazard ratios (HRs), were evaluated after adjusting patient mortality as a competing risk. (3) Results: Among 1960 anti-HBc-positive patients receiving systemic therapy, 366 were HBsAg-positive and 1594 were HBsAg-negative. In HBsAg-positive patients without prophylactic NUC, 3-year cumulative incidences of HBV reactivation were similar between patients receiving chemotherapy and patients receiving TKI (15.0%, 95% confidence interval (CI): 0−31.2% vs. 21.2%, 95% CI: 10.8−31.7%; p = 0.680). Likewise, 3-year cumulative incidences of HBV-related hepatitis were similar between the two groups (chemotherapy vs. TKI: 15.0%, 95% CI: 0−31.2% vs. 9.3%, 95% CI: 2.8−15.7%; p = 0.441). In 521 HBsAg-negative TKI users, the 3-year cumulative incidence of HBV reactivation was only 0.6% (95% CI: 0.0−1.9%). From multivariable regression analysis, we found that the only independent risk factor for HBV reactivation in TKI users was HBsAg positivity (HR 53.8, 95% CI: 7.0−412.9; p < 0.001). (4) Conclusion: Due to high risks of HBV reactivation in HBsAg-positive TKI users, NUC prophylaxis can be considered. However, in patients with resolved HBV infection, such risks are lower, and therefore regular monitoring is recommended.

Effect of EGFR amplification on the prognosis of EGFR-mutated advanced non–small-cell lung cancer patients: a prospective observational study

BackgroundEpidermal growth factor receptor (EGFR) amplification refers to the copy number increase of EGFR gene, and is often identified as a “bypass” way of Epidermal growth factor receptor Tyrosine kinase inhibitors (EGFR-TKI) resistance. We aimed to explore the effect of EGFR amplification on EGFR mutation treatment-naive advanced non-squamous non-small cell lung cancer (NSCLC) patients.MethodsWe conducted a prospective observational study in single center, enrolling advanced non-squamous NSCLC patients receiving Tyrosine kinase inhibitors (TKIs) between March 3, 2019, and February 1, 2022. Next-generation sequencing (NGS) was used to detect genetic alterations in tumor tissue samples. Progression-free survival (PFS) curves were performed using the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate factors affecting the efficacy of TKIs.ResultsA total of 117 treatment-naive advanced NSCLC patients were identified in this study. EGFR amplification was found in 22 of 117 (18.8%) patients with EGFR mutations. Of 22 patients with EGFR amplification, 10 patients harbored EGFR 19 del, 11 patients with 21-L858R. The median follow-up time was 22.47 months. The median PFS of the patients with or without EGFR amplification was 8.25 months and 10.67 months, respectively (log-rank test, P = 0.63). In multivariate analysis, EGFR amplification was not an independent prognosis factor for the patients receiving first-line TKIs [HR = 1.38, 95%CI (0.73–2.58), P = 0.321]. Subgroup analysis revealed that EGFR amplification is a risk factor for progression in the brain metastasis population. [HR = 2.28, 95%CI (1.01, 5.14), P = 0.047].ConclusionEGFR amplification is not an independent prognosis factor for PFS in advanced non-squamous NSCLC patients receiving first-line TKIs. However, it is an independent risk factor for PFS in the brain metastasis population.

Cognition in patients treated with targeted therapy for chronic myeloid leukemia: a controlled comparison

This controlled comparison study evaluated objective and subjective cognitive function and their relationships with patient-reported symptoms (depression, fatigue, insomnia) in patients receiving tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and non-cancer controls. Patients with CML in chronic phase treated with the same oral TKI for ≥6 months (n = 90) and non-cancer controls (n = 87) completed a neurocognitive battery and self-report measures. Patients demonstrated worse overall neuropsychological performance (p = .05) and verbal memory (p = .02) compared to controls. Patients were not more likely to meet criteria for impaired cognitive performance compared to controls (ps>.26). Patients reported worse subjective global and domain-specific cognitive complaints and less satisfaction with cognitive function compared to controls (ps < .05). Patients also reported greater fatigue and insomnia symptoms (ps < .001). In both groups, greater fatigue, insomnia, and depressive symptoms were associated with worse subjective cognition (ps < .01). Longitudinal studies are needed to examine changes in cognitive function in patients before and during TKI treatment.

Longitudinal monitoring of cell-free DNA methylation in ALK-positive non-small cell lung cancer patients

BackgroundDNA methylation (5-mC) signals in cell-free DNA (cfDNA) of cancer patients represent promising biomarkers for minimally invasive tumor detection. The high abundance of cancer-associated 5-mC alterations permits parallel and highly sensitive assessment of multiple 5-mC biomarkers. Here, we performed genome-wide 5-mC profiling in the plasma of metastatic ALK-rearranged non-small cell lung cancer (NSCLC) patients receiving tyrosine kinase inhibitor therapy. We established a strategy to identify ALK-specific 5-mC changes from cfDNA and demonstrated the suitability of the identified markers for cancer detection, prognosis, and therapy monitoring.MethodsLongitudinal plasma samples (n = 79) of 21 ALK-positive NSCLC patients and 13 healthy donors were collected alongside 15 ALK-positive tumor tissue and 10 healthy lung tissue specimens. All plasma and tissue samples were analyzed by cell-free DNA methylation immunoprecipitation sequencing to generate genome-wide 5-mC profiles. Information on genomic alterations (i.e., somatic mutations/fusions and copy number alterations) determined in matched plasma samples was available from previous studies.ResultsWe devised a strategy that identified tumor-specific 5-mC biomarkers by reducing 5-mC background signals derived from hematopoietic cells. This was followed by differential methylation analysis (cases vs. controls) and biomarker validation using 5-mC profiles of ALK-positive tumor tissues. The resulting 245 differentially methylated regions were enriched for lung adenocarcinoma-specific 5-mC patterns in TCGA data and indicated transcriptional repression of several genes described to be silenced in NSCLC (e.g., PCDH10, TBX2, CDO1, and HOXA9). Additionally, 5-mC-based tumor DNA (5-mC score) was highly correlated with other genomic alterations in cell-free DNA (Spearman, ρ > 0.6), while samples with high 5-mC scores showed significantly shorter overall survival (log-rank p = 0.025). Longitudinal 5-mC scores reflected radiologic disease assessments and were significantly elevated at disease progression compared to the therapy start (p = 0.0023). In 7 out of 8 instances, rising 5-mC scores preceded imaging-based evaluation of disease progression.ConclusionWe demonstrated a strategy to identify 5-mC biomarkers from the plasma of cancer patients and integrated them into a quantitative measure of cancer-associated 5-mC alterations. Using longitudinal plasma samples of ALK-positive NSCLC patients, we highlighted the suitability of cfDNA methylation for prognosis and therapy monitoring.

Gimema ALL2418: Interim Analysis of a Phase Iia Study of Feasibility and Effectiveness of Inotuzumab Ozogamicin in Adult Patients with B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease before Any Hematopoietic Stem Cell Transplantation

Background: Persistence of minimal residual disease (MRD) is associated with a high rate of treatment failure, relapse, and death in B-cell acute lymphoblastic leukemia (B-ALL). Particularly, patients who remain MRD positive before an allogeneic hematopoietic stem cell transplant (HSCT) have an expected disease-related death rate due to the disease of about 60%. The T cell-engager CD19-directed therapy blinatumomab demonstrated considerable efficacy in this setting, however resistant or unsuitable patients have no alternative therapy. Inotuzumab Ozogamicin (IO) is a CD22-directed antibody-drug conjugate with remarkable efficacy in B-ALL with overt disease. Furthermore, IO does not need a high effective immune system to exert activity. Methods: In this multicenter phase 2 trial (NCT03610438), we are investigating the efficacy of IO in obtaining MRD negativity in two cohorts of 38 Ph+ and 38 Ph- B-ALL patients. IO was administered at the dose of 0.5 mg/sqm on days 1, 8, and 15 of a 28-days cycle. Patients who did not obtain MRD negativity after the 1st IO cycle had the option to receive the 2nd IO cycle maintaining the same dosage. Responding Ph- patients received short-term maintenance with low-dose chemotherapy (alternating vincristine, cyclophosphamide, prednisone, methotrexate, and 6-mercaptopurine), responding PH+ patients received tyrosine kinase inhibitor (TKI) for up to 12 weeks, allowing proper IO washout before HSCT. HSCT ineligible patients entered into low-dose chemotherapy or TKI maintenance for up to 2 years. For the primary endpoint, MRD was centrally assessed at baseline, after course 1, after course 2, and eventually before transplant with high sensitive molecular methods for BCR-ABL1 or V(d)J fusion transcripts. Here, we present the results of an unplanned interim analysis that was generated to evaluate the continuation of the study considering the slow accrual due to the Sars-COV2 pandemic. Results: To date, 51 patients underwent screening procedures, and 43 were considered eligible. We report data from the first 39 patients treated in the study. Nineteen out of 39 patients had Ph- B-ALL and 20/39 Ph+ B-ALL. Eighteen out of 39 (46%) patients were male. The median age was 55 years (22-84), 15/39 patients (38%) were older than 65 years. Demographics were comparable between Ph+ and Ph- patients. Within Ph+, ALL 39% of patients harbored p190 and 61% p210 fusion transcript. Within Ph- B-ALL, 1 patient harbored ALL1/AF4 and 1 patient harbored ALL1/ENL fusion transcript. Most of the patients received 1 (16/39, 42%) or 2 (19/39, 50%) previous lines of therapy; 5 patients (13%) were resistant to blinatumomab, and all of them had Ph- B-ALL. Twelve out of 19 (63%) Ph- B-ALL patients received only 1 IO cycle, 7/19 (37%) received 2 cycles; 5/20(25%) Ph+ B-ALL received only 1 IO cycle, and 15/20 (75%) received 2 cycles. To date, central MRD monitoring is available for 20 patients (12 Ph- and 8 Ph+ B-ALL, ongoing for the remaining cases). Overall, MRD negativity was obtained in 7/20 patients (35%); Particularly, in Ph- B-ALL cohort 5/12 (42%) patients achieved MRD negativity, 4/12 (38%) achieved disease reduction at low level MRD positivity (<10-4); in Ph+ B-ALL cohort, 2/8 (25%) patients achieved MRD negativity. One out of 5 (20%) blinatumomab pre-treated patients obtained MRD negative response. IO was an effective bridge to HSCT for 10/39 patients (26%; in patients <65 years old, 9/24 patients, 37%); Specifically, all 7 patients who obtained MRD negativity after IO, a patient with low-positive MRD and 2 patients with non yet available MRD data were bridged to HSCT. Accordingly, with the caveat of a short median follow-up (2.8 months, range 0.6-20.0 months), overall survival in the study population seems promising (figure 1, median OS not reached). Overall, adverse events collected during the study were limited in number and grading. Also, myelotoxicity was manageable. Out of 39 patients, we documented 1 veno-occlusive disease (2.5%) that occurred within 20 days from the last IO dose and before any HSCT. Conclusions: IO administration demonstrated activity with a good safety profile in the setting of MRD positive B-ALL, including blinatumomab resistant patients. Importantly, IO was capable to bridge 37% of eligible patients to HSCT, augmenting the chance to achieve a cure. The continuation of the study will deliver mature efficacy and survival data for a proper evaluation of this promising strategy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of Treatment Efficacy of Tyrosine Kinase Inhibitors in Rare Single EGFR Exon 21 L861Q Mutation: Single Center Experience.

OBJECTIVE:Epidermal growth factor receptor mutations are the second most common oncogenic driver event in non-small cell lung cancer. We aimed to compare the first generation erlotinib treatment with the second generation afatinib treatment in patients with non-small cell lung cancer with epidermal growth factor receptor exon 21 L861Q mutation.MATERIAL AND Methods:Progression-free survival and overall survival of 30 non-small cell lung cancer patients treated with erlotinib or afatinib due to single epidermal growth factor receptor L861Q positivity were compared retrospectively. The number of patients included in the first, second, and third treatment line was 15 (50.0%), 11 (36.7%), and 4 (13.3%), respectively.Results:There were 23 patients in the erlotinib arm and 7 patients in the afatinib arm. Median progression-free survival was 12.8 months in the erlotinib group and 9.3 months in the afatinib group. Median overall survival in erlotinib and afatinib groups was 77.9 months and 30.3 months, respectively. No statistically significant difference was found in the comparison of these survival times. Conclusion:Survival times of erlotinib and afatinib treatment are similar in patients with a single epidermal growth factor receptor L861Q mutation. In patients receiving tyrosine kinase inhibitors treatment, the female gender has a positive effect on progression-free survival, and being a non-smoker has a positive effect on overall survival. In patients with rare mutation exon 21 L861Q positivity, both first-generation and second-generation tyrosine kinase inhibitors should be considered.

Abstract 5161: Exome-scale longitudinal tracking of emerging therapeutic resistance in GIST via analysis of circulating tumor DNA

Abstract Gastrointestinal stromal tumors (GIST) are lethal tumors characterized by constitutively activating mutations to KIT or PDGFRA. Transient disease control in the first-line setting is achieved via inhibition of tyrosine kinase signaling using the KIT inhibitor imatinib. As patients progress through subsequent lines of therapy a molecularly heterogeneous disease evolves, characterized by distinct subtypes and shifting repertoires of exon-specific KIT variants which directly impact treatment outcomes. Here, we use tumor-informed exome-scale liquid biopsy to identify and track the evolution of multiple resistance mechanisms in patients receiving tyrosine kinase inhibitors (TKIs) to address the unmet need of comprehensive understanding of GIST evolution in response to therapy. Matched tumor, normal and serial plasma samples were obtained from 15 heavily pretreated metastatic GIST patients. Following baseline sample collection, all patients received systemic TKI therapy, and were monitored until disease progression. Exome-scale detection of somatic variants in cfDNA from longitudinal matched plasma samples was achieved using the NeXT Liquid BiopsyTM platform. The ImmunoID NeXT PlatformⓇ, an augmented exome/transcriptome platform and analysis pipeline which generates comprehensive tumor and immune data was used to profile paired tumor and normal samples. Longitudinal whole exome sequencing of plasma identified dynamic shifts in existing clones harboring exon-specific KIT mutations, and evolution of new KIT mutations arising prior to identification of tumor progression using standard imaging techniques. We detected a correlation between the number of damaging mutations detected in baseline ctDNA and tumor exon 11 KIT mutation status, suggesting that plasma mutation profiles may be KIT-variant dependent. ctDNA from patients with shorter overall survival (OS) was enriched for variants in the PI3K-AKT and MAPK pathway, potentially contributing to immune evasion observed in those patients. Additional associations were observed between gene copy-number changes and OS (P = .0097). Previous studies have demonstrated that immune infiltration and activity may be KIT variant specific, here we broaden those findings, identifying a significant correlation between TCRɑ clonality and variants detected only in plasma (P = .04), as well as a significant association between TCRβ diversity and OS (HR = 2.55, log rank P = .04). Comprehensive profiling of paired tumor tissue (WES and RNA-Seq) and WES of serially collected ctDNA sensitively and repeatedly identified evolving KIT mutations and other molecular alterations prior to radiologically confirmed disease progression. These findings suggest plasma-based monitoring of late-stage GIST malignancies may be useful for non-invasive disease tracking, providing treatment guidance prior to traditional approaches. Citation Format: Charles W. Abbott, Niamh Coleman, Jing Wang, Josette Northcott, Jason Pugh, Dan Norton, Fábio C. Navarro, Lee D. McDaniel, Eric Levy, Rachel Marty Pyke, John Lyle, Jason Harris, Gabor Bartha, Filip Janku, John West, Richard O. Chen, Sean Boyle. Exome-scale longitudinal tracking of emerging therapeutic resistance in GIST via analysis of circulating tumor DNA [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 5161.

Cardiovascular Adverse Events and Mitigation Strategies for Chronic Myeloid Leukemia Patients Receiving Tyrosine Kinase Inhibitor Therapy.

Cardiovascular (CV) risk mitigation is an important consideration in the management of chronic myeloid leukemia (CML) patients. Although BCR-ABL1 inhibition by tyrosine kinase inhibitors (TKI) has led to a significant improvement in prognosis, the majority of CML patients will require indefinite TKI therapy. Given the success of therapy, there has been a shift in focus to include CV care as part of routine patient management. To optimize outcomes, both patient-specific comorbidities and a detailed understanding of the cardiotoxicity safety profiles imparted by each TKI should be considered during agent selection. Clinicians face the challenge of early detection and management of these cardiotoxicities while balancing the risk-benefit ratios of maintaining life-saving cancer therapy. Advanced practitioners play a critical role in CML patient management that extends to the recognition and management of TKI-associated side effects. They should be cognizant of the potential for TKI-associated cardiotoxicities along with appropriate baseline risk assessments, active surveillance, and mitigation strategies as part of a collaborative team effort with cardio-oncologists.

PD-1 targeted immunotherapy for advanced hepatocellular carcinoma: current utilization and outcomes in the USA.

Objective: To evaluate the utilization and outcomes of PD-1-directed immunotherapy(PD-1 IMT) for advanced hepatocellular carcinoma. Methods: Patients with advanced hepatocellular carcinoma receiving systemic therapy and PD-1 IMT (nivolumab/pembrolizumab) were included from the Flatiron database. Overall survival (OS) was evaluated using multivariable Cox models with the following subgroup analyses: patients with data on clinical performance and liver function and patients receiving tyrosine kinase inhibitors. Results: n=1770 patients were included (PD-1 IMT 19.3%). Overall, PD-1 IMT was associated with longer OS (hazard ratio [HR]: 0.57). This effect was robust across both subgroup analyses with HR: 0.72 (subgroup 1) and HR: 0.57 (subgroup 2). Conclusions: PD-1 IMT is increasingly used in clinical practice and associated with an OS benefit.

16P Evaluation of the relationship between clinicopathological features at diagnosis and acquisition of T790M resistance mutation in patients with EGFR-mutant metastatic lung cancer

Data of the acquisition of T790M resistance mutation in patients with EGFR-mutant metastatic lung cancer is limited. This study aimed to assess the relationship between clinicopathological features at diagnosis, and acquisition of T790M mutation in patients with EGFR-mutant metastatic non-small cell lung cancer. We evaluated the EGFR-mutant metastatic lung cancer patients' data who progressed under first-line treatment with tyrosine kinase inhibitors and acquired T790M resistance mutation retrospectively. Survival analyses were assessed with Kaplan-Meier and Cox-regression methods. The relationship between the acquisition of T790M mutation and clinicopathological parameters was evaluated with logistic regression analysis. Fifty-two patients were included in the study. The median age was 58 (range, 33-78) years. The proportion of female patients was 53.2%. The proportions of exon 19, exon 21, and rare mutations were 68.7%, 23.5%, and 7.8%, respectively. Forty-five (86.5%) patients were de-novo metastatic. The proportion of patients who had one, two, and three or more metastatic sites at diagnosis were 25.5%, 41.3%, and 33.2%, respectively. The proportio of brain, liver and adrenal gland metastasis were 29.4%, 13.7%, and 7.8%, respectively. All patients received tyrosine kinase inhibitors. After the disease progressed, the acquisition of T790M mutation was detected with liquid (75.5%) or standard biopsies (24.5%). T790M mutations were detected in 33 (63.5%) patients. In logistic regression analysis, age, gender, de-novo metastatic disease, number of metastatic sites, primary tumor localization (left or right lung), and type of tyrosine kinase inhibitor was not statistically significant for the acquisition of T790M mutations. Due to rarity, the data on the acquisition of T790M mutations are limited. In this study, we showed that clinicopathological features were not related to the acquisition of T790M mutations.

Non-thrombotic ischemic cerebrovascular events related to the use of tyrosine kinase inhibitors in patients with cancer: high-resolution magnetic resonance imaging findings

The targeted cancer therapies that have been introduced in recent years are directed against cancer-specific molecules and signaling pathways, and thus, they have limited nonspecific toxicities. However, major vascular events, including stroke, are common in patients receiving tyrosine kinase inhibitors (TKIs). Inhibition of vascular endothelial growth factor receptor by some TKIs probably explains such events. Moreover, venous and arterial thromboses, atherosclerosis, and bleeding have been reported. Ischemic lesions can also occur due to impaired angiogenesis or endothelial dysfunction. However, the exact mechanisms of arterial stroke in patients with cancer receiving TKIs are unknown. Here, we have report two cases of non-thrombotic ischemic cerebrovascular events related to TKIs and described the high-resolution magnetic resonance imaging findings.