United States

Title: FOLR1 Upregulation- A Mechanism Behind Minimal Residual Disease in Tepotinib-Treated MET Amplified NSCLC

[1]Soumya Malhotra, [2] Simon Baldacci, [2 ] Francesco Facchinetti, [2] William Feng, [2] Pasi A. Janne
[1]Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, Florida
[2]Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts

Background: MET proto-oncogene encodes a receptor tyrosine kinase involved in cell proliferation and survival. Therefore, MET dysregulation can lead to unchecked tumor growth, invasion, and metastases. MET tyrosine kinase inhibitors (TKIs), such as tepotinib, have changed the landscape of MET Amplified Non-Small Cell Lung Cancer (NSCLC); however, patients relapse frequently due to the incomplete removal of tumor cells, resulting in the establishment of minimal residual disease (MRD). MRD, described as persister cancer cells remaining in the body after treatment, forms the basis for increased resistance development in MET Amplified NSCLC. In recent years, through systematic evaluation, Folate Receptor Alpha (FOLR1), a cell surface folate binding protein, has been implicated in cell growth regulation, DNA biosynthesis, repair, and methylation, contributing to cancer growth and metastases in solid tumors. This study investigates FOLR1 upregulation as a resistance mechanism in tepotinib-treated MET Amplified NSCLC.

Methods: Cell populations were divided into control and treated. The control population was subdivided into two to account for growth time and plate crowding. Drug toxicity assays were conducted using the Pierce BCA Protein Assay protocol to determine optimal treatment dosage. The control population was treated with low concentrations of dimethyl sulfoxide (DMSO), while the treated population received 5nM tepotinib. Both populations were treated the day following cell plating, with drug renewal performed on day five. All live cells and their culture media were harvested separately on day ten. FOLR1 expression was assessed in the harvested cells utilizing Reverse Transcription- Quantitative Polymerase Chain Reaction (RT-qPCR), Flow Cytometry, Western Blot, and in the culture media using enzyme-linked immunosorbent assay (ELISA) assays. 

Results: The results were analyzed using the GraphPad Prism program. Both populations were confirmed to express FOLR1. Control populations showed a baseline FOLR1 expression, thus confirming its presence in MET Amplified cancer cells. Moreover, the persister cells in the treated population showed a significant upregulation consistent across qPCR, ELISA, Western Blot, and Flow Cytometry assays. These results indicate that FOLR1 changes start at the transcriptional level, as shown by the increased mRNA expression through RT-qPCR. mRNA changes lead to increased cell surface and total FOLR1 protein, evidenced by the Flow Cytometry and Western Blot. Furthermore, increased FOLR1 concentrations in the culture media, measured through ELISA, affirms high FOLR1 cleavage in persister cells. These results are consistent with previous studies confirming increased FOLR1 serum concentrations in NSCLC patients.

Conclusion: Our findings provide a rationale for targeting FOLR1 in MET Amplified NSCLC. Ongoing studies to elucidate tepotinib response on FOLR1 knockout cells would strengthen our results. Furthermore, simultaneous in-vivo testing is helping progress our understanding of adverse effects related to targeting FOLR1. Antibody-drug conjugates and Chimeric Antigen Receptor T-cells are at the forefront of cancer research as targeted agents that link a cytotoxic drug to a monoclonal antibody or re-engineer T cells to specifically recognize a cellular surface antigen, improving the efficacy of chemotherapy and reducing systemic exposure and toxicity. Using this technology for FOLR1 targeted treatments could provide a new advent for managing MET Amplified NSCLC with decreased resistance-related failures.

AMA Research Challenge 2024 

FOLR1 Upregulation- A Mechanism Behind Minimal Residual Disease in Tepotinib-Treated MET Amplified NSCLC

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Background: Pre-treatment characteristics of women with early breast cancer that are associated with persistent fatigue or suboptimal health-related quality of life (HRQOL) post-chemotherapy need to be identified as potential targets for pre-habilitation. 

Patients and Methods: Ancillary analysis of previously collected data from patients with newly diagnosed Stage I-III breast cancer scheduled to receive chemotherapy. The objective was to identify baseline (pre-chemotherapy) variables associated with meaningful deteriorations in fatigue and other measures of HRQOL from pre-treatment to 6 months after chemotherapy completion. Percentages are reported along with unadjusted and adjusted relative risks.

Results: In a sample of 249 women post-chemotherapy, 32% reported worsening fatigue (FACIT-F), 35% worsening Physical Well-Being (PWB), 16% worsening Functional Well-Being (FWB), 8% worsening Emotional Well-Being (EWB), and 30% worsening Social Well-Being (SWB). In multivariable (MV) analysis, variables that were significant in univariate analysis – Black race, high BMI, and baseline poorer EWB – remained significant for worsening post-chemotherapy fatigue (FACIT-F). In MV analysis that included race, education, falls and baseline EWB, Black race and a positive falls history remained significant for worsening PWB. In MV analysis inclusive of race, Short Physical Performance Battery (SPPB) and FWB, lower SPPB and FWB remained significant predictors of worsening FWB. In MV analysis that included baseline Mental Health Index-Anxiety, EWB and SWB, a higher SWB and lower EWB remained significant for worsening SWB. 

Conclusion: Pre-chemotherapy characteristics in women with early-stage breast cancer that are associated with increased fatigue and reduced HRQOL post-treatment could be used to identify patients who may benefit from pre-habilitation interventions. 

Keywords: breast cancer, pre-habilitation, cancer-related fatigue, chemotherapy, long-term toxicity

Identifying pre-habilitation targets for the mitigation of long-term side effects of chemotherapy in patients with early breast cancer

Background: Leiomyomatosis Peritonealis Disseminata (LPD) is characterized by multiple smooth muscle intra-abdominal and pelvic nodules that may recur after complete resection. Predominantly described in females of childbearing age, LPD has only isolated case reports indicating its malignant potential, and a comprehensive collation of cases is lacking. This manuscript presents the first comprehensive collation of published data on LPD to provide insights into its management. Additionally, we present a case of a single patient's progression from benign to malignancy over two decades, highlighting the need for long-term follow up.
Methods: We present a case of LPD's malignant transformation over two decades. Initially diagnosed with a uterine atypical smooth muscle tumor, the patient later developed frank malignancy, resulting in liver and lung metastases almost 23 years later, as confirmed by our included imaging. Additionally, we compiled an Excel database of all 213 available cases in English literature, documenting hormone receptor status, age, tumor size, follow-up time, and surgical interventions. Patients were categorized into G1 (reportedly benign), G2 (malignant at presentation), and G3 (malignant transformation).
Results: Compared to G1, patients in G2 were more likely to be symptomatic (73% vs. 88%), larger in size (4.1 cm vs. 8.4 cm), and older in age (38 vs. 44 years). The average age in G1, G2, and G3 was 38.5, 44.3, and 37.5 years, respectively, while disease-specific survival was 100%, 71%, and 40%. The mean number of surgeries performed in G1, G2, and G3 was 1.6, 1.8, and 3.8, respectively. Hormone receptors were found in 24.4% of cases. The mean reported follow-up time in G1, G2, and G3 was 44.9, 13.1, and 70.5 months, respectively. This suggests that with longer follow up, even apparently benign tumors may develop malignancy. The transformation time to malignancy in G3 was 77.8 months, which is more than the average reported follow-up in G1 (32.9 months).
Conclusion: Although LPD has been considered benign, this case shows a significant lag between initial diagnosis and malignancy development. LPD is potentially malignant with a long latency period before transformation. Lifelong surveillance should be considered even for cases presumed benign. Our results suggest that loss of hormone receptor expression may indicate malignant transformation. Circulating tumor DNA (ctDNA) levels could be associated with hematogenous metastases and serve as a novel biomarker.

Leiomyomatosis Peritonealis Disseminata (LPD): A Potentially Malignant Disease Requiring Long Term Follow-Up, Comprehensive Literature Review and Case Report of Transformation Into Malignancy

Background
Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening thrombotic disorder. Therapeutic plasma exchange (TPE) remains the mainstay treatment, with thawed plasma (TP) being the primary product used. Liquid plasma (LP), derived from whole blood donations and stored at 4°C, shares the same expiration as the corresponding unit of whole blood and primarily serves as a bridge to TP for emergency transfusions. While the efficacy of coagulation profiles in TP and LP is well-documented, there is limited information on the stability
of ADAMTS13 activity during the shelf life of these products and the experience of LP utilization in iTTP management.
Methods
Ten units of LP from distinct whole blood donations were collected on day 27. Ten units of TP from products frozen within 24 hours (PF24) were collected on day 6. Two units of LP within 5 days of collection underwent longitudinal sampling until day 30, with the initial collection designated as day 0. ADAMTS13 activity was assessed using fluorescence resonance energy transfer (FRETS) and ELISA-based assays. A retrospective study was performed to identify the use of LP in TPE for iTTP patients in our institute from June 15, 2019, to January 1, 2023.
Results
The average level of ADAMTS13 activity in 10 LP units was 0.97±0.14 IU/mL by FRETS assay, with a median of 0.967 IU/mL (range: 0.79-1.22 IU/mL). For 10 TP units, the average level of ADAMTS13 activity was 0.89±0.13 IU/mL with a median of 0.91 IU/mL (range: 0.63-1.05 IU/mL). No statistically significant difference was observed between the two products regarding ADAMTS13 activity on day 1 post-expiration (P=0.1717). ADAMTS13 activity in LP consistently remained stable over the 30-day observation period. ELISA results were consistent with FRETS assay findings. The retrospective analysis showed that seven iTTP patients with nine acute
episodes received a total of 93 TPE sessions, of which, 25 (26.9%) included LP. The amount of LP was 23.7±19.7% of total plasma units. The median number of TPE sessions per episode was 10, which was comparable to that in the literature. All patients achieved complete remission, and no adverse events associated with the use of LP were observed.
Conclusion
Both liquid plasma and thawed plasma exhibit comparable and sustained ADAMTS13 activity throughout their shelf-life. A successful utilization of LP during TPE in a small cohort of iTTP patients suggests that LP may be a potential alternative to TP in the management of iTTP.

Liquid Plasma: A Potential Product in Managing Immune Thrombotic Thrombocytopenic Purpura

Background
The obesity paradox has been shown in many cancers, with improved overall survival in higher BMI groups. Lower incidence, better prognosis, and improved treatment response of lung cancer have been associated with increased BMI. However, these differences have varied based on age, gender, and race. This variability can be explained by the heterogeneity of fat deposition across gender and race, which is poorly captured by BMI. Other measures of central adiposity better portray the effects of obesity on lung cancer risk and prognosis. We report the results of another measure of central adiposity, liver fat, on survival and treatment tolerance in NSCLC.
Methods:
This retrospective cohort study enrolled 106 patients with stage IIIA-IIIC NSCLC treated to 60 Gy at Fox Chase Cancer Center. Liver fat percentage was assessed via CT in Hounsfield units (HU). Patients were separated into two groups, high HU and low HU, correlating to low and high liver fat percentages, respectively. The primary objective assessed mortality while secondary objectives assessed treatment response, disease progression, and acute/chronic treatment toxicities.
Results
Initial staging was the only categorical variable with significant difference in HU groups. BMI and primary tumor size varied significantly between groups. Overall survival (OS) and progression-free survival (PFS) appeared to be better in the higher HU group, but not statistically significant. No significant difference in acute or chronic treatment-related adverse events between HU groups.
Conclusion
Liver fat percentage has the potential to be used as a proxy for central adiposity to risk stratify NSCLC patients. Excess adiposity may provide an energy reserve to endure biological stress from disease progression and treatment, leading to a survival advantage. This study showed no statistical significance in OS or PFS between HU groups. One limitation is the small sample size leading to reduced statistical power and difficulty in detecting subgroup effects. Future studies should focus on involving large and diverse cohorts, considering confounding factors like BMI, smoking history, and tumor characteristics. If statistical significance can be measured, liver fat may have the potential to be used as a prognostic marker for outcomes to stratify patients into different risk categories, guiding treatment decisions and improving personalized medicine approaches.

Liver Adiposity as a Predictor of Mortality in NSCLC Patients

Background: Osteosarcoma, a highly aggressive pediatric cancer originating from aberrant bone cells, presents with symptoms like local pain and swelling, often leading to delayed diagnosis with imaging and biopsy. Chemotherapy and resection boosts prognosis, but metastatic cases, often lung-affected, have a poor 20% survival rate. Despite advancements, osteosarcoma remains prevalent, with 4.4 million cases annually and a 60% survival rate; early detection is paramount. CAR-T cell therapy is a cutting-edge personalized immunotherapy where genetically engineered patient T-cells, expanded ex vivo, recognize and target tumor cells. They show promise in treating malignancies by targeting the tumor microenvironment. However, their effectiveness against solid tumors is uncertain due to challenges in marker specificity and expression. High specificity against tumor-expressed markers is essential for solid tumor treatment to avoid off-target effects and maximize efficacy.

Methods: An online search in the PubMed database was conducted from 2019 to 2024 using the following keywords: "osteosarcoma", " CAR-T cell therapy", and " Chimeric Antigen Receptor T-cell”.

Results: Orthotopic implantation models demonstrated superior representation of osteosarcoma biology and metastasis compared to traditional models. Utilizing this model, targeting markers like ALP, B7-H3, CD166, and GD2, showed significant tumor suppression and improved survival rates.

Targeting ALP, two CAR-T constructs targeting OSCAR-1 and OSCAR-3 efficiently controlled peritoneal and lung metastases, significantly prolonging animal survival. Further, targeting the B7-H3 surface marker with CAR-T cells resulted in significantly smaller tumors, indicating its potential therapeutic benefit. Flow cytometric analysis revealed preferentially higher expression of B7-H3 in osteosarcoma cells, validating its suitability as a CAR-T target. CD166 CAR-T therapy efficiently targeted osteosarcoma cells, correlating with tumor CD166 expression. In mice, it effectively regressed tumors without acute toxicity. Additionally, a clinical trial evaluating GD2-CAR-T cell therapy highlighted the correlation between monocytes expressing CXCR3 and poor tumor eradication, suggesting the importance of immune cell dynamics in CAR-T therapy outcomes. In addressing CAR-T therapy drawbacks, an alternative approach employing IL12-modified mononuclear cells demonstrated efficacy against osteosarcoma with reduced toxicity and constrained tumor growth, serving as a promising alternate.

Conclusion: CAR-T cell therapy has shown limited success in treating blood cancers, but its effectiveness in solid tumors has been less promising, possibly due to lower surface expression levels of antigens on cancer cells. Skepticism exists about its superiority over alternative treatments like mononuclear cell therapy. However, CAR-T cell therapy has made strides in personalized treatment for osteosarcoma and holds potential as adjunct therapy for metastases, although its long-term efficacy remains uncertain.

Modern Treatments for Bone Cancer: The role of CAR-T cell Therapy in Aggressive Osteosarcoma

Background: Hematopoietic stem cell transplantation (HSCT) can significantly disrupt gut 
microbiota, increasing susceptibility to Enterococcus infections. These infections pose a high 
mortality risk, with rates between 18% on day 7 and 31% by day 30 post-transplant. This study 
investigates the mortality in HSCT recipients admitted for Enterococcus bloodstream infections 
(EBSI).
Methods: We conducted a cross-sectional study utilizing the 2018-2021 National Inpatient 
Sample database, focusing on adult HSCT recipients (≥18 years) primarily hospitalized for EBSI 
(n=471). Our analysis included descriptive statistics, propensity score matching (based on age, 
gender, race, and comorbidities), and multivariate regression to adjust for confounding 
variables. The results were expressed as adjusted Odds Ratios (aOR) with significance at 
p≤0.05.
Results: Among 198,045 transplant patients, 20.4% (n=40,462) had undergone HSCT, with 
1.3% (n=531) being admitted due to EBSI. Among HSCT recipients, EBSI was seen in 1.4% of 
HSCT-Leukemia cohort and 2.4% of HSCT-AML cohort. In all HSCT recipients, the 
Enterococcus cohort had 38.98% of patients with urinary tract infection and 0.56% had 
peritoneal abscesses. In HSCT recipients with EBSI, patients with pancytopenia revealed higher 
mortality than survival (63.64% vs 44.33%, p<0.01). Crude analysis suggested higher all-cause 
mortality in the Enterococcus cohort compared to non-Enterococcus cohort (10.4% vs 4.6%, 
p<0.001). However, after adjusting for confounders, the mortality risk in the Enterococcus cohort 
was found to be lower (aOR 0.09, 95% CI 0.03-0.3, p<0.001). Key factors associated with 
increased mortality (p≤0.05) included the need for invasive ventilation (aOR=9.7), acute 
respiratory failure (aOR=4.3), fungal infections (aOR=4.2), severe sepsis (aOR=3.0), and 
acidosis (aOR=2.9). Additionally, palliative care was needed more in the Enterococcus cohort 
compared to the non-Enterococcus cohort (11.1% vs. 6.9%, p<0.001).
Conclusion: Enterococcus infections in HSCT recipients have a high mortality rate, but their 
mortality risk is low. This indicates that Enterococcus infection is a sign of clinical deterioration 
but is not a direct cause of mortality. When encountering patients with signs of bone marrow 
failure and severe sepsis, along with symptoms of respiratory failure and urinary tract infection, 
aggressive treatment and multidisciplinary care are required, as Enterococcus infection is a 
marker of poor prognosis.
Keywords: Hematopoietic stem cell transplant, Enterococcus infection, Mortality, Sepsis, HSCT, Transplant

Mortality Risk Factors Associated with Enterococcus Infection in Hematopoietic Stem Cell Transplant (HSCT) Recipients.

Introduction 
Databases such as the National Cancer Database (NCDB) are important for analyzing care provisions and clinical outcomes. However, missing data limits the scope and skews the accuracy of analyses. It may be correlated with the quality of care at the institution. This study aims to assess the prevalence of and characteristics of missing data in the NCDB for gallbladder, biliary, and hepatic cancers.

Methods 
This retrospective cohort study reviewed 12 key variables within the NCDB for missing values for patients diagnosed with a hepatic, biliary, or gallbladder cancers from 2010 to 2019. Key variables included demographic (age, race, ethnicity, insurance, education, income, comorbidities), tumor (grade, TNM stages), and treatment characteristics (surgery, chemotherapy, radiation therapy). The percentage of patients with complete and missing number of key variables was analyzed. Characteristics of the missing data including the distribution of missing data by cancer stage, percentage of patients with missing data by year, and the percentage of patients missing per number of studied variables was calculated. 

Results 
A total of 308,354 patients (mean [SD] age, 66.3 [11.5] years; 197,876 [64.2%] male) in the NCDB were identified; 13.1% were missing at least 1 key variable. Missing data was similarly prevalent amongst the cancers (12.2% in gallbladder, 13.25% in liver, and 13.26% in biliary cancers). Demographic data was most likely to be missing in biliary cancers (13.2%) and tumor data was most likely to be missing in liver cancers (0.12%), though very little tumor data was missing. Of those missing data, most patients were missing seven key variables. Gallbladder and biliary cancers are most likely to be missing stage 4 data, while liver cancers are more likely to be missing stage 1 cancer. The percentage of patients with missing data has increased from 2010-2019.

Conclusion 
Missing data of select variables in the NCDB prevalent and the percentage of missing key variables is similar across hepatic, biliary, and gallbladder cancers. Understanding that the patients missing data are not random impacts the generalizability of NCDB analysis.

Prevalence and Characteristics of Missing Variables in the National Cancer Database for Hepato-Biliary-Gallbladder Cancers

Background
Viral infections, including SARS-CoV2/COVID-19, have been associated with high incidence of DVT. There is evidence that patients infected during the first wave of COVID-19, and especially those with pre-existing cardiovascular disease (CVD), have increased immediate risk of thrombosis and mortality. However, the short- and long- term incidence and risk of thrombosis, in patients with SARS-CoV2/COVID-19 with CVD in the era of vaccine availability is less clear. The purpose of this study is to evaluate the rate of venous and arterial thrombotic events and mortality at 1 month after COVID-19 diagnosis in patients with and without CVD.
Methods
This is a retrospective analysis from 9/12/2021 to 10/12/2022, during the Delta and Omicron variant eras, of patients over 18 years old with and without preexisting CVD and a positive COVID-19 diagnosis at our university hospital. Patient data including sex, age, BMI, comorbidities, lab tests, imaging, and procedures were reviewed at time of COVID diagnosis and at the 1-month timepoint following COVID-19 diagnosis. Pearson’s chi square tests were performed to calculate the statistical significance of the relation between pre-existing CVD and thrombotic outcomes of interest within 1 month of COVID-19 diagnosis.
Results
This interim analysis includes 16,228 patients who were diagnosed with COVID-19 over a 1- year time period with a mean age of 31 ± 23 years. Of these, 2,938 had pre-existing CVD with advanced age compared to patients without CVD (CVD 59 ± 18 years vs 25 ± 19 years). There is a significant relationship between pre-existing CVD and the development of venous thrombosis; venous thromboembolism (p < .00001), deep venous thrombosis (p = .0001), and pulmonary embolism (p = .0001). There was also a significant relationship between CVD and the development of arterial thrombosis; stroke (p = .00002) and myocardial infarction (p < .00001). Lastly there was a significant relationship with mortality (p < .00001).
Conclusion
Our preliminary data show that patients with CVD may have increased rates of thromboembolic events in the month following COVID-19 infections occurring after the availability of vaccines. Further multivariate analysis may be helpful to evaluate the combined effect of multiple factors including age, gender, and smoking on thrombotic risk. Additional studies investigating the persistence of the increased risk of thrombotic events after viral infections such as COVID-19 may help guide preventative or prophylactic strategies and duration for patients with CVD.

Rates of thrombotic events in patients with cardiovascular disease following COVID-19 delta variant in the era of vaccine availability

The Impact of Cancer on one year mortality in multimorbid geriatric patients with palliative consultation

Authors: Ellie Soheili, Hussain Dalal, Nadeem Hussain, Michael J. Mader, Hanh Trinh, Aneela Hussain, Sandra Sanchez-Reilly, Marcos I. Restrepo

Affiliation: University of Texas Health San Antonio and South Texas Veterans Health care system

Background 
In older adults, malignancy and other comorbidities can pose substantial challenges to treatment and complicate clinical outcomes. Palliative care is one solution to address the challenges of treating multimorbid older adults. Currently, there are limited studies comparing mortality rates among multimorbid patients receiving palliative care that focus on the independent impact of malignancy on mortality. We aimed to assess the effect of cancer on one-year mortality among multimorbid older adults. 
Methodology 
We conducted a cohort study with outpatient geriatric veterans at the South Texas Veterans Health System. The inclusion criteria encompassed older adults > 65 with complex medical comorbidities (Charleson comorbidity index (CCI) > 1) irrespective of cancer for a period of 5 years prior to the initial palliative consultation. The primary objective as to compare the one-year mortality among the two groups. We adjusted for comorbidities including congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus, dementia, renal and hepatic diseases.
Results 
We selected 1,449 outpatient geriatric veterans with comorbidities. Among these, 425 veterans (29.3%) had concurrent cancer and complex medical conditions (CCI > 1) while 1,024 geriatric patients (70.7%) had only complex medical conditions. The median CCI among the veteran with comorbidities and cancer was 6 as compare to CCI of 3 among veterans without cancer. Patients with cancer had a higher 1-year mortality 55.3% (n=235) as compared to 44% (n=450) patients without cancer (aOR 1.97, 95% CI). 
Conclusion   
Our analysis showed that cancer, combined with high comorbidity, led to a higher one-year mortality rate in older adults receiving palliative care, while those receiving palliative care with high comorbidity alone had a lower one-year mortality rate. After adjusting for comorbidities, cancer independently doubled the odds ratio of 1 year mortality, emphasizing the need for earlier interventions and palliative care in this population.



The Impact of Cancer on one year mortality in multimorbid geriatric patients with palliative consultation

Background: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML), significantly improving patient outcomes, particularly in the chronic phase (CML-CP). First-generation TKI imatinib and second-generation TKIs such as dasatinib and nilotinib have proven highly effective, achieving deep molecular responses like major molecular response (MMR). However, resistance or intolerance to TKIs results in treatment failure in 20%–25% of cases, despite an initial good response.
Methods: This clinical study involved ten CML patients, aged between 38 and 83 years, including 6 males and 4 females, receiving TKI therapy at our clinic. Patients were treated with imatinib, dasatinib, or nilotinib, depending on insurance approval. BCR-ABL levels were monitored through regular PCR tests, with relapse defined as a 10-log increase from a previous level. Potential causes of relapse, including non-compliance, side effects, and resistance development, were identified through medical records, patient interviews, and consultations.
Results: The study analyzed the causes of relapse in ten CML patients treated with TKIs:
Patient 1: Noncompliance and developed resistance to dasatinib, so was switched to imatinib, eventually achieving remission.
Patient 2: Switched from dasatinib to nilotinib for pleural effusion, achieving undetectable BCR-ABL levels.
Patient 3: Stable on imatinib with steady BCR-ABL levels.
Patient 4: Switched from dasatinib to nilotinib due to heavy vaginal bleeding.
Patient 5: Reached negative BCR-ABL on nilotinib, then switched to dasatinib due to GI side effects.
Patient 6: Responded well, BCR-ABL undetectable on Scemblix.
Patient 7: Non-compliance due to side effects of vomiting and nausea led to erratic BCR-ABL levels, switched from nilotinib to dasatinib, eventually achieving remission.
Patient 8: Non-compliance on imatinib due to insurance problems. Stable after switching from imatinib to nilotinib due to progression.
Patient 9: Non-compliant, fluctuating BCR-ABL levels.
Patient 10: Positive response to nilotinib, with significant reduction in BCR-ABL levels.
Conclusion: CML is a highly treatable hematological cancer with the use of TKIs. We employ highly sensitive PCR tests to detect even the slightest molecular relapse. Our study revealed that 7 out of 10 patients experienced a molecular relapse at some point during their treatment. The primary cause of relapse was non-compliance, followed by side effects, and, although rare, resistance to TKIs. Therefore, patient education and effective communication during consultations are crucial components of treatment.


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