Tyrosine Kinase Inhibitors Dose Reduction Research Articles

Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

Real-World Evidence of Treatment-Free Remission in Chronic Myeloid Leukemia at an Academic Center in the Deep South

Background: Treatment-free remission (TFR) is increasingly becoming a treatment goal for patients with chronic myeloid leukemia (CML) in chronic phase (CP). Although strict criteria guide tyrosine kinase inhibitor (TKI) discontinuation, there exists a knowledge gap in understanding patient and provider experience regarding TFR in real-world clinical practice. Here, we report our TFR experience in patients with CML-CP, treated at an academic center in the Deep South. Methods: A retrospective chart review was performed to evaluate outcomes of patients with CML-CP at the University of Alabama at Birmingham. The NCCN Version 2.2023 criteria for TKI discontinuation was utilized. Institutional review board approval was obtained. Results: We identified 204 patients with CML-CP through electronic medical records (EMR) . The median follow-up for the entire population was 95m (range 2-246m). The median age was 54y (range 21-75y) and majority of the patients were females (62%) and non-Hispanic whites (NHWs) (70%). A diagnostic bone marrow biopsy was performed on 59% of the patients. Most of the patients had p210 breakpoint (93%). Frontline therapy mainly consisted of imatinib (42%), dasatinib (32%) and nilotinib (16%). Out of the 204 patients, 44 (22%) met all the criteria for TKI discontinuation (Table 1). The median age for these patients was 53y (range 20-75y) and majority of the patients were females (68%) and NHWs (68%). Frontline therapy consisted of imatinib (59%), dasatinib (23%) and nilotinib (18%). Out of the 44 patients eligible for TFR attempt, 35 (80%) were offered TKI discontinuation by their provider whereas 9 (20%) were not. Reasons for not offering TKI discontinuation were not documented in the EMR. Twenty-four out of 35 patients attempted TKI discontinuation. The median time to TKI discontinuation for these patients was 114m (range 45-246m). Frontline therapy consisted of imatinib (n=13), dasatinib (n=7) and nilotinib (n=4) for those that attempted TFR. Ten patients had to resume TKI (imatinib=5, dasatinib=1, nilotinib=4) due to an increasing transcript after a median of 8m (range 2-29m). The remaining 14 patients (58%) remain in TFR to date with a median follow-up of 29m (6-51m). Eleven patients, eligible for TKI discontinuation, were offered a trial of TFR but did not attempt it. Three patients were satisfied with ongoing therapy and did not want to attempt TKI discontinuation or dose-reduction. Eight patients were hesitant to discontinue therapy and agreed to reduce the dose of the current therapy after discussing with their provider. Seven of those eight patients remain on a reduced TKI dose and 1 had to increase the dose due to an increase in transcript. Conclusion: In our single-center experience, we report that although most of the patients eligible for TKI discontinuation were offered a TFR attempt by their provider, there remains room for improvement. More than half the patients that attempted TKI discontinuation remain off therapy. Patient preference was the main reason for not attempting TKI discontinuation but there was willingness to attempt dose-reduction. Further studies are needed to understand both patient and provider perspectives regarding TFR to identify opportunities for improvement.

Tyrosine Kinase Inhibitor Withdrawal Syndrome in Chronic Myeloid Leukemia Patients Participants of Two Discontinuation Clinical Trials

Discontinuation of tyrosine kinase inhibitors (TKI) is currently one of the main goals in CML treatment. One of the known adverse events after TKI discontinuation is withdrawal syndrome (WS), which can occur in about 30% of patients (pts), characterized by musculoskeletal pain that begins or worsens weeks after interruption and may be more severe in some cases, but rarely leading to the need for TKI reintroduction. Some studies suggest TKI dose reduction or optimization before stopping treatment may reduce WS rates. Aims: To estimate the incidence of WS after TKI discontinuation in CML in two clinical trials and to correlate the incidence of these events with patients' characteristics and molecular relapse-free survival (MRFS). Methods: We analyzed two cohorts of CML patients of two prospective, single-arm, phase II clinical trials: EDI-PIO (Clinicaltrials.gov: NCT02852486) and DES-CML (ReBEC UTN code : U1111-1252-7312). In both trials, inclusion criteria were CML in the chronic phase, treated with TKI for at least three years, and with deep molecular response (MR4.5) for two years. In the first trial, TKI was discontinued after using three months of pioglitazone, and in the DES-CML trial, after reducing the dose of the TKI by 50% for six months before discontinuation. TKI was reintroduced if the patient lost MR4.0 (EDI-PIO trial) or major molecular response (MMR) (DES-CML trial). Adverse events related to WS were evaluated until the fourth month after discontinuation. WS was defined as the onset of new musculoskeletal pain and/or an increase in pre-existing pain and/or the need to start any pain medication. The adverse event classification followed the Common Terminology Criteria (CTCAE- Version 4.0), musculoskeletal and connective tissue disorder. The data were collected and stored using the REDcap Platform (by Vanderbilt). MRFS was defined by discontinuation date until the last seen date or loss of MR4.0/MMR. The Kaplan-Meier method was applied for OS, whereas Log-Rank tests were applied to compare its curves. All statistical analysis were done by IBM-SPSS v. 24 and considered significant p-value < 5%. Results: Between September 2016 and April 2023, we analyzed 63 patients, 32 from the DES-CML study and 31 from the EDI-PIO trial. The median age at discontinuation was 58 years (24-79), 59% male, 52% Sokal low-risk, 35% intermediate, and 13% high; at discontinuation, 94% of the patients were using Imatinib, 3% Dasatinib, 1.5% Bosutinib and 1.5% Nilotinib. The median duration of TKI treatment until discontinuation was 10 years (3-20). Withdrawal syndrome occurred in 41% of cases and was more frequent in females (58% vs. 42%, P=0.02). Fourteen pts from the EDI-PIO study (45%) and 12 (37.5%) from DES-CML developed WS (P=0.61). According to CTCAE, the events were classified as grade 1, 36%, and 33%, while grade 2 was 57% and 58%; and grade 3 was 7% and 8% (P=0.90), respectively, in EDI-PIO and DES-CML trials. Symptoms started at month 1 in 20% of the patients and 73% in months 2 and 3. Seventeen (30%) pts used anti-inflammatory drugs, analgesics, steroids, or muscle relaxants (64% EDI-PIO vs. 66% DES-CML, P=0.90). There was no need to reintroduce TKI for treating WS. Molecular relapse free-survival (MRFS) at 12 months was 72% (95% CI 60-84%), with no difference by protocol (75% DES-CML, 70% EDI-PIO). MRFS at 12 months was 73% and 74% in the group with or without WS, respectively (P=NS). Conclusions: The incidence and severity of WS were similar in the two trials, corroborating data from the literature. WS was more frequent in females. The dose reduction did not reduce WS rates. However, this condition was self-limited and managed with drugs, without reintroducing TKI. There was no difference in MRFS between the groups with or without WS.

Management and Risk Factors for Pleural Effusion in Japanese Patients with Chronic Myeloid Leukemia Treated with First-line Dasatinib in Real-world Clinical Practice.

Objective Pleural effusion (PE) is a common adverse event that occurs during dasatinib therapy for chronic myeloid leukemia (CML). However, the pathomechanism of PE and appropriate management of Asian patients with CML have not been elucidated. This study investigated the incidence rate, risk, and appropriate management of PE in Asian patients with CML treated with dasatinib. Methods We retrospectively collected data on patients in the chronic phase of CML who received first-line dasatinib therapy and were registered in the CML-Cooperative Study Group database. Patients We identified 44 cases of PE in a series of 89 patients and analyzed previously reported risk factors and effective management of PE. Results A univariate analysis revealed that age, diabetes mellitus, chronic renal failure, hypertension, the history of cardiovascular events, and dasatinib dose were significantly associated with PE. A multivariate analysis revealed that age ≥65 years old was the only independent risk factor for PE. Dasatinib dose reduction and switching to a tyrosine kinase inhibitor showed a statistically significant difference in effectively reducing PE volume compared to single diuretic use. Conclusion Although further studies are warranted, our observations showed that advanced age is a significant risk factor for PE, and tyrosine kinase inhibitor dose reduction or replacement of dasatinib may be an effective management strategy for PE in Asian CML patients who received first-line treatment with dasatinib in real-world clinical practice.

Management of chronic myelogenous leukemia with COVID-19 and hepatitis B.

The application of immunosuppressive agents and targeted drugs has opened a novel approach for the treatment of hematological tumors, and the application of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia is one of the landmark breakthroughs that has considerably improved the prognosis of CML patients. However, with the extensive use of TKI, the co-infection of CML patients has become increasingly apparent, especially regarding infectious diseases such as hepatitis B and COVID-19. The underlying mechanism may be related to the inhibition of the immune function by TKI. Poor management, including disease progression due to the infectious disease or TKI dose reduction or discontinuation, may lead to adverse clinical outcomes and can even be life-threatening. Therefore, this review principally provides an overview of the pathogenesis and standardized management principles of CML patients with comorbid COVID-19 or hepatitis B in order to improve clinicians' awareness of the risks so as to more effectively diagnose and treat CML and improve the survival rate and quality of life of patients. In the past two decades, owing to the advent of imatinib, chronic myeloid leukemia (CML) has transformed into a chronic controllable disease, and even treatment-free remission can be anticipated. Earlier studies have indicated that tyrosine kinase inhibitor (TKI) exerts a peculiar inhibitory effect on the body's immune function. Therefore, with the widespread application of TKI, more and more attention has been paid to the comorbidity of infectious diseases in CML patients, especially in patients with progressive disease or non-remission. Despite some studies revealing that the proportion and severity of SARS-CoV-2 infection in CML patients receiving TKI treatment are lower than in patients with other hematological malignancies, CML patients with stable disease are still recommended to be vaccinated against SARS-CoV-2, while TKI may or may not be discontinued. Meanwhile, the management of CML patients during the epidemic of coronavirus disease 2019 (COVID-19) still necessitates further discussion. This article also provides an overview of TKI-related hepatitis B reactivation. If not managed, patients may face adverse consequences such as hepatitis B reactivation-related hepatitis, liver failure, and progression of CML after forced withdrawal of medication. Therefore, this review aimed to comprehensively describe the management of CML patients with comorbid COVID-19, the pathogenesis of hepatitis B reactivation, the indicated population for prophylactic antiviral therapy, the time of antiviral drug discontinuation, and drug selection.

Quality-of-life, mental health, and perspective on TKI dose reduction as a prelude to discontinuation in chronic phase chronic myeloid leukemia.

Treatment-free remission (TFR) has become the main target for chronic myeloid leukemia (CML). Tyrosine kinase inhibitors (TKI) dose optimization is crucial in managing adverse events, and improving adherence in clinical practice. In persons achieving a deep molecular response (DMR), some data suggest TKI dose reduction before discontinuation does not change success rate of achieving TFR, but this is controversial. However, data on quality-of-life (QoL) and mental health in CML patients with full-dose TKI, low-dose TKI, and TKI discontinuation are limited. Moreover, recent evidence indicating the feasibility of TKI dose reduction and discontinuation after dose reduction, which may change CML patients' perspectives on TKI discontinuation. We conducted a cross-sectional study using online questionnaires to explore the QoL, mental health in patients with diverse TKI dose, and perspective on TKI dose reduction as a prelude to discontinuation. 1450 responses were included in the analysis. 44.3% of respondents reported a moderate-to-severe impact of TKI treatment on their QoL. 17% of respondents had moderate-to-severe anxiety. 24.4% of respondents had moderate-to-severe depression. In 1326 patients who had not discontinued their medication, 1055 (79.6%) patients reported they would try TKI discontinuation because of concerns over side effects of long-term medication (67.9%), financial burden (68.7%), poor QoL (77.9%), pregnancy needs (11.6%), anxiety and depression while taking TKI (20.8%), inconvenience of TKI treatment (22.2%). 613 of 817 (75.0%) patients on full-dose TKI therapy indicated they preferred trying a dose reduction before discontinuing TKI therapy after dose reduction compared with 31 (3.8%) preferring no dose reduction before stopping. TKI dose reduction showed a significant improvement of patients' QoL and mental health, comparable to the effect of TKI discontinuation. Most patients indicated they preferred dose reduction before stopping TKI therapy. In clinical practice, TKI dose reduction can be considered as a bridge from full-dose treatment to discontinuation. Our results showed that tyrosine kinase inhibitors (TKI) dose reduction showed a significant improvement of patients' quality-of-life and mental health, comparable to the effect of TKI discontinuation. Most patients desire to discontinue TKI in the future. TKI discontinuation after dose reduction is more acceptable compared to discontinuing it directly. In clinical practice, TKI dose reduction can be considered as a bridge from full-dose treatment to discontinuation. Please do not hesitate to contact me in case further clarification is needed with this submission.

Effect on outcomes of toxicity-related dose reduction in TKI monotherapy or TKI-IO combination therapy for advanced renal cell carcinoma.

4528 Background: Tyrosine kinase inhibitors (TKI) in monotherapy or TKI in combination with immunotherapeutic agents (IO) are standard of care fist-line treatment for advanced or metastatic renal cell carcinoma (RCC). Dose reduction due to toxicity is extremely frequently and represents an important clinical management issue, with frequent dose reduction, treatment suspension and change of schedule. We examined the outcomes of patient treated with TKI in monotherapy and in combination with immunotherapy (TKI-IO). Methods: We performed a retrospective analysis of clinical outcomes in patients with RCC treated with TKI (cohort 1) or TKI-IO (cohort 2) in Italian and Spanish institutions. A descriptive analysis was performed. Univariate logistic regression models were carried out to estimate the association between best response (CR or PR vs SD or PD) and type of TKI (monotherapy or combination therapy). Survival curves were estimated using the Kaplan-Meier method and were compared by the log-rank test. Cox proportional-hazard models were used to obtain hazard ratios (HRs) with 95%. Median follow-up was calculated using the reverse Kaplan-Meier method. Results: A total of 401 patients were divided in cohort 1 (329 patients) and cohort 2 (72 patients). Median Follow-up was 81.22 months in cohort 1 and 19.02 months in cohort 2. Most frequent toxicities that lead to dose reduction were mucositis (20.13%), Asthenia (16.88%) and Hand-foot syndrome (15.58%). Overall Response Rate was higher in patients that reduced dose, both in cohort 1 (48% vs 29%, p<0.01) and cohort 2 (81% vs 40%, p<0.01). In cohort 1 Progression Free Survival (PFS) was longer in patients with dose reduction (27.14 months vs 16.59 months) (HR 0.77 [0.6; 0.98]; p=0.04). Overall Survival (OS) was also improved (55 months vs 34.17) (HR 0.71 [0.53; 0.93]; p=0.01). In cohort 2, both PFS (39.13 months vs 41.3 months) (HR 0.63 [0.27; 1.48]; p=0.29) and OS (39.13 months vs 55.85 months) (HR 0.65 [0.26; 1.63]; p=0.29) did not statistically differ between patients that reduced dose and patients that did not reduce dose. Conclusions: TKI dose reduction due to toxicity seems to be related to improved outcomes, both in ORR and PFS/OS. ORR was statistically improved in both cohort 1 and cohort 2. PFS and OS in cohort 1 favoured patients that experienced dose reduction. PFS and OS in cohort 2 did not show a statistically significant difference, probably due to the short follow-up and small number of patients. However, outcomes seem to show a trend toward favouring patients that reduce dose.

Successful treatment discontinuation in CML patients with full-dose and low-dose TKI: Results from real-world practice.

Background: In clinical studies, some patients who achieve deep molecular response (DMR) can successfully discontinue tyrosine kinase inhibitor (TKI). TKI dose reduction is also an important aspect of alleviating adverse effects and improving quality of life. This study aimed to explore the outcome after drug withdrawal in Chinese CML patients. Methods: We conducted a retrospective analysis of the outcome of 190 patients who stopped TKI. 27 patients experienced dose reduction before TKI discontinuation. The median duration of TKI treatment and MR4 before discontinuation was 82months and 61months. Results: With median follow-up after stopping TKI treatment of 17months, the estimated TFR (Treatment Free Remission) were 76.9% (95%CI, 70.2%-82.4%), 68.8% (95%CI, 61.3%-75.2%), and 65.5% (95%CI, 57.4%-72.5%) at 6, 12 and 24months. For full-dose and low-dose TKI groups, the TFR at 24months was 66.7% and 55.8% (p = 0.320, log-rank). Most patients (56/57) quickly achieved MMR after restarting TKI treatment. Multivariable analysis showed that patients with TKI resistance had a higher risk of molecular relapse than patients without TKI resistance (p < 0.001). Conclusion: TFR rates were not impaired in patients experiencing dose reduction before TKI discontinuation compared to patients with full-dose TKI. Our data on Chinese population may provide a basis for the safety and feasibility of TKI discontinuation, including discontinuation after dose reduction, in clinical practice.

Modelling of immune response in chronic myeloid leukemia patients suggests potential for treatment reduction prior to cessation.

Discontinuation of tyrosine kinase inhibitor (TKI) treatment is emerging as the main therapy goal for Chronic Myeloid Leukemia (CML) patients. The DESTINY trial showed that TKI dose reduction prior to cessation can lead to an increased number of patients achieving sustained treatment free remission (TFR). However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials. Here, we apply an established mathematical model of CML therapy to investigate different TKI dose reduction schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success. Our systematic analysis confirms clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while highlighting that lower dose TKI treatment for the same duration is equally sufficient for many patients. Our results further suggest that a stepwise dose reduction prior to TKI cessation can increase the success rate of TFR, while substantially reducing the amount of administered TKI. Our findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically testable strategies that are applicable to many CML patients.

Challenges of Maintenance Tyrosine Kinase Inhibitor Therapy after Allogeneic Hematopoietic Cell Transplantation in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Background: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) relapse after allogeneic hematopoietic cell transplantation (HCT) is difficult to manage. One strategy to prevent this is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but the vast majority of data discusses the use of imatinib in this setting, with few reports on newer generation TKIs (NG-TKI). Here, we present our institutional experience with TKI maintenance post-HCT. Methods: Ph+ ALL patients who underwent HCT and received TKI maintenance anytime post-HCT from 2003-2019 were included through retrospective chart review. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), and cumulative incidence of non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and graft-vs-host disease (GVHD). OS and PFS were calculated via the Kaplan Meier method, NRM, CIR, and GVHD were calculated through a competing risk analysis, where CIR was used as a competing risk for NRM and GVHD, and NRM for CIR and GVHD. Results: 110 patients were included, and their baseline characteristics are described in Table 1. 45 (40.9%) patients received imatinib initially, and 65 (59.1%) received NG-TKI initially, of whom, 59 (90.8%) received dasatinib, 4 (6.2%) received nilotinib, and 2 (3.1%) received ponatinib. The median age (range) of the initial imatinib and NG-TKI groups were 42 years (19-64) and 47 (21-73), respectively. 25 (55.6%) vs 43 (66.2%) in the initial imatinib vs NG-TKI groups were >40 years, respectively. 18 (40.0%) vs 39 (60.0%) of the patients receiving initial imatinib vs NG-TKI were female (P=0.052). 20 (44.4%) vs 54 (83.1%) patients in the imatinib vs NG-TKI group underwent HCT ≥2010, respectively (P<0.001). 41 (91.1%) vs 57 (87.7%) in the imatinib vs NG-TKI groups underwent HCT in first complete remission (CR1) (P=0.76), and 21 (46.7%) vs 31 (47.7%) had no measurable residual disease (MRD) detected by PCR at the time of HCT, although 10 (22.2%) vs 10 (15.4%) did not have a PCR report at the time of HCT available (P=0.66). 42 patients (38.2%) required a dose reduction due to toxicity, and 67 patients (60.9%) experienced TKI interruption due to toxicity. Initial imatinib vs NG-TKI maintenance was discontinued in 20 (46.5%) vs 29 (44.6%) due to toxicity, respectively. The median cumulative initial TKI exposure in patients initially receiving imatinib and NG-TKI was 354 days (range, 6-4,473) and 301 days (range, 5-2,740), respectively. Reasons for TKI discontinuation are listed in Table 2. There was no difference in 5-year OS and PFS in patients receiving imatinib vs NG-TKI, 84.1% vs 69.8% (P=0.47) and 75.1% vs 62.5% (P=0.48), respectively. Likewise, 5-year NRM, 5-year relapse, and 4-year GVHD were similar between imatinib vs NG-TKI, 9.0% vs 18.3% (P=0.48), 15.9% vs 19.2% (P=0.92), and 40.7% vs 47.7% (P=0.47), respectively. Univariate analyses showed an improvement in OS and PFS in those who received ≥12 months of TKI maintenance vs those who received <12 months, hazard ratio (HR) 0.26 (95% confidence interval (CI), 0.12-0.55), P<0.001 and HR 0.33 (95% CI, 0.17-0.64), P<0.001. There was no difference in OS and PFS for those who completed ≥12 months of TKI maintenance based on initial TKI of choice, HR 0.85 (95% CI, 0.21-3.51), P=0.8 and HR 0.91 (95% CI, 0.28-2.94), P=0.9. Conclusions: Our findings demonstrate the challenges of delivering post-HCT TKI maintenance. Toxicity leading to TKI interruptions, discontinuation, and dose reduction was common. Post-transplant outcomes were comparable with imatinib and NG-TKI. Therefore, TKI selection for post-HCT maintenance should be based on patient tolerability to maximize TKI maintenance exposure. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survey and analysis of the concerns of patients with chronic myeloid leukemia in China in 2021

Objective: To investigate the concerns of adult patients with chronic myeloid leukemia (CML) in the chronic phase receiving tyrosine kinase inhibitor (TKI) therapy in China. Methods: A cross-sectional questionnaire including 23 issues of concern was filled by patients with CML nationwide from August to September 2021. The results were compared with those from 2015 to 2016. Results: Data from 952 questionnaires were analyzed. The five most concerned issues were "TKI-related adverse effects and management" (66%) , "stopping TKI therapy" (46%) , "CML risk assessment" (46%) , "TKI dose reduction" (42%) , and "restrictions in daily life activities" (41%) . Compared with the results from 2015 to 2016, patients paid more attention to "TKI-related adverse effects and management" , "monitoring" , and "interpretation of laboratory reports" (all P<0.01) . Concerns of "TKI reimbursement policies" , "price reduction of TKIs" , and issues related to generic TKIs decreased significantly (all P<0.01) . Multivariate analysis showed that female patients (OR=1.8, 95% CI 1.4-2.5, P<0.001) , elderly patients (OR=1.0, 95% CI 1.0-1.0, P<0.001) , or patients with bachelor's degree or higher (OR=1.8, 95% CI 1.3-2.4, P<0.001) were more concerned with "TKI dose reduction" than others. Patients with a bachelor's degree or higher (OR=1.6, 95% CI 1.2-2.2, P=0.002) paid more attention to "CML risk assessment" , whereas those currently receiving a second- or third-generation TKI therapy (OR=1.9, 95% CI 1.3-2.6, P<0.001) were more concerned about "TKI resistance" . Conclusion: Patients with CML paid the most attention to "TKI-related adverse effects and management" , "stopping TKI therapy" , "CML risk assessment" , "TKI dose reduction" , and "restrictions in daily life activities" . Patients' sociodemographic covariates and treatment status were associated with their concerns.

Clinical characteristics and outcomes of tyrosine kinase inhibitor-related lower GI adverse effects.

A variety of tyrosine kinase inhibitors (TKIs) are currently approved for the treatment of solid tumors and hematological cancers. However, TKIs are often associated with gastrointestinal (GI) adverse effects (AEs), especially diarrhea. Therefore, in the present study, we aimed to describe the clinical features and outcomes of TKI-associated lower GI AEs. This was a retrospective single-center cohort study of patients with cancer treated with TKIs from March 2016 to September 2020 who experienced diarrhea without other identifiable causes. Basic and GI AE-related characteristics and outcomes were compared using χ2 and Mann-Whitney U tests. Of 2172 patients who received TKIs over the study period, we included 228 in the final analysis. Of these, 166 (72.8%) had hematological cancers. Besides diarrhea, GI symptoms included nausea (36.4%), vomiting (21.9%), abdominal pain (15.4%), and bleeding (3.1%). Symptoms were typically mild, with 209 patients (91.7%) presenting with Common Terminology Criteria for Adverse Events grade 1-2 diarrhea. Only 5 patients (2.2%) received immunosuppressants for diarrhea treatment, 83 (36.4%) received no treatment, 29 (12.7%) received antibiotics, 101 (44.3%) received supportive antidiarrheal medications, and 17 patients (7.5%) needed TKI dose reduction or cessation of TKI use. When compared with patients with hematological cancers, those with solid tumors had a higher rate of hospitalization (29.0% vs. 7.2%; p < 0.001) and mortality (75.8% vs. 43.4%; p < 0.001) but a lower rate of recurrence of GI AEs (21.0% vs. 42.8%; p = 0.003. Only 15 patients (6.6%) underwent colonoscopy, with normal endoscopic findings in 8 patients (53.3%) and nonulcerative inflammation in 5 patients (33.3%). The inflammation universally involved the left colon. Twelve of the 15 patients who underwent colonoscopy had active colitis. In the hematological cancer group, patients with acute myeloid leukemia had a lower GI AE recurrence rate than did patients with other hematological cancers (7.2% vs. 30.1%; p = 0.001). Ten percent of cancer patients receiving TKIs experienced lower GI AEs, which were usually mild. Symptoms TKI-related GI adverse effects were nonspecific, often overlapping those of other cancer therapy-related GI AEs. Treatment of GI AEs was largely supportive, with limited roles for antibiotics and immunosuppressants.

Chylothorax and chylous ascites during RET tyrosine kinase inhibitor therapy.

9080 Background: Spontaneous, atraumatic chylous effusions are rare. Investigators have observed a higher than anticipated incidence of chylothorax and chylous ascites in patients (pts) treated with RET tyrosine kinase inhibitors (TKIs). A systematic analysis of the occurrence of chylous effusions during RET TKI therapy and management strategies was thus performed. Methods: In this multicenter, retrospective study, the frequency of biochemically confirmed chylothorax or chylous ascites in pts treated with multikinase inhibitors (MKIs) with anti-RET activity or selective RET TKIs was determined. Clinicopathologic features and management of pts with chylous effusions were assessed. Results: A pan-cancer cohort of 7517 pts treated with at least 1 of 17 MKIs and selective RET TKIs and an independent cohort of 96 pts treated with the selective RET TKIs, selpercatinib or pralsetinib, were identified. Across cohorts, chylous effusions were identified in 22 pts and were most common with selpercatinib (7%; 15/217), followed by the MKIs agerafenib (4%; 1/24), cabozantinib (0.3%; 3/918), and lenvatinib (0.3%; 3/1185). Chylous effusions were not noted in 28 pts treated with pralsetinib. The distribution of malignancies included lung adenocarcinoma (54%) medullary thyroid carcinoma (23%), renal cell carcinoma (19%), and desmoplastic small round cell tumor (4%). Of the 22 pts, 12 had chylothorax, 5 had chylous ascites, and 5 had both. The cumulative incidence of chylous effusions from TKI initiation at 12 months was 3.09%. Median fluid triglyceride level was lower in chylothorax than in chylous ascites [397 mg/dL (IQR 282-4000) vs. 3786 mg/dL (IQR 676-6596), p = 0.035]. Median pleural fluid triglyceride level was higher with selpercatinib compared to MKIs [4,000 mg/dL (IQR 356-4425) vs. 287 mg/dL (IQR 216-395); p = 0.017]. Malignant cells were identified in the effusions from 12% (2/17) and 10% (1/10) of pts with chylothoraces and chylous ascites, respectively. Median time to disease progression from radiographic index and biochemical index across the full cohort was 1.5 years (IQR: 0.6-2.4) and 1.0 year (IQR: 0.1-1.2), respectively. Anatomic chyle leak was not identified in 6 pts who underwent lymphangiography. After initial drainage, additional drainage procedures were required in all cases with chylothorax and 50% of cases with chylous ascites. Chylous effusions prompted TKI dose reduction in 47% (7/15) of pts treated with selpercatinib and 14% (1/7) treated with MKI; none discontinued TKI due to chylous effusions. Conclusions: Chylous effusions can emerge on treatment with certain MKIs or selective RET TKIs. Recognition of this potential side effect is key to prevent misattribution of worsening effusions to progressive malignancy and to motivate a better understanding of its biology and management.

Russian Prospective Non-Randomized Clinical Study on Dose Reduction of Tyrosine Kinase Inhibitors with Subsequent Complete Therapy Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response (READIT-2020): Background, Aim, Main Objectives, Design, and Expected Results

Background. A withdrawal of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients with optimal response, especially in patients with drug toxicity, is a matter of current interest. According to the results of numerous clinical studies, the probability of sustaining treatment-free remission (TFR) in CML patients with deep molecular response (DMR) is about 40-60 %. Great attention has recently been paid to personalized therapy consisting in TKI dose modification aimed at reducing or preventing therapy adverse events. Many large retrospective studies showed that reduced TKI doses in CML patients with major molecular response (MMR) and DMR is a safe therapy option. The follow-up of patients receiving reduced TKI doses is also carried out under prospective clinical studies as a stage prior to therapy discontinuation. This approach shows that the probability of sustaining TFR after the stage of TKI dose reduction is about 70 % which is higher than that after the withdrawal of standard TKI doses. Aim. To present the background, aim, and mai n objectives of the study as well as the design and expected results. Materials &amp; Methods. READIT-2020 (Russian prospective study of REduction And DIscontinuation Treatment of TKI) is a Russian prospective non-randomized clinical study with the main aim of developing a safe management regimen for CML patients with MMR and DMR, who receive reduced TKI doses, with subsequent follow-up in the period of TFR under the control of minimal residual disease. The study is going to enroll 100 patients. Each stage of the clinical study will include a regular molecular genetic monitoring at the central laboratory (National Research Center for Hematology, Moscow). The primary objective is to assess survival without MMR loss (BCR-ABL &gt; 0.1 %) both on reduced TKI doses and during TFR. The primary endpoint is the follow-up period of 12 months after TKI discontinuation. Trial Registration No.: NCT04578847 (Clinicaltrial.gov).

A Retrospective Analysis of TKI Discontinuation in Patients with CML

To investigate the clinical characteristics of the patients with chronic myeloid leukemia (CML) discontinued tyrosine kinase inhibitors (TKI) therapy and the outcome of the patients. 35 cases of CML patients experienced initiative discontinuation of TKI therapy in our hospital from June 1st 2015 to December 31th 2019 were retrospectively analyzed. The TFR of the patients and the factors affecting it were analyzed. The median duration of TKI administration was 72 (range 35-173) months in the 35 patients. Among these patients, 8 had experienced TKI dose reduction or suspension. All the enrolled patients have achieved at least MMR. The median time for these patients achieving MMR was 15 (range 3-75) months after administration of TKI, and for MMR maintenance before TKI suspension was 55 (range 13-164) months. After TKI withdrawal the median follow up time was 20.3 (range 3-57.9) months, 22 out of 35 patients kept TFR, among them, 2 （5.71%） patients restarted TKI after 12 month suspension, and maintained MMR during suspension. 13 （37.1%）patients lost MMR, among them, 9 patients restarted TKI treatment, and 5 of them achieved MR4.0 after the median duration of 3(2-5) month. No patients were found to have disease progression. The estimated TFR rate was 57.8% and 51.8% at 12 and 24 months after discontinuation, respectively. Other clinical characteristic related to relapse were also analyzed, including the cumulative TKI administration duration, cumulative MMR duration, time to achieve MMR, median age at diagnosis, risk stratification by Sokal score, TKI dose reduction and discontinuation history, and second-generation TKI administration before stopping TKI, however, no statistical difference was found. TKI discontinuation is practical for CML patients in our center.

Half: A Prospective Multi-Centre Phase II Clinical Trial Evaluating the Efficacy and Safety of Tyrosine Kinase Inhibitors' Discontinuation after Two-Step Dose Reduction in Patients with Chronic Myeloid Leukemia in Deep Molecular Remission

Background.Treatment-free remission (TFR) has become a new treatment goal for chronic myeloid leukemia (CML) patients. However, usually abrupt tyrosine kinase inhibitors (TKIs) therapy discontinuation has been successful only in about half of eligible patients and it can cause burdening TKI withdrawal syndrome (TWS) in about 30% of them. Moreover, any robust clinical or biological factor predictive for successful TFR has not been identified yet. On top of that, sustainable deep molecular response (DMR) as the main prerequisite for TKI discontinuation attempt is achieved only in 20-40% of patients. The majority of CML patients, therefore, need to be treated with the effective and well-tolerated drug for a long time or even life-long.Study design and methods.With the recognition of all these aspects, we designed a nationwide prospective investigator-initiated phase II clinical trial HALF (ClinicalTrials.gov NCT04147533) in order to evaluate efficacy and safety of TKI discontinuation after previous two-step dose reduction in patients with CML in DMR (Fig. 1). Step-wise TKI dose reduction, i.e. half of the standard during the first 6 months after study entry, and the same dose given alternatively (every other day) during the next 6 months, was derived from pharmacokinetics and experimental data as well as from clinical trials' results. We assume that the step-wise and eventually meaningful TKI dose reduction enables a higher rate of patients achieving successful TFR with less pronounce TWS, or even would represent a more reasonable and safer alternative to the complete and sudden TKI interruption. This unique nationwide academic project has been facilitated by hematological patients care centralization in the Czech Republic.A primary study objective is to evaluate the proportion of patients in major molecular response (MMR) at 6 and 12 months and in TFR at 18, 24, and 36 months after the study enrollment, respectively, and molecular recurrence-free survival at all mentioned time points as well. Main secondary and exploratory objectives are: to evaluate the proportion of patients loosing MMR and in whom MMR and MR4.0 would be re-achieved after TKI re-introduction, time to MMR and MR4.0 re-achievement, FFS, PFS, OS, TWS, and QoL assessment, predictive factors for successful TFR identification, quantification of BCR-ABL1 using digital droplet PCR at both the DNA and mRNA levels, immunological profiling, BCR-ABL1 kinetics mathematical modeling, assessment of TKI pharmacokinetics, clonal hematopoiesis and pharmaco-economics.Results.The study was launched in December 2019; however, due to the COVID-19 outbreak, patients' recruitment started on June 16, 2020. Here, characteristics of the first 74 patients included in the study until April 2021 are presented. There were 37 males and 37 females, with median age at the time of diagnosis of 53 years (range, 23-74) and at the time of the study entry of 67 years (range, 35-86). A median time of CML disease, TKI treatment, and DMR duration before the study initiation was as follows: 9.9 years (range, 4.4-22.5), 9.8 years (range, 4.2-20.2), and 7.3 years (range, 3.2-18.3), respectively. The ELTS score was low, intermediate, high and unknown in 62.2%, 21.6%, 13.5%, and 2.7% of patients, respectively. At the time of study entry, 58 patients (79.5%) were treated with imatinib, 10 (13.7%) with nilotinib, and 5 (6.8%) with dasatinib, respectively, whereas in 63 patients (86.3%) it was in the first line of therapy. With almost half of patients (48.6%), the TKI dose was already reduced at the time of study entry. With 10 (13.5%) patients, interferon-α treatment preceded TKI administration. At the time of this abstract preparation, on July 26, 2021, altogether 102 patients (from planned 150) have been enrolled in the study; 48 of them (47.1%) have already moved to the second de-escalation phase and 9 (8.8%) patients to the TFR phase. There were 2 cases of confirmed MMR loss (both in month 8 after the study entry) and no patient experienced symptoms resembling TWS.Conclusions.Despite the COVID-19 pandemic, the HALF study was successfully launched and initiated in the majority of centers, with 102 already included patients and continuing intensive enrolment. Based on our very preliminary results, the step-wise dose reduction seems to be an effective and safe approach. More included patients, longer follow-up and further analyses are needed in order to reach all set up objectives. [Display omitted] DisclosuresŽácková: Angelini: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Faber: Angelini: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Pfizer: Other: conference fees; TERUMO: Other: conference fees. Bělohlávková: Novartis: Consultancy; BMS/Celgene: Consultancy. Horňák: Angelini: Honoraria. Svobodník: Roche: Speakers Bureau; Janssen-Cilag: Speakers Bureau. Machová Poláková: Incyte: Consultancy; Angelini: Consultancy; Novartis: Research Funding. Mayer: Principia: Research Funding.

Dose Optimization of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A New Therapeutic Challenge.

The chronic myeloid leukemia (CML) therapeutic landscape has dramatically changed with tyrosine kinase inhibitor (TKI) development, which allows a near-normal life expectancy. However, long-term TKI exposure has been associated with persistent adverse events (AEs) which negatively impact on quality of life (QoL) and have the potential to cause significant morbidity and mortality. In clinical practice, TKI dose reduction is usually considered to reduce AEs and improve QoL, but dose optimization could have also another aim, i.e., the achievement and maintenance of cytogenetic and molecular responses. While therapy cessation appeared as a safe option for about half of the patients achieving an optimal response, no systematic assessment of long-term TKI dose de-escalation has been made. The present review is focused on the most recent evidences for TKIs dose modifications in CML clinical studies and in the real-life setting. It will consider TKI dose modifications in newly diagnosed patients, dose reduction for AEs, or in deep molecular response, either as a prelude to treatment-free remission (TFR) or as continuous maintenance therapy in those patients not wishing to attempt TFR. In addition, it will focus on patients not achieving a molecular response deep enough to go to TFR, and for whom dose reduction could be an option to avoid AEs.

Cognitive Dysfunction Associated with Tyrosine Kinase Inhibitors in Patients with CML in Chronic Phase

Introduction: The effect of tyrosine kinase inhibitors (TKIs) on cognition in patients with chronic myeloid leukemia in chronic phase (CML-CP) is not well understood. Memory impairments have been reported in limited studies in CML patients on dasatinib and in gastrointestinal stromal tumor patients on imatinib, but additional research is needed. At our institution, we have observed that CML-CP patients spontaneously report new cognitive dysfunction (CD) while on TKIs. We sought to determine the prevalence of CD in CML-CP patients on TKIs, the TKIs associated with cognitive changes, and the management and outcomes of CML-CP patients with CD at our institution. Methods: We performed a single-center, retrospective cohort study of active CML-CP patients in our Hematology clinic seen between January 2017 and December 2019. Patients were identified by ICD-10 codes and chart notes were reviewed for treatment course. Patients met criteria for CD if they reported new difficulties with cognition while on TKI treatment (as documented in the subjective or review of systems) and had no prior history of cognitive impairment. Descriptive statistics, Chi-square tests, and two-tailed t-tests were used to summarize the data. Results: We identified 216 CML-CP patients who were actively or previously treated with a TKI, with 29 patients (13.4%) reporting CD while taking a TKI. The median age for patients with CD was 51 years (range 23-73), compared to a median age of 56 years (range 20-91) in those without CD (P=0.114); there were no significant differences in sex (P=0.984) or in median time since diagnosis (P=0.167) (Table 1). The 29 patients generated 36 reports of CD, as 7 patients (24.1%) reported 2 types of cognitive changes while on TKI. The types of CD were documented as "mental fog" (n=19/36, 52.8%), memory problems (n=7/36, 19.4%), decreased mental acuity (n=6/36, 16.7%), problems with concentration (n=2/36, 5.6%), word-finding difficulties (n=1/36, 2.8%), and impaired creativity (n=1/36, 2.8%) (Figure 1). Of the 29 patients who reported CD, 5 experienced it on 2 different agents, leading to 34 individual reports of CD. Among the 216 patients with CML-CP treated with TKIs, many used more than 1 agent: 31 used bosutinib, 183 dasatinib, 132 nilotinib, and 10 ponatinib. The percentage of CD reported in patients treated with each TKI was as follows: bosutinib 12.9% (n=4/31), dasatinib 11.5% (n=21/183), imatinib 5.3% (n=7/132), nilotinib 4.1% (n=2/49), and ponatinib 0% (n=0/10) (Table 2). For management, 20.7% (n=6/29) underwent successful prescribed discontinuation, 27.6% (n=8/29) attempted discontinuation but resumed TKI after loss of MMR, 24.1% (n=7/29) underwent TKI dose reductions, 20.7% (n=6/29) changed TKIs, and 6.9% (n=2) had no change in management. In the 6 patients who successfully discontinued TKI, all but 1 (83.3%) reported complete resolution of their CD while off of TKI. For those who attempted discontinuation but had loss of MMR, 6 of 8 (75%) had documented improvement of CD off of treatment; after restarting TKI, CD returned in 5 patients (83.3%). Of the remaining patients who underwent TKI dose reductions (n=7), 1 patient had documented improvement of CD, 2 had no change, and 4 had unspecified outcomes. Of the patients who changed TKIs (n=6), 1 patient had documented improvement of CD, 4 had no change, and 1 had unspecified outcomes. In the 2 with no change in management, outcomes were not specified. Conclusion: Cognitive dysfunction in CML-CP patients was reported with all first- and second-generation TKIs; the analysis of ponatinib was limited by small numbers. Bosutinib had the highest proportion of CD in our cohort, an association that has not been previously reported. Our analysis supports that TKI-associated CD is reversible since it resolved in 78.6% (n=11/14) patients when off of TKI during discontinuation. While 13.4% of our CML-CP patients had CD, due to spontaneous reporting and subtle presentation of cognitive impairment, the true prevalence of CD in CML-CP patients on TKIs is likely substantially higher. Future studies should involve prospective data collection of objective cognitive testing and patient reported outcomes in CML-CP patients for further evaluation of TKI-associated cognitive dysfunction. Disclosures Schoenbeck: American Society of Hematology: Research Funding. Smith:Sanofi: Honoraria; FujiFilm: Other: Research support, Research Funding; Revolution Medicines: Other: Research Support, Research Funding; Astellas Pharma: Honoraria, Other: Research Support, Research Funding; Daiichi Sanyko: Consultancy, Honoraria; Abbvie: Other: Research Support, Research Funding. Shah:Bristol-Myers Squibb: Research Funding.

CML-270: Dose De-Escalation of Second-Generation Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia Patients with Major and Deep Molecular Response

Context Chronic myeloid leukemia (CML) patients (pts) receive a long-term treatment with tyrosine kinase inhibitors (TKI) in standard doses. A new approach with reduced dose TKI use is desirable for the CML pts with adverse effects (AE) or with a high risk of AE, particularly in pts with major molecular response (MMR) and deep molecular response (DMR) receiving second generation TKI (2GTKI). Objective To evaluate the stability of MMR in CML pts after dose reduction of 2GTKI. Patients We included 36 pts taking 2GTKI, all in chronic phase, in retrospective analyses. Median (Me) age was 47 years (range 22-71). Me therapy duration was 42.5 months (mo). MMR was in 7 (19%) pts, DMR in 29 (81%) pts. Me duration of MMR was 21.5 mo at the time of dose reduction. The AEs were in 21 (58%) pts before the dose reduction. Interventions The dose reduction of nilotinib and dasatinib was done in 28 (78%) and 8 (22%) pts. Initial dose of nilotinib was 800, 600 and 400 mg in 18 (64%), 8 (28%) and 2 (7%) pts. The dose of nilotinib was reduced to 600, 400, 300, and 200 mg in 1 (4%), 21 (75%), 2 (7%) and 4 (14%) pts. The initial dose of dasatinib was 140 mg in 1 (12.5%) and 100 mg in 7 (87.5%) pts, and the reduced dose was 70 and 50 mg in 2 (25%) and 6 (75%) pts. Results Me follow-up after 2GTKI dose reduction was 13 mo. The MMR loss occurred in 3 pts with MMR duration 3, 6 and 8 mo at the time of dose reduction. Survival without MMR loss at 12 mo was 96% (CI 89% -100%) and 64% (CI 23-100%) in the DMR and MMR cohort. MMR was regained in all pts after the standard dose therapy was recommenced. The toxicity after dose reduction was resolved in 19 (90%) of 21 pts with the previously observed AE. Conclusions This option allows reduction of the drug toxicities and prevents the potential AE of TKI therapy. In January 2020 in Russia, the prospective clinical trial was started in order to evaluate a relapse-free survival after discontinuation of therapy with the previous 12-months two-stage phase of TKI dose reduction.

Successful use of long-term follow-up in patients with chronic myeloid leukemia with a deep molecular response at reduced doses of 2nd generation tyrosine kinase inhibitors: clinical cases and literature review

Therapy with tyrosine kinase inhibitors (TKI) allows to achieve a deep molecular response in 6070% of patients with chronic myeloid leukemia (CML). According to the current guidelines CML patients receive a long-term treatment with TKI in standard dose. The frequently observed adverse effects (AE) of TKI therapy are mostly dose-dependent. A new treatment approach with TKI use in reduced dose is desirable for the CML patients with existing AE or with a high risk of AE occurrence. We report the two cases of successful long-term treatment of CML patients with reduced doses of second generation TKIs. The aim of the TKI dose reduction was to reduce the clinical manifestations of drug toxicities and to prevent the AE.