Tyrosine Kinase Inhibitors Dose 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.

Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

Navigating the Management of Chronic Phase CML in the Era of Generic BCR::ABL1 Tyrosine Kinase Inhibitors.

Over the past several years, advances in research, treatment, and market dynamics have impacted treatment strategies in chronic myeloid leukemia in chronic phase (CML-CP). They include the broader availability of cost-effective generic imatinib, and soon other generic second-generation tyrosine kinase inhibitors (TKIs). Access to affordable generics means that all patients with CML-CP should have access to safe and highly effective lifelong therapies. When overall survival is the treatment endpoint, imatinib provides a good treatment value. Second-generation TKIs may be the best frontline strategy when treatment-free remission is the goal. Recent studies have shown maintained efficacy and reduced toxicity when TKIs are used at reduced dosing. Reduced-dose schedules of second-generation TKIs (which are less toxic and induce faster deep molecular responses) may render generic second-generation TKIs a more attractive treatment option. Adjusting the dose of TKI in the presence of mild-to-moderate, or even severe but reversible, adverse events may be preferable to switching to a different TKI. The selection of second-line and beyond therapies depends on the evolving patterns observed with frontline treatment. Dose-adjusted ponatinib schedules have demonstrated improved efficacy and safety in patients resistant to second-generation TKIs or those with T315I-mutated disease. For asciminib, longer-term follow-up is needed to better evaluate its safety and efficacy compared with ponatinib. Allogeneic stem cell transplantation represents a valid alternative to newer-generation TKIs, with a better treatment value when TKIs are priced at >$40,000/year.

Safety and Efficacy of TKIs in very Elderly Patients (≥75 Years) with Chronic Myeloid Leukemia.

While the outcomes of chronic phase chronic myeloid leukemia (CP-CML) patients aged over 65 years have been extensively evaluated in real-life experiences, limited data exist for the very elderly population (i.e., aged ≥ 75 years), especially for next-generation tyrosine kinase inhibitors (TKIs). In this retrospective study, we sought to evaluate the safety and efficacy of TKIs in this particular setting of patients. We conducted a retrospective analysis of a multicenter cohort of 123 newly diagnosed CP-CML very elderly patients. The median age at diagnosis was 80 years (range: 75-96). In the first line, 86.1% of patients received imatinib, 7.1% dasatinib, 5.6% nilotinib, and 0.81% received bosutinib. A total of 31 patients (25.2%) switched to second-line therapy, nine patients to a third line, and one patient to a fourth line of therapy. Resistance to treatment was the primary reason for switching therapy in both the first (64.5%) and second lines (77.7%). At diagnosis, reduced doses were administered in 36.5% of patients, in 61.2% in the second line, and in all patients in subsequent lines of therapy. In the first-line setting, 71.9% of patients achieved an early molecular response (EMR, i.e., 3-month BCR::ABL1IS < 10%); at 6, 12, and 24 months, MR3 was reached by 35.7%, 55.7%, and 75.0% of patients, respectively, with 16.6%, 35.7%, and 51.7% achieving a deep molecular response (DMR) at the same time points. Treatment-free remission (TFR) was successfully attempted in 11 patients. During the follow-up period, adverse events (AEs) were observed in 78.8% of patients, including 22 cases of cardiovascular AEs. Toxicity grade ≥ 3 was more commonly observed in patients treated with standard doses of TKIs compared to reduced doses (p = 0.033). Overall, the median follow-up was 46.62 months (range: 1.8-206.2), and 43 patients died due to non-CML-related causes. Three patients died due to disease progression to advanced (n = 1) and blastic (n = 2) phases. The 5-year overall survival (OS) for the entire cohort was 71.9% (95% CI: 0.63-0.81), with no significant difference between the patients treated with standard doses of TKIs compared to those treated with reduced doses (p = 0.35). TKIs appear to be safe and effective even in very elderly CML patients, and dose optimization strategies yield satisfactory molecular responses for adequate disease control with an improved safety profile.

Successful maintenance of a sustained molecular response in CML patients receiving low-dose tyrosine kinase inhibitors.

The development of tyrosine kinase inhibitor (TKI) therapy has positively impacted the survival rates of patients with chronic myeloid leukemia (CML). It is common in medical practice to adjust the dosage of TKI downward because of TKI-associated adverse events, financial burden, comorbidity, or an attempt at treatment-free remission. This investigation sought to explore the feasibility of employing a reduced dosage of TKI for treating CML. This was a retrospective study. Patients with CML in its chronic phase who had been on a reduced dose of TKI for a minimum of 3 months for various reasons in a practical clinical environment, irrespective of molecular response, were included. Regular molecular monitoring was performed, and changes in adverse events were recorded after dose reduction. This research included a total of 144 participants. Upon reducing the dosage, 136 of 144 patients achieved major molecular response or deeper, and 132 of 144 achieved molecular response 4 (MR4). Following a median observation period of 16 months, the calculated 1- and 2-year survival rates free from MR4 failure were estimated to be 96.5% (95% CI: 90.8-98.7) and 90.5% (95% CI: 81.3-95.3), respectively. MR4 failure-free survival was better in patients with longer MR4 durations (⩾34 months) before dose reduction (p = 0.02). The median interval from dose reduction to MR4 loss was 15 months. Improved TKI-associated adverse events after dose reduction were observed in 61.3% of patients. Lowering the TKI dose can effectively preserve a deep molecular response over time while relieving adverse events caused by TKIs.

The new Systematic Coronary Risk Evaluation (SCORE2 and SCORE2-OP) estimates the risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib or ponatinib

Patients with chronic myeloid leukemia (CML) treated with nilotinib or ponatinib may experience arterial occlusive events (AOEs). It is currently recommended to thoroughly assess cardiovascular risk factors before treating CML. We identified 455 consecutive CML adult patients, 335 treated with nilotinib and 120 with ponatinib; 380 patients without previous cardiovascular diseases or diabetes were stratified according to the Systematic Coronary Risk Evaluation (SCORE2) and SCORE2-Older Persons (SCORE2-OP). This updated algorithm from the European Society of Cardiology (ESC) estimates a 10-year risk of fatal and non-fatal cardiovascular diseases. It is based on sex, age, smoking habits, systolic blood pressure, non-high-density lipoprotein cholesterol, and European geographical region of cardiovascular risk. The SCORE2/SCORE2-OP algorithm translated more patients (50.2%) to the high–very high cardiovascular risk category than the previous SCORE (25.3%). Patients with a high to very high SCORE2/SCORE2-OP risk showed a significantly higher incidence rate of AOEs (69.2% vs. 46.5%, p < 0.001). The older SCORE was less specific in estimating AOEs in patients classified as low-intermediate risk (69.8 vs. 54.2%). In multivariate analysis, no associations were found between AOEs and gender, age, and type or dose of tyrosine kinase inhibitor. Only the SCORE2/SCORE2-OP risk was confirmed as a significant predictive factor (p = 0.028; hazard ratio = 2.2; 95% confidence interval = 1.1–4.5). Patients with AOEs required, in most cases, imaging diagnostic tests, additional drugs, and sometimes invasive procedures, increasing access to visits and hospital management. This real-life study suggested that the SCORE2 and SCORE2-OP charts could help identify cardiovascular fragility in CML patients providing them with more attention and a proper TKI selection.

Predictive Value of BCR::ABL1 Transcripts Kinetics in the Molecular Relapse of Chronic Myeloid Leukemia Patients after Tyrosine Kinase Inhibitors Discontinuation: Results from the DES-CML Study

Duration of previous treatment, duration and depth of molecular response, previous resistance, BCR::ABL1 transcript, and lymphocyte subtypes are known predictive factors of molecular recurrence after tyrosine kinase inhibitors (TKI) discontinuation in chronic myeloid leukemia (CML) patients (pts). Few studies explored the kinetics of BCR::ABL1 during a dose de-escalation phase before discontinuation in predicting molecular relapse. This study aimed to evaluate the kinetics of BCR::ABL1 transcripts during the de-escalation phase of the DES-CML trial and to correlate with molecular relapse after TKI discontinuation. Methods: This prospective, multicenter, single-arm, phase 2 study included CML pts treated DES-CML Study. Inclusion criteria: Adult CML pts treated with TKI for a minimum of 3 years that achieved sustained deep molecular response (DMR), defined by a minimum duration of MR4.5 for two years, confirmed by four real-time quantitative reverse-transcription polymerase chain reaction (qPCR) tests with six months interval. Exclusion criteria: pts with atypical BCR::ABL1 transcripts, previous or current advanced stage CML, previous resistance to TKI or ABL mutations. The TKI dose was reduced by 50% for six months before discontinuation (de-escalation phase). Molecular monitoring was performed by qRT-PCR, using ABL as the control gene. The results were reported using the International Scale. BCR::ABL1 transcripts were evaluated monthly during the de-escalation phase. After discontinuation, assessments were performed monthly for six months, every two months at months 7-24, and then every three months. Therapy was restarted at the same dose before dose reduction if loss of MMR (qPCR&amp;lt;0.1%). Statistical analysis was performed by using SPSS software. Rates of MRFS were calculated by Kaplan-Meier analysis, and groups were compared using a log-rank test. P values of &amp;lt;.05 were considered statistically significant. This trial is registered at ReBEC (RBR-6f5xbq; UTN code: U1111-1252-7312) and was approved by the ethics committees of the participating centers. All pts signed informed consent. Results: This study is ongoing. Forty-one pts were enrolled from September 2020 to July 2023, with a median age of 61 years (23-85), 60% men, 33% Sokal low risk, 50% intermediate, 17% high; 78% with b3a2 BCR::ABL1 transcript type; 85% using imatinib, 7.5% dasatinib, 5% nilotinib, and 2.5% bosutinib. For 3 pts, it was the second attempt at stopping TKI. The median duration of TKI treatment until discontinuation was 11 years (3-20). The cutoff date was July 2023, with a median follow-up of six months (1-26) after TKI discontinuation. One patient had a screen failure; another was enrolled but has not started the de-escalation phase yet. Five patients are in the de-escalation phase, and 25 are in the discontinuation phase. Two patients did not complete the de-escalation phase due to a lack of medication and went to the discontinuation phase. One patient died from causes unrelated to CML in the discontinuation phase and was censored in the MRFS analysis. 15/33 (45%) patients lost MR4.5 at any time in the de-escalation phase, and 4/15 (31%) lost MMR after discontinuation. Three of the 18 patients who did not lose MR4.5 during de-escalation relapsed (16%, P=0.05). The two patients who did not undergo de-escalation were censored in this analysis. Nine pts lost MMR: one during de-escalation and 8/39 (20%) after discontinuation. The median time between discontinuation and loss of MMR was two months (0-10). The median time to MMR recovery was 1.5 months (1-5). The overall MRFS was 72% (95% CI: 56-88%)(Figure A) and 81% in the first-attempt discontinuation group. All pts in the second attempt relapsed (3 patients) (P&amp;lt;0.0001). There was no difference in MRFS by gender, BCR::ABL1 transcript type, Sokal, and ELTS. Molecular response status at discontinuation: 23 (74%) had MR4.5, 6 (19.5%) MR4.0, and 2 (6.5%) MMR. Patients with MR4.5 at discontinuation had a higher MRFS than those in MR4.0 and MMR (78% vs. 62% vs. 0%, respectively, P=0.012)(Figure B). No patient lost hematologic response or had disease progression. Conclusions: Loss of MR4.5 during the de-escalation phase or molecular status not in MR4.5 before discontinuation was predictive of subsequent loss of MMR. Treatment-free remission was not successful in the second attempt of discontinuation.

Retrospective Study to Evaluate Probability of MR4 Maintenance Following Frontline Nilotinib Dose De-Escalation after MR4 Achievement in the Patients with Chronic Myeloid Leukemia in Chronic Phase

Introduction: Nilotinib (NIL) is a potent second-generation tyrosine kinase inhibitor (TKI) approved for the treatment of newly diagnosed chronic myeloid leukemia (CML) patients (pts) in chronic phase, but reported to increase long-term toxicity such as cardiovascular (CV) risks. The ENESTfreedom study (Leukemia 2021) has reported 55% of treatment-free remission (TFR) rate after front line NIL discontinuation with a median 43.5 months of NIL treatment duration. Question still remains how to improve TFR rate after NIL frontline therapy. A potential solution is dose de-escalation (DESC) after MR4 achievement which could reduce the CV risk while extending MR4 duration prior to TFR attempt, thus increasing the chance of successful TFR attempt. DESTINY trial (Lancet Haematology 2019) had attempted TKI dose DESC to half of the standard dose for 12 months before stopping TKI therapy, reporting only 3 pts (2.4%) lost molecular response after TKI dose DESC in 125 pts who achieved molecular response with 4 log or deeper (MR4). However, 85% of this cohort is mainly treated with imatinib, limiting applying this experience in NIL treated pts. Accordingly, the present study attempted to evaluate the efficacy of NIL dose DESC following MR4 achievement based on real-world experience. Patients &amp; Method: We have retrospectively analyzed the outcome of adult pts with CML in chronic phase treated with NIL frontline therapy and achieved sustained MR4 ( BCR::ABL1 transcript ≤0.01%IS). From the pts treated with NIL frontline therapy, we identified the cases attempted NIL de-scalation after achievement of MR4. The molecular response after NIL de-escalation was closely monitored every 3 months using BCR::ABL1 qPCR. Molecular recurrence was defined as an increase in BCR::ABL1 transcript levels above MR4 on at least two consecutive occasions or a single increase in BCR::ABL1 transcript level above MR3 ( BCR::ABL1 transcript ≤0.1%IS). At any time, pts who lost MR3 had returned Nilotinib dose to 300 mg BID. Primary endpoint of the study was event-free survival (EFS) following NIL de-escalation, which was defined from NIL DESC starts to molecular recurrence or death from any cause. Results: We have identified 52 pts who started NIL as first line therapy for CML-CP under clinical practice. With median follow-up duration of 9 years (range:2-12 years), 33 patient (64%) remains on NIL at the last follow-up visit. In 33 pts on NIL treatment, with a median follow up duration of 8 years (range;2-12), 25 (76%) had attempted NIL DESC at median of 6 years (range; 1-10 years) after frontline NIL therapy start, of whom the median time from NIL start to MR4 achievement was 12 months (range: 5-50 months). The median time from first achievement of MR4 to NIL DESC starts was 50 months (range: 3-105 months), while the median time from NIL start to NIL DESC was 77 months (range: 13-121 months). At the latest follow up, only one patient experienced molecular recurrence at 3 months after DESC but regained MR3 in 9 months after re-escalation of NIL to 300mg BID. One patient died of cardiac arrest at 80 months after NIL DESC with other comorbidities of coronary artery disease, hypertension and diabetes. One patient discontinued NIL at 51 months post DESC and has sustained MR4 till last follow up. In the DESC group, the EFS at 3 years, 95% (69.5-99.3%). There is another case developed myocardial infarction while on DESC dose of NIL, who switched the treatment to Asciminib. Conclusion: Achieving early and sustained MR4 with frontline NIL treatment facilitates DESC approach without compromising molecular response and might promote the TFR rate by extending MR4 duration. This DESC strategy can bridge CML pts on NIL frontline therapy prior to NIL discontinuation for TFR attempt.

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.

TKI Dose Optimization Based on Therapeutic Drug Monitoring（TDM) with Encouraging Outcomes and Well-Tolerated for Chronic Myeloid Leukaemia Patients

Background Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). Series studies indicated TKIs had a high therapeutic index, which led to the registration of these medications at fixed doses. Therapeutic drug monitoring (TDM) is a strategy for dosage optimization to provide individual treatment through dose adjustment to improve efficacy or avoid TKI-related adverse events (AEs). Objective We prospectively analyzed the outcome based on trough plasma concentrations (Cmin) to manage TKI dosage optimization during imatinib, nilotinib, and dasatinib therapy in patients with CML by 12 months. The primary efficacy endpoint was the rate of MMR at 12 months, the secondary endpoints included the cumulative rate of significant AEs defined as grade 3/4 fluid retention, all grade pleural effusion and pulmonary hypertension, grade 3/4 bilirubin increased, and grade 3/4 hematological toxicity related to TKIs within the first 12 months of therapy. Methods We examined 204 CML patients treated with imatinib, nilotinib, or dasatinib in the first line for CML-CP. We used high-performance liquid chromatography-tandem mass spectrometry (UPLC/MS-MS) to detect the Cmin of TKIs. Dasatinib or imatinib Cmin (24±3h post-dose) and nilotinib Cmin (12±3 h post-dose) were assessed after 7~10 days of therapy. We set the Cmin of imatinib at 1000~1500 ng/mL and that of nilotinib at 600~800 ng/mL, dasatinib at 1~3 ng/ml, respectively. Results Imatinib group (n = 67), Nilotinib group (n = 72), and Dasatinib group (n = 65), respectively. The initial dose of imatinib was 400mg qd, based on Cmin of imatinib was 900~1100ng/mL, there were 17 patients with dose reduction(1 case with 100mg qd, 5 cases with 200mg qd, 11 cases with 300mg qd) and 2 patients increased dose to 500mg qd; The initial dose of nilotinib was 300mg bid, based on Cmin of imatinib was 600~800ng/mL, there were 21 patients with dose reduction( 4 cases with 150mg bid, 16 cases with 450mg daily, 1 cases with 150mg qd) and 1 patients increased to 400mg bid; the initial dose of dasatinib was 100mg qd, based on Cmin of dasatinib was1~3 ng/ml, there were 32 patients with dose reduction(1 case with 20mg qd, 4 cases with 40mg qd, 20 cases with 50mg qd, 7 cases with 70mg qd ). Among the patients treated with imatinib, dasatinib, and nilotinib, no statistically significant associations were observed between gender, age, ELT scores, and plasma trough concentration (p&amp;gt;0.05). Early molecular reaction (EMR BCR: ABL(IS) &amp;lt;10%) was achieved by 83.6% (95% confidence interval [CI], 74.6%-92.5%) in the imatinib group, 87.7% (95% CI, 80.0%-95.4%) in the nilotinib group, and 83.3% (95% CI, 75.0%-91.7%) in the dasatinib group of patients at 3 months. The incidence of MMR at 12 months was 82.1% (95% CI, 73.1%-93.0%) in the imatinib group, 73.8% (95% CI, 64.6%-84.6%) in the nilotinib group, and 75.0% (95% CI, 65.3%-84.7%) in the dasatinib group, respectively. The cumulative incidence of grade 3/4 hematological toxicity was 7.8% (16/204), all-grade pleural effusion was 23.1% (15/65) in the dasatinib group, grade 3/4 bilirubin increased was 6.9% (5/72) in the nilotinib group, and there were no patients with pulmonary hypertension. Conclusion There are large individual differences in plasma trough concentrations in CML patients taking TKIs, the TKI dosage should be adjusted based on target plasma concentrations to maximize efficacy and minimize the incidence of adverse events.

Disparities in dosing, drug reduction, and drug discontinuation among US FDA approved tyrosine kinase inhibitors

Background: Tyrosine kinase inhibitors (TKIs) have altered the therapeutic landscape of multiple hematological and solid malignancies. FDA approved starting doses of TKIs are based on the recommended phase 2 dose (RP2D) in clinical trials. However, patients are started on lower doses in practice. We assessed the dosing, drug reduction rates, and drug discontinuation rates among FDA approved TKIs and observed the disparity among study populations to understand if there was adequate representation of diversity in race. Methods: We established a database of all FDA approved TKIs from the FDA online label repository. We extracted descriptive data for indications and usage, type of approval, approval dosage, dose reduction recommendation, median age, race, dose reduction rates, drug discontinuation rates, dose modification, warnings, adverse reactions, clinical trial experience, and geriatric use above 65 yrs and 75 yrs. Results: Among all TKIs, median dose was 200 mg and average dose was 307.7 mg; 36 (24%) were approved bid vs 107 (72%) qd. Among approved indications, median rates of dose reduction rate (DRR), drug interruption rate (DIR), drug discontinuations rate (DDR) were 31%, 52%, and 10% respectively. Reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. Black and Hispanic races are consistently underrepresented among the TKI studies. Conclusions: TKIs have a variable dose reduction and drug discontinuation rate but these studies were done mostly in White individuals. Clinical trials should evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve QOL in patients while broadening the study population so that the studies will be generalizable to patients in clinical practice. Future studies are warranted to increase representation in the studies to address the disparities.

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.

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 &amp;lt; 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 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.

ASC2ESCALATE: A US phase 2, single-arm, dose-escalation study of asciminib monotherapy in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with 1 prior tyrosine kinase inhibitor (TKI).

TPS7082 Background: ATP–competitive TKIs extend life expectancy in CML; yet up to 40% of newly diagnosed pts with CML-CP stop first-line (1L) therapy by 5 years due to resistance or intolerance and switch to second-line (2L) therapy. There is also an unmet need to overcome high rates of resistance in 2L. Studies show some pts with resistance achieve responses with higher doses of TKIs, while use of another second-generation (2G) TKI may not clinically benefit pts with resistance to a 2G TKI. Asciminib is the 1st BCR:ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP), giving it activity against most BCR:ABL1 mutations imparting resistance to ATP-competitive TKIs. Asciminib was 1st approved in the US for patients with CML-CP after ≥2 TKIs at 80 mg once daily (QD) and 40 mg twice daily (BID) and CML-CP with the T315I mutation at 200 mg BID. In the phase 3 ASCEMBL study, asciminib 40 mg BID showed superior efficacy vs bosutinib 500 mg QD in pts with CML-CP after ≥2 prior TKIs at weeks 24 (major molecular response [MMR], 25.5% vs 13.2%) and 96 (MMR, 37.6% vs 15.8%) and favorable tolerability with &gt; 2 years’ follow-up. The phase 1 dose-finding X2101 trial investigated asciminib doses of 80-200 mg QD and 10-200 mg BID; the maximum tolerated dose of asciminib was not reached and no differing safety signals were noted in patients receiving 200 mg BID vs the total treatment population. Here, we describe the phase 2 ASC2ESCALATE trial investigating efficacy and safety of 2L asciminib with dose escalation in pts with CML-CP (NCT05384587). Methods: This is a phase 2, open-label, multicenter, single-arm, dose-escalation study in the US. Adults with CML-CP without the T315I mutation with treatment resistance/failure ( BCR:ABL1IS &gt; 10% with 6-12 months of 1L treatment or &gt; 1% with &gt; 12 months of 1L treatment ) or intolerance ( BCR:ABL1IS &gt; 0.1%) with ≥6 months of treatment with 1 prior ATP-competitive TKI are eligible. All pts start treatment with asciminib 80 mg QD. For pts not achieving BCR:ABL1IS ≤1% at 6 months, dose will be escalated to 200 mg QD if pts do not have grade ≥3 or persistent grade 2 toxicity refractory to optimal management. For those without MMR at 12 months, either dose escalation from 80 to 200 mg QD or from 200 mg QD to 200 mg BID will occur or pts can be switched to an investigator’s agent of choice and taken off study treatment. Pts achieving MMR at 12 months will continue asciminib at their current dose. Pts continuing to derive clinical benefit from asciminib per investigator assessment may receive post-trial access. Recruitment for this study began August 2022 with an estimated enrollment of 92 pts with CML-CP across ≈40 sites. The primary endpoint is MMR at 12 months. Secondary endpoints include additional efficacy outcomes at 3, 6, 18, and 24 months and safety measures. Clinical trial information: NCT05384587 .

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&lt;0.01) and cohort 2 (81% vs 40%, p&lt;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.

A Real-World Evidence-Based Study of Long-Term Tyrosine Kinase Inhibitors Dose Reduction or Discontinuation in Patients with Chronic Myeloid Leukaemia.

The therapeutic approach to chronic myeloid leukaemia (CML) has changed in recent years. As a result, a high percentage of current patients in the chronic phase of the disease almost have an average life expectancy. Treatment also aims to achieve a stable deep molecular response (DMR) that might allow dose reduction or even treatment discontinuation. These strategies are often used in authentic practices to reduce adverse events, yet their impact on treatment-free remission (TFR) is a controversial debate. In some studies, it has been observed that as many as half of patients can achieve TFR after the discontinuation of TKI treatment. If TFR was more widespread and globally achievable, the perspective on toxicity could be changed. We retrospectively analysed 80 CML patients treated with tyrosine kinase inhibitor (TKI) at a tertiary hospital between 2002 and 2022. From them, 71 patients were treated with low doses of TKI, and 25 were eventually discontinued, 9 of them being discontinued without a previous dose reduction. Regarding patients treated with low doses, only 11 of them had molecular recurrence (15.4%), and the average molecular recurrence free survival (MRFS) was 24.6 months. The MRFS outcome was not affected by any of the variables examined, including gender, Sokal risk scores, prior treatment with interferon or hydroxycarbamide, age at the time of CML diagnosis, the initiation of low-dose therapy and the mean duration of TKI therapy. After TKI discontinuation, all but four patients maintained MMR, with a median follow-up of 29.2 months. In our study, TFR was estimated at 38.9 months (95% CI 4.1-73.9). This study indicates that low-dose treatment and/or TKI discontinuation is a salient, safe alternative to be considered for patients who may suffer adverse events (AEs), which hinder the adherence of TKI and/or deteriorate their life quality. Together with the published literature, it shows that it appears safe to administer reduced doses to patients with CML in the chronic phase. The discontinuation of TKI therapy once a DMR has been reached is one of the goals for these patients. The patient should be assessed globally, and the most appropriate strategy for management should be considered. Future studies are needed to ensure that this approach is included in clinical practice because of the benefits for certain patients and the increased efficiency for the healthcare system.

BCR-ABL Tyrosine Kinase Inhibitors in Parkinson’s Disease and Lewy Body Dementia: A Systematic Review (P2-11.009)

<h3>Objective:</h3> To assess the effect of BCR-ABL Tyrosine Kinase Inhibitors (TKI) on Parkinson’s Disease (PD) and Lewy Body Dementia (LBD). <h3>Background:</h3> Abelson tyrosine kinase activation is higher in PD. Inhibiting its activation could be a disease-modifying therapy. <h3>Design/Methods:</h3> On a systematic review of MEDLINE, Embase, and Cochrane, 427 papers were selected after deduplication. RCTs and Non-RCTs on BCR-ABL TKI in PD and LBD were included using a PRISMA protocol. After full-text screening, 6 articles remained. <h3>Results:</h3> 189 patients were randomized into 2 groups: BCR-ABL TKI vs Levodopa equivalent daily dose. Pagan et al., 2016 analyzed Nilotinib in PD and LBD with an average decrease of 3.4 and 3.6 points on the UPDRS-III, and 7 and 11.1 in the UPDRS I–IV score with 150 and 300 mg, respectively. Simuni et al., 2020 evaluated 76 patients for both doses of Nilotinib in moderately advanced PD; the results showed no difference in MDS-UPDRS-III OFF and a worsening in MDS-UPDRS-III ON. Pagan et al., 2019 randomized 75 patients into both doses of Nilotinib, resulting in a 2.82 points reduction in the MDS-UPDRS-III for Nilotinib 150 mg. MDS-UPDRS I-III and MDS-UPDRS I–IV scores increased by 2.47 and 2.13 points in the placebo group but remained stable in the Nilotinib groups. Pagan et al., 2021 randomized 63 of the same patients for Nilotinib 150 vs 300 mg, suggesting that Nilotinib 300 mg maintained stability for 27 months while Nilotinib 150 mg did not. Pagan et al., 2022 randomized 26 patients for Busotinib in LBD with no impact in UPDRS I, II, or III. Also, Watson-Fargie et al., 2018 reported in a review of 2 cases that Imatinib could reduce UPDRS-III progression in PD. <h3>Conclusions:</h3> Reviewed data suggests possible stabilization but no solid clinical improvement. Larger-sample trials might bring further information on all 3 drugs and BCR-ABL TKI in general. <b>Disclosure:</b> Mr. Berton has nothing to disclose. Ms. Rodrigues has nothing to disclose. Mr. Borges has nothing to disclose. Miss Cardoso has nothing to disclose. Dr. Marques has nothing to disclose. Dr. OLIVEIRA has nothing to disclose.

Dose optimization strategy of the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib for chronic myeloid leukemia: From clinical trials to real-life settings.

With the advent of tyrosine kinase inhibitors (TKIs), the treatment prospects of chronic myeloid leukemia (CML) have changed markedly. This innovation can lengthen the long-term survival of patients suffering from CML. However, long-term exposure to TKIs is accompanied by various adverse events (AEs). The latter affect the quality of life and compliance of patients with CML, and may lead to serious disease progression (and even death). Recently, increasing numbers of patients with CML have begun to pursue a dose optimization strategy. Dose optimization may be considered at all stages of the entire treatment, which includes dose reduction and discontinuation of TKIs therapy. In general, reduction of the TKI dose is considered to be an important measure to reduce AEs and improve quality of life on the premise of maintaining molecular responses. Furthermore, discontinuation of TKIs therapy has been demonstrated to be feasible and safe for about half of patients with a stable optimal response and a longer duration of TKI treatment. This review focuses mainly on the latest research of dose optimization of imatinib, dasatinib, and nilotinib in CML clinical trials and real-life settings. We consider dose reduction in newly diagnosed patients, or in optimal response, or for improving AEs, either as a prelude to treatment-free remission (TFR) or as maintenance therapy in those patients unable to discontinue TKIs therapy. In addition, we also focus on discontinuation of TKIs therapy and second attempts to achieve TFR.