Tyrosine Kinase Inhibitors Dose Research Articles

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.

Abstract 3884: Targeting the ARID1A mutations overcomes primary resistance to ALK inhibitors in EML4-ALK positive NSCLC

Abstract Introduction: Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) have improved an initial clinical response of non-small-cell lung cancer (NSCLC) patients with ALK-rearrangements. However, a subset of patients shows a poor response to ALK-TKIs. Here, we aimed to identify novel mechanism of primary resistance in preclinical model from a patient who presented an impressive resistance to sequential treatment with ALK TKIs. Experimental design: The PDC YU-1076 cells were established from pleural effusion of the patient at the time he was receiving chemotherapy and radiotherapy after failure of ALK-TKI treatment. Sanger sequencing confirmed ML4-ALK variant 1 detected at the initial diagnosis. No resistance mutations in the ALK kinase domain were detected. To investigate co-occurring genetic alterations, we performed whole exome sequencing (WES) on YU-1076 cells and the matched blood sample. We further investigated the molecular profile of YU-1076 cells using RNA-sequencing analysis. Results: YU-1076 cells exhibited cross-resistance to clinically available ALK-TKIs including crizotinib, ceritinib, alectinib, and lorlatinib. However, immunoblot analysis of YU-1076 cells treated with incremental doses of TKIs unexpectedly revealed an effective reduction of ALK activity and downstream signals. We noticed that YU-1076 cells gradually changed from a small, round shape to a fibroblast-like shape following the treatment of ALK-TKIs. Transcriptome analysis confirmed enrichment for gene signatures related epithelial-to-mesenchymal transition (EMT) in ALK TKI-treated YU-1076 cells, suggesting that ALK-TKIs treatment promotes YU-1076 cells toward a more mesenchymal phenotype. WES analysis identified a major chromatin remodeling complex subunit, AT-rich interacting domain 1A (ARID1A), as well as MYC amplification, CDKN2A loss, and TP53 mutations. We focused on a synthetic lethal strategies using the SFK inhibitor dasatinib and the EZH2 inhibitor GSK126 in ARID1A mutant cancers. The combination of dasatinib with ALK-TKIs restored the sensitivity to the ALK TKIs in YU-1076 cells, accompanied by suppression of EMT marker genes VIM and CDH2 and increase of apoptotic markers BIM, PARP, and CAS3. Congruently, dasatinib significantly impaired tumor growth in YU-1076-xenografts. GSK126 also induced synergistic inhibition of cell growth with upregulation of apoptosis marker genes in YU-1076 cells, but did not affect the expression of EMT marker genes. Conclusion: Our data indicate that ARID1A could be potentially used as a predictive biomarker for unfavorable ALK-TKI response. In this context, a combination strategy of ALK TKI with dasatinib may be effective in overcoming primary resistance. Citation Format: Seung Yeon Oh, You Won Lee, Eun Ji Lee, Ju Young Kim, Sewon Park, Ju Yeon Park, Su-Jin Choi, Mi Ra Yu, Sowon Aum, Jiyun Lee, Chang Gon Kim, Jii Bum Lee, Sun Min Lim, Min Hee Hong, Mi Ran Yun, Byoung Chul Cho. Targeting the ARID1A mutations overcomes primary resistance to ALK inhibitors in EML4-ALK positive NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3884.

Patient-guided dose reduction of tyrosine kinase inhibitors in chronic myeloid leukaemia (RODEO study): study protocol for a prospective, multicentre, single-arm trial

BackgroundDose reduction of tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukaemia (CML) with an optimal response to TKIs may support cost-effective medication use by maintaining therapeutic effectiveness while reducing adverse events and medication costs. As the choice for dose reduction depends on patients’ individual needs and preferences, a patient-centred approach is warranted. Therefore, a study to evaluate the effectiveness of patient-guided dose reduction in patients with CML who are in a major or deep molecular response is designed.MethodsThis study is a prospective, multicentre, single-arm study. 147 patients with CML (aged ≥ 18 years) in chronic phase, who are treated with imatinib, bosutinib, dasatinib, nilotinib or ponatinib, and have reached at least major molecular response (defined as having BCR-ABL levels < 0.1% for an uninterrupted period of 6 months) are eligible. Patients will use an online patient decision aid and a shared decision making consultation will be held, after which patients who choose to will receive a personalised, lower TKI dose. Primary outcome is the proportion of patients with intervention failure at 12 months after dose reduction, defined as patients who have restarted their initial dose due to (expected) loss of major molecular response. For this, BCR-ABL1 levels will be analysed from blood samples drawn at baseline, 6 weeks after dose reduction and 3-monthly thereafter. Secondary outcomes include the proportion of patients with intervention failure at 6 and 18 months after dose reduction. Other outcomes include differences before and after dose reduction regarding the number and severity of patient-reported side effects; quality of life; beliefs about medicines; and medication adherence. Patients’ level of decisional conflict and regret after choosing dose reduction will be assessed, as will the decisional process experienced by patients and healthcare providers.DiscussionOutcomes of this trial using a personalised approach will provide clinical and patient-reported data to guide future dose reduction of TKIs in CML. If the strategy appears to be effective, it may be implemented as another valid option to offer next to standard of care to prevent potential unnecessary exposure to higher TKI doses in this selected group of patients.Trial registrationEudraCT number 2021-006581-20.

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.

Insights into the medical management of gastrointestinal stromal tumours: lessons learnt from a dedicated gastrointestinal stromal tumour clinic in North India.

The advent of molecular driver alterations has brought in a revolutionary transformation in the treatment landscape of gastrointestinal stromal tumour (GIST). However, there is a paucity of data regarding mutational testing prevalence and associated outcomes from India. It was a retrospective study. We reviewed the case records of all patients diagnosed with GIST in a tertiary care centre from 2015 to 2021. The clinicopathological, mutational analysis and treatment plans were recorded. The study cohort was characterised by descriptive statistics. Our study included 120 patients with a median age of 53 years (range: 28-77), with a male preponderance of 2:1. The most common site of the primary was the stomach (50%), followed by the small intestine (37%), with 55.8% of the patients having disseminated disease at presentation with a predominance of liver metastasis (67%). The prevalence of mutational analysis among patients prior to referral was 4%. 60.8% of the patients at our clinic had mutational analysis performed, and unavailability of analysis in the rest was due to financial constraints (12.5%), exhaustion of tissue (7.5%), reluctance to repeat biopsy (4.1%) and low-risk patients. We report c-kit in the majority (52%), platelet-derived growth factor receptor (PDGFR) in 19.2% and wild type in 16.4% along with the rarer subtypes: succinate dehydrogenase (SDH)-deficient GIST in 10.9% and Neurotrophic tyrosine receptor kinase (NTRK) fusion in 1.3%. Four of the eight SDH-deficient GIST patients had germline mutations (50%). The knowledge of driver mutations led to a change of treatment in 39.7% (29/73), i.e. stoppage of tyrosine kinase inhibitor (TKI) in 3, switch of TKI in 23, increase in TKI dose in 2 and upfront surgery in 1. The most common change was the use of sunitinib and regorafenib in patients with SDH-deficient GIST. Our study is one of the largest comprehensive series describing the clinical and mutational profile of GIST from India. The mutation testing rates at primary care centres continue to be low. Despite the hurdles, a large percentage of our patients underwent molecular testing, aiding in therapeutic decision-making.

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

Retrospective Study of Treatment Free Remission in Patients with Chronic Myeloid Leukaemia(CML) Treated at Tertiary Care Oncology Centre from India

Background Tyrosine kinase inhibitors (TKI) have dramatically improved outcomes in Chronic Myeloid Leukemia(CML) patients, but lifelong TKI therapy can negatively impact patients' quality of life due to chronic adverse events. Treatment free remission(TFR) is now the new goal of CML therapy. Studies have shown this is feasible in developed countries. Literature on discontinuation of TKI therapy in resource limited countries such as India is scarce. The purpose of this study was to investigate whether some chronic myeloid leukemia patients with excellent and sustained molecular responses to tyrosine kinase inhibitor treatment can gradually de-escalate TKI therapy and stop therapy in Indian setting. Methods We included all patients above the age of 18years with diagnosis of CML in first Chronic Phase (CP) on TKI therapy of minimum 3 years duration with major molecular response (MMR i.e., <0.1% BCR-ABL1 transcript) of minimum of 2 years duration, enrolled for treatment free remission between January 2018 to December 2021. Starting dose of imatinib was 400mg once daily, dasatinib 100mg once daily and nilotinib 300mg twice a day. In this study the dose of these drugs was reduced by 25% every 6 months . This dose reduction was done with 2 monthly outpatient clinic visits and 2 monthly BCR-ABL1 quantitative PCR monitoring. Patients who maintained MMR during 6 months of dose de-escalation qualified for next level of dose de-escalation. Eventually treatment was stopped completely and monitoring continued. This was retrospective medical record based study done at a tertiary care centre in North India. Results Between Jan 2018 to Dec 2021, 29 patients were enrolled for dose de-escalation and treatment cessation. Among these 29 patients, 19 were on imatinib, 2 on dasatinib and 8 patients on nilotinib. Median age was 39 years( range 21 years to 67 years). Twelve patients were male and 17 female. Median duration of TKI therapy prior to de-escalation was 8 years (range 4years-14 years). Median duration of major molecular response prior to dose reduction was 6 years( range 3years-12 years). In our study 17 of 29 patients had an outcome, while 12 patients are still on de-escalation phase with maintained MMR and are not included in the outcome analysis. Eight patient had loss of MMR(47.05%), 6 while on dose de-escalation and 2 after cessation of TKI. All eight patients achieved MMR after re-initiation of the prior dose, out of these 6 patients had sustained MMR(>6months) at reduced TKI dosing compared to conventional dose. Nine patients (52.9%) have successfully stopped TKI for median duration of 11months (range 6 to 19 months). Conclusion TKI de-escalation was safe for most patients with excellent prior response to TKI therapy. This way of dose reduction , ensured motivation and commitment of patients by doing regular OPD follow ups and BCR-ABL1 PCR testing. In our study 52.9% patient could successfully maintain TFR at a median follow up of 11 months of stopping the drug. We also identified that a subgroup of patients(35.29%) who were unsuccessful in complete cessation of therapy but maintained their molecular response at reduce dose of TKI . These findings show that lower TKI doses might maintain molecular responses in these patients, implying that such patients could be overtreated with routine dosing. More studies of dose de-escalation are warranted.

Patient-Versus Physician-Perceptions of Symptoms, Treatment and Management in Chronic Myeloid Leukemia

BackgroundChronic myeloid leukemia (CML) is a chronic disease with treatment-free remission (TFR) increasingly regarded as a feasible goal of treatment. The optimal outcome achieved in CML requires both prolonged adherence to oral tyrosine kinase inhibitor (TKI) therapy by patients and careful monitoring of treatment responses by their physicians. Various factors would impact doctors following international guidelines for CML management in real-word, however, very few studies has investigated possible discrepancies between patient- and physician-reporting in the CML setting. Objective To compare the reporting of care between CML patients and their treating doctors, and to explore the underlying causes for both physicians and patients non-adherence. MethodsParallel patient and physician online surveys were conducted between September 22, 2021 and March 15, 2022, using the WeChat-based survey program Wenjuanxing. Descriptive analysis of the results mainly focused on CML adults patients and physicians treating CML regarding TKI treatment options, monitoring and toxicities, TFR, and facing challenges. ResultsA total of 1882 patients and 305 physicians completed the survey. Among the enrolled patients, 69.9% received imatinib as first-line therapy, of them 47.0% switched to other TKIs due to imatinib resistance/intolerance (58.5%), exploration on more potent TKI to achieve TFR (13.1%), and treating physicians’ recommendation (15.8%). 91.8% of the physicians believed BCR-ABL1 level should be assessed every 3 months, however, only 42.7% patient respondents committed to 3-monthly testing and 17.8% strictly followed their treating physicians’ recommendation. Half of the patients (49.9%) aimed at TFR, however, just 45.2% physicians considered TFR as one of the three major treatment objectives, obstacles to achieve TFR mainly attributed to their patients. Fatigue and anemia were the key negative impactors for patients who were significantly associated with higher incidence of mental disorders, whilst physicians paid more attention to platelet and neutrophil count. Incidence of moderate to severe anxiety or depression is 12.0% and 20.8%, respectively; but only 41.3% of patients needed support from their doctors, and 53.7% physicians provided their patients with additional support. 13.7% patients had delayed follow-up visit and molecular monitoring, 7.4% patients discontinued TKI or reduced TKI dose due to economic difficulties (69.2%), which resulted in 10.2% patients suffering from disease progression amid the COVID-19 pandemic. 42.3% patients were vaccinated for SARS-CoV-2, another 57.7% patients against vaccine because of safety concern. Cost is the major impactor for treatment choices, molecular monitoring, treatment objective, mental health, and even the treatment under the pandemic, which were fully recognized by both the patients and physicians. ConclusionsPhysicians who joined our survey had low awareness on patients’ fatigue and anemia. Mental disorders existed in a significant proportion of patients, whereas less concerned by both patients and physicians. Cost is the major impactor for physician and patient adherence to current clinical practice guidelines, especially under current COVID-19 pandemic in China.

Chronic-Phase Chronic Myeloid Leukemia Times to Death By Disease Support Tyrosine Kinase Inhibitor Dose Reductions When BCR::ABL1 Level Is

Tyrosine kinase inhibitors (TKIs) are commonly believed to provide almost-normal lifespans to patients with chronic-phase (CP) chronic myeloid leukemia (CML). This is, however, not supported by Surveillance, Epidemiology, and End Results (SEER) mortalities >10 years after diagnoses that reveal a CP-CML relative risk (RR) of death of 2.14 (95% confidence interval [CI], 1.97-2.32); normal lifespans yield RR = 1.00, and by 10 years after diagnoses, most CML patients still alive were in CP at diagnosis, dates of which were between 2001 and 2009. This CP-CML RR estimate of 2.14 is comparable to those of Hodgkin's lymphoma (2.08; 95% CI, 1.95-2.22) and acute myeloid leukemia (2.22; 95% CI, 1.99-2.47) and higher than those of non-Hodgkin's lymphoma (1.62; 95% CI, 1.59-1.65) and chronic lymphocytic leukemia (1.84; 95% CI, 1.79-1.9). Thus, CP-CML is not functionally cured. In contrast, the RRs of hairy cell leukemia (1.14; 95% CI, 0.98-1.31) and acute promyelocytic leukemia (1.15; 95% CI, 0.87-1.49) are consistent with these leukemias being functionally cured. Of excess CP-CML deaths, roughly two thirds were by disease. These excess deaths by disease may be due in part to prolonged dose interruptions in response to treatment-related toxicities or to reduce financial burdens (ie, absence of TKI therapy). Frequencies of such events, and thus deaths by disease, could be decreased by reducing TKI doses moderately as cancer loads fall low enough to pose negligible progression risks. We present CML-intrinsic, TKI-agnostic support for reducing TKI doses when BCR::ABL1IS is <1% and decreasing. Times from diagnosis to death for 2732 SEER patients with CML diagnosed between 1975 and 1985 (before the availability of TKIs) informed a Markov model of CP → accelerated phase → blast crisis → death that assumed CML-saturated marrows in the absence of disease-modifying therapies during this time. The probabilities of transitioning from each phase to the next were fitted to the excess absolute risk of death (compared with the general US population) as a function of years after diagnosis (Panel A). To predict TKI effects on the probability of death by disease, the chronic-to-accelerated phase transition rate was assumed to be proportional to TKI-induced reductions in CML load fraction L, due to the reduced number of leukemic cells susceptible to a transforming mutation. Reducing L by a factor of 10 (from 1 to 0.1) increased the amount of time needed to reach a 5% probability of death by disease from 1 to 3 years. Lowering L by an additional factor of 10 (to 0.01 [1%]) increased the expected number of years to 16 (ie, ~5-fold). Finally, a third reduction of L by a factor of 10 (to 0.001 [0.1%]) yielded nearly an additional 10-fold increase in the time needed to reach a 5% probability of death by disease, from 16 to 145 years (Panel B). Gains in relative delay in 5% probability of death by disease divided by relative decrease in L were maximal at L = 0.015, which can be argued to correspond to BCR::ABLIS = 0.75% = ~1%, which appears to be a point of departure in Panel B. Based on data that predates TKIs, our analysis suggests that there is a strong need to lower disease burdens (BCR::ABLIS) below 1% and essentially no need to lower them below 0.1%. Thus, while it is important to use drug dosing that maintains responses at 1% or lower, if BCR::ABLIS is <1% and decreasing, dose reductions should be considered. Such reductions may prevent deaths associated with mismanagement of drug directly and deaths by disease indirectly, as reducing doses prospectively may avoid toxicities that may otherwise result in prolonged interruptions that cause to rise enough to cause death by disease. These dose reduction benefits should be included in patient-physician discussions of pursuing lower BCR::ABLIS levels in hopes of achieving a treatment-free remission versus pursuing lower doses to mitigate toxicity risks. Envisioned here is a future in which personalized patient safety parameters are weighed against personalized predictions of BCR::ABLIS response dynamics that, through computer simulations incorporating our Markov model, project to risks of progression and death by disease. Decision support based on such models may help patients and physicians balance drug versus disease risks. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Update in Childhood Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) in childhood represents only 3% of newly diagnosed pediatric leukemia. The diagnostic hallmark of CML is the Philadelphia (Ph) chromosome, which derives from the fusion of the ABL1-oncogene located on chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22, resulting in a constitutively dysregulated ABL1 tyrosine kinase, either as 210 kDa or 190 kDa. Depending on the localization of the breakpoint site within the major BCR region, the majority of CML patients exhibit transcripts with either the b3a2 or b2a2 junction, or both. Several questions are still open with regard to childhood CML, especially concerning the biologic and clinical features of the disease, and the treatment of choice for pediatric patients with CML. Moreover, over the last few years, several tyrosine kinase inhibitors (TKIs) have been available for children and adolescents with CML, and current clinical practice investigates what the effective and optimal doses of TKIs are in these two categories of patients. The use of TKIs in pediatric patients with CML has also opened up questions on the following items: (1) the long-term effects of these drugs on children; (2) the management of pediatric CML forms resistant or intolerant to TKIs; (3) the monitoring of disease outcomes during treatment; (4) and the right timing to discontinue therapy. Despite the efficacy of TKIs also in the pediatric population, the potential late adverse effects, and the drug resistance, leave open the possibility of allogeneic hematopoietic stem cell transplantation as a treatment option in pediatric CML. Published data and personal experiences regarding these issues will be analyzed and discussed.

Deep molecular response in patients with chronic phase chronic myeloid leukemia treated with the plasminogen activator inhibitor-1 inhibitor TM5614 combined with a tyrosine kinase inhibitor.

We recently showed that pharmacological inhibition of plasminogen activator inhibitor-1 (PAI-1) activity, based on TM5614, increases cell motility and induces the detachment of hematopoietic stem cells from their niches. In this TM5614 phase II clinical trial, we investigated whether the combination of a PAI-1 inhibitor and tyrosine kinase inhibitors (TKIs) would induce a deep molecular response (DMR) in patients affected by chronic myeloid leukemia (CML) by quantifying BCR-ABL1 transcripts. Patients with chronic phase CML treated with a stable daily dose of TKIs for at least 1year and yielding a major molecular response (MMR) but not achieving MR4.5 were eligible for this study. After inclusion, patients began to receive TM5614 as well as a TKI. The primary objective was an evaluation of the cumulative incidence of patient progression from an MMR/MR4 to MR4.5 by 12 months. Thirty-three patients were enrolled in the study. The median age was 59.0 years and 58% were male. No Sokal high-risk patients were enrolled in this trial. The median TKI treatment duration was 4.8 years. At the start of this study, seven patients and 26 patients received imatinib and second-generation TKIs, respectively. The cumulative MR4.5 incidence by 12 months was 33.3% (95% confidence interval, 18.0%-51.8%). The cumulative MR4.5 spontaneous conversion over 12 months was estimated as 8% with TKIs alone based on historical controls. The halving time of BCR-ABL1 at 2months was significantly shorter for patients who achieved an MR4.5 , by 12 months than for the other patients (cutoff value: 48 days; sensitivity: 0.80; specificity: 0.91; ROC-AUC: 0.83). During this study, bleeding events and abnormal coagulation related to the drug were not reported, and TM5614 was found to be highly safe. TM5614 combined with TKI was well tolerated and induced MR4.5 in more patients than stand-alone TKI treatment.

De-escalation or discontinuation of tyrosine kinase inhibitor in patients with chronic myeloid leukemia: A multicentral, open-label, prospective trial in China.

Background: Long-term treatment-free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). Optimizing dose of tyrosine kinase inhibitors (TKIs) in the CML treatment maybe a new challenge to maintain effective and improving patients' quality of life. We hypothesized that administration of low-dose TKIs does not compromise major molecular response (MMR) in patients with CML who have a deep molecular response (DMR). Methods: We did an open-label, randomized trial at eight hospitals in China. Eligible CML-CP patients (aged 18-70 years) had shown continuous response to TKI more than 5 years and maintained MR4.5 (BCR-ABLIS ≤ 0.0032%) in recent 18 months. Patients were randomly assigned (1:1) to the TKI de-escalation group or the discontinuation group. Randomization was done with permuted blocks (block size four) and implemented through an interactive web-based randomization system. Recurrence was defined as the single sample with real time Quantitative PCR (RT-qPCR) measurement greater than 0.1% (MMR). The primary endpoint was 12-month MMR rate in patients who received de-escalation or discontinuation of TKIs. This study was registered at ClinicalTrials.gov (NCT04143087). Results: Around 125 patients were enrolled between October 23, 2019 and October 31, 2020, 62 patients received dose de-escalation of TKIs, while 63 patients in the discontinuation group. In the de-escalation group, molecular recurrence-free survival at 12 months was 88.32% (95% CI 79%-98%), whereas molecular recurrence-free survival in the discontinuation group at 12 months was 59.98% (95% CI 47-73). No progressions occurred at the data cut-off date. All 29 recurrence cases restart TKI treatment returned to MMR. Cytolytic NK cells as a proportion of lymphocyte cells were significantly increased from baseline after 6 months whether in the de-escalation or TKIs cessation group (P=0.048, 0.001, respectively); compared with the relapsing patients, Tregs proportion was decreased (P=0.003), and higher proportion of NK cells were found in non-relapsing patients whetherin TKI de-escalation or discontinuation group (P=0.011, 0.007, respectively). We also found that the de-escalation group showed better disease-specific HRQOL in regards to its impact on emotional functioning, fatigue, pain, and financial difficulties. Conclusion: With 88.32% MMR in 12-months follow-up after de-escalation TKIs' treatment, dose-halving could become a new treatment paradigm for CML patients who with DMR under continuing maintenance therapy with TKIs.

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.

LOCL-11 EGFR-MUTATED NON-SMALL CELL LUNG CANCER (NSCLC) LEPTOMENINGEAL DISEASE (LMD) IN A LARGE STEREOTACTIC RADIOSURGERY PATIENT COHORT: INCIDENCE AND OUTCOME

Abstract AIM Patients with EGFR-mutated NSCLC brain metastases (BM) treated with targeted agents +/- radiosurgery (SRS) have increasing life expectancies. Systemic treatment may become less effective in preventing CNS progression as survival is prolonged. We sought to identify subsequent LMD in patients with EGFR-mutated NSCLC treated initially with SRS for BM and describe the associated features, treatment, and outcome. METHODS Review of our prospective Gamma Knife registry identified 177 patients with EGFR-mutated NSCLC between 2005 and 2021 treated with SRS. The EMR was queried for development of LMD, and type of LMD was recorded (focal/nodular or diffuse). RESULTS 38 (21%) of the 177 patients developed LMD at a median of 10 months (range 1-25 IQR) following SRS. 27 (71%) of these were on tyrosine kinase inhibitors (TKI) at time of LMD diagnosis. Median overall survival (OS) from initial SRS for the entire cohort was 21 months (18-27 95%CI). Median OS after LMD diagnosis was 5 months (2-32 95%CI). LMD was diagnosed radiographically in 35 patients (92%); 20 patients had diffuse, 15 had focal/nodular, and 3 had positive CSF cytology. 26 (68%) had systemic progression synchronously with LMD. 33 (87%) had treatment for LMD including 19 with whole brain radiation therapy, 16 with the addition of or increased dosing of TKI, 6 with SRS for nodular disease, and 9 with intraventricular chemotherapy. The one- and two-year survival rates following the diagnosis of LMD was 21% and 3%, respectively. CONCLUSION LMD developed in a substantial subset of our patients, and despite the use of a variety of salvage therapies, survival was poor. Investigation to identify factors correlating with the development of LMD and those related to outcome are ongoing. The development of LMD on TKI in several of our patients supports efforts to pursue development of therapeutic agents with long-lasting CNS efficacy.

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.