Tyrosine Kinase Inhibitors Discontinuation Research Articles

Efficacy of Consolidation Therapy with Ponatinib 15mg on Treatment-Free Remission Rate in Patients with Chronic Myeloid Leukemia. Results of the Ponazero Trial

Introduction: Discontinuation of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has become part of routine clinical practice in recent years, thanks to growing evidence on their feasibility and safety. However, and despite adequate patient selection based on current recommendations, loss of response is observed in approximately 50% of patients. In this scenario, efforts are focused on finding strategies to increase the rate of successful discontinuations. Ponatinib has shown to induce deeper molecular responses compared with imatinib, but its risk of arterial occlusive events (AOE) limits its use in first line at its standard dose of 45mg. The risk of AOEs appears to be dose-related and following the results of the OPTIC study, dose reduction to 15mg in patients with good response is an increasingly popular strategy. Under these premises it has been postulated that a consolidation with ponatinib 15mg may increase the proportion of patients who could discontinue treatment successfully. Our aim is to evaluate the efficacy and safety of one year of consolidation therapy with ponatinib 15mg on treatment-free remission (TFR) rate in patients with CML who have achieved a deep molecular response with imatinib. Material and Methods: A multicenter open-label, single-arm, phase II, exploratory, prospective clinical trial (NCT 04043676) was conducted including patients with philadelphia-positive CML who met discontinuation criteria according to European LeukemiaNet recommendations, had received 4 years or more of imatinib therapy, with a documented grade 4 molecular response (MR4) at least 12 months prior to study entry. Uncontrolled arterial hypertension, active cardiovascular disease, or concomitant medication with potential for QTc prolongation were exclusion criteria. The study has two main phases: ponatinib consolidation (48 weeks), and ponatinib TFR phase (48 weeks); where patients remain without treatment. During the TFR phase, patients with a confirmed loss of MR4 or a single value above major molecular response (MMR) were scheduled to restart treatment with a TKI at investigator's discretion. The present abstract reports the results of the primary endpoint of the study; the proportion of patients with no loss of MR4 at the end of the TFR phase. Results: A total of 23 patients started treatment with ponatinib 15mg. One patient subsequently failed screening due to a major protocol deviation. Baseline patient characteristics were as follows: median age was 51.8 years (range 26-74), 65.2% were male. Ninety-five percent were Caucasian and 5% were Hispanic, ECOG was 0 in 83% and 1 in 17%, Sokal was low in 69.5%, intermediate in 17.5% and unknown in 13%. Eighteen patients were receiving imatinib 400mg daily (82%) at study entry, 2 patients 800mg and two 200mg. Median time on prior imatinib was 10 years (range 4-17), with a median time on MR4 of 3.6 years (range 1.9-13.3). Prior to initiation 13 patients (56.5%) had a grade 5 molecular response, 4 had a 4.5 molecular response (26%) and the remainder had a MR4. The adverse events (AEs) reported with ponatinib are summarized in Table 1, the most frequent being constipation (30%), asthenia (26%), myalgias and arthralgias (26% respectively) and skin rash (17%). A high rate of SARS-CoV2 infections was reported during the treatment period (26%), which should be interpreted considering that the study took place during the COVID-19 pandemic. Three patients out of 22 (13.6%) had serious AEs with ponatinib leading to treatment discontinuation; thrombophlebitis, erectile dysfunction, and intermittent claudication. Of the patients who entered the TFR phase, 14/19 (74%) continue with MMR without requiring treatment after a median follow-up of 12 months (68% with MR4) (table 1). Six patients (31%) lost MR4, five of them required reintroduction of an TKI (4 imatinib, 1 dasatinib; median time to reintroduction 5.4 months). All patients with MR4 loss were receiving the 400 mg dose of imatinib at study entry. All patients who restarted treatment recovered MMR. The sixth patient lost MR4 while maintaining an MMR without requiring treatment reinduction to date. Conclusions: Consolidation with 12 months of ponatinib 15mg in this study shows a high discontinuation success rate with an adequate safety profile, although not free of AEs. The results make this approach attractive for the design of further randomized clinical trials.

Full Treatment-Free Remission Outcome in Patients with Chronic Myeloid Leukemia in Chronic Phase Following One Year of Nilotinib De-Escalation: 96-Week Update of Dante Study

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is achievable and recommended for patients (pts) in sustained deep molecular response (DMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment while maintaining responses. Studies investigating TKI de-escalation before TFR are mainly in imatinib-treated CML chronic phase (CP) pts and suggest that this stepwise approach is feasible. Although nilotinib (NIL) is the first and only TKI approved for stopping therapy, nilotinib-based TFR optimization strategy has not been formally studied. Our phase II, single-arm, prospective, multicenter DANTE study (NCT03874858) aims to shed light on frontline NIL de-escalation in terms of full treatment-free remission (FTFR) (primary endpoint) and TFR rate (secondary endpoint) 96 weeks after the start of consolidation in CML-CP Italian patients. Our previously analysis on 40 pts with sustained DMR who entered in the TFR phase showed that approximately 68% of pts remained disease-free 1 year after stopping NIL 1. Here we present the data of 89 patients who successfully completed NIL de-escalation and at least 1 year of TFR. Methods: Adults patients with CML-CP treated with NIL 300 mg twice daily (bid) in first line for ≥3 years who achieved sustained DMR for ≥1 year (≥MR 4.0; BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sustained DMR entered TFR phase and NIL was discontinued. Patients with major molecular response (MMR [BCR-ABL ≤0.1% IS]) but without sustained DMR continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96 and then every 3 months. Here we report updated results collected until the cut-off date of 8th February 2023, when all patients who entered the TFR phase had completed at least one year of TFR or switched to full-dose phase or entered in survival follow-up or discontinued the study. The primary endpoint of the study is FTFR, defined as the percentage of patients (in both TFR phase and NIL half-dose) in MMR or better at week 96. Results: Overall, 113 pts were screened and 107 entered in consolidation phase. The baseline characteristics and the clinical outcome of the 107 patients are shown in Tab 1. Specifically, 98/107 (92%) completed the consolidation phase, while 9 pts discontinued permanently (2 due to loss of MMR, 3 due to adverse events (AEs) and 4 due to patient decision). Noteworthy, 89/107 (83%) with sustained DMR entered in the TFR phase, while 9 pts maintained MMR but not sustained DMR (7 entered in NIL half dose follow-up period and were in FTFR at 96 weeks, while 2 discontinued the study before week 96). At 1 year cut-off data, 71/107 pts (66.4%) were in FTFR, meeting the primary endpoint of study. We observed 64/89 pts (72%) who entered in the TFR phase remained in MMR or better after a median duration of 20.4 months (interquartile range [IQR] 1.9-32.4), meeting the main secondary endpoint of the study. The median time to loss of MMR in TFR phase was not reached (Fig 1). The remaining 25/89 pts (28%) had discontinued the TFR phase (21 pts due to loss of MMR, 1 due to AEs and 3 pts for subject/guardian decision). The median time spent in TFR phase until loss of MMR was 3.6 months (IQR 2-19 months). At the cut-off data, 23/24 pts (96%) who restarted NIL after MMR loss regained MMR and MR4 after a median time of 2.7 months (IQR 1.0-5.6) and 4.1 months (IQR 1.2-10), respectively. Notably, 20/24 (83%) who restarted NIL after MMR loss achieved MR4.5 after a median time of 6.4 months (IQR 2.0-16.9). During the TFR phase, all-grade AEs were reported in 64/89 pts (72%). One pt (1.1%) had serious AE (pneumonia). No deaths and disease progressions were observed. Conclusions: Our findings show that 66.4% pts who entered in consolidation phase achieved FTFR 96 weeks after the start of the consolidation period, and approximately 72% of pts remained disease-free at 1 year after stopping NIL. Overall, our data suggest that de-escalation of NIL before TFR attempt in CML-CP pts with sustained DMR can be a successful dose-optimization strategy. 1Stagno F. et al., Blood (2022) 140 (Supplement 1): 9614-9616.

Characteristics, Outcomes, Tfr Rates in Young Adults with Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era: A French Observational Study

Introduction. Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a median age of approximately 60 years. Our study emphasizes the fact that CML can present at younger ages. These patients have significantly different life challenges compared with older patients. The 2020 update of the ELN recommendations mentioned that“ TFR may be the main goal for any patient, irrespective of age, but it is clear that the younger the patient the stronger the case for achieving TFR”. We report here the main characteristics and TFR data in CML young adults. Methods. The French CML group (FI-LMC) initiated an observational study (CCTIRS no. 14.745) to describe the characteristics of CML in young adult patients in terms of characteristics at diagnosis, treatment choices, tolerance, adherence, therapeutic response, evolution and survival. Patients ranging from 18 to < 30 years with newly diagnosed CML in chronic phase (CP) or accelerated phase (AP) treated with a tyrosine kinase inhibitor (TKI) in first line were eligible for enrolment. Results. The observatory included 253 unselected young adults from 22 centers with newly diagnosed CML in CP (n=246) or in AP (n=7) among which 51.6% were treated within a first line trial. At the time of CML diagnosis, the median patient age was 24 years (range, 18-29 years); 165 patients were males (63%). Median (range) values were: WBC 154.3 G/L (6.5; 841); platelets 374 G/L (51; 1799), hemoglobin 11.3 g/dL (4.1; 18.3), blast cells 1 % (0; 20), spleen below costal margin 4 cm (0; 30). In CP patients, Sokal score was low in 132 (53.6%) patients, intermediate in 46 (18.7%), high in 37 (15.1%) and unknown in 31 (12.6%) and ELTS score was low in 142 (57.7%) patients, intermediate in 48 (19.5%), high in 22 (9%) and unknown in 34 (13.8%). Initial TKI was imatinib alone (52.4%) or in combination with IFN (2.4%) or Ara-C (0.8%), nilotinib alone (24.6%) or in combination with IFN (4%), dasatinib alone (8.2%) or in combination with IFN (0.4%), bosutinib (1.2%), ponatinib (4.8%) or asciminib (1.2%). Median follow-up is 106.2 months (range: 0.03; 279.2). Ninety-nine (39.3%) patients remained under first-line TKI at latest follow-up and 21 pts (8.3%) underwent bone marrow transplantation (BMT) for resistance or transformation. Median overall survival at 9 years is 96.9% [95% CI: 94.5- 99.4]. Event free survival without death, transformation, or BMT at 9 years is 93.1% [95% CI: 89.7- 96.7]. Six patients died, 1 from sarcoma, 5 from CML including 1 before any therapy (brain hemorrhage). We investigated the TFR strategy. In 169 patients treated for at least 5 years, 56 (33.1%) attempted TKI discontinuation. TKI free survival at 24 months is 57.9% [95% CI: 45.8- 73.2] (Figure 1). Complete analysis comparing characteristics and outcome between the 2 groups of patients (TFR vs no TFR), will be available for ASH presentation. Conclusion. Despite aggressive features including prominent splenomegaly, high WBC counts and high blast cell percentage, TFR seems achievable in young adults with CML.

Long-term Results of Imatinib Discontinuation in Patients with Chronic Phase Chronic Myeloid Leukemia: National Multicenter Prospective Study.

The discovery of imatinib is a milestone for chronic myeloid leukemia (CML) (1). As life expectancy in CML patients has approached that of the general population (2), research has shifted towards improving quality of life and economic considerations. After 2010, it has been shown that some patients could maintain molecular response even after discontinuing imatinib (3). This national multicenter prospective cohort study aimed to observe the long-term consequences of discontinuing imatinib therapy in adult chronic phase CML patients. A total of 41 patients were included. The median follow-up time after imatinib discontinuation was 48 months (minimum-maximum 6-81 months). The rate of molecular relapse-free survival (MRFS) at 48 months was 33,2% (CI:48.2-18.2). Twenty-seven of 41 patients lost their major molecular response MMR, treatment was started again, and the molecular response was re-achieved with imatinib in all patients. There was no significant relationship between molecular relapse and clinical factors like duration of treatment or molecular response status. Discontinuing imatinib resulted in approximately 4,392,000 Turkish Liras (TRY) or 245,150 US dollars (USD) in savings. In conclusion, imatinib discontinuation with close molecular monitoring is a safe option and provides important national economic benefits and enhanced quality of life. This approach should be considered for all eligible patients. This is the first tyrosine kinase inhibitor discontinuation study from Turkey.

In-depth characterization of NK cell markers from CML patients who discontinued tyrosine kinase inhibitor therapy.

Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase is considered a safe option if suitable molecular monitoring is available. However, the question arises as to which factors can contribute to the maintenance of TFR, and immunologic surveillance of the remaining leukemic cells is believed to be one of them. Argentina Stop Trial is an open-label, single-arm, multicenter trial assessing TFR after tyrosine kinase inhibitors interruption, that after more than 4 years showed a successful TFR rate of 63%. In this context, we set up an immunological study by flow cytometry in order to analyze specific NK cell subsets from peripheral blood patient samples both at the time of discontinuation as well as during the subsequent months. At the time of discontinuation, patients show a mature NK cell phenotype, probably associated to TKI treatment. However, 3 months after discontinuation, significant changes in several NK cell receptors occurred. Patients with a higher proportion of CD56dim NK and PD-1+ NK cells showed better chances of survival. More interestingly, non-relapsing patients also presented a subpopulation of NK cells with features associated with the expansion after cytomegalovirus infection (expression of CD57+NKG2C+), and higher proportion of NKp30 and NKp46 natural cytotoxicity receptors, which resulted in greater degranulation and associated with better survival (p<0.0001). This NK cell subset could have a protective role in patients who do not relapse, thus further characterization could be useful for patients in sustained deep molecular response.

Final report of TKI discontinuation trial with dasatinib for the second attempt of treatment-free remission after failing the first attempt with imatinib: Treatment-free Remission Accomplished by Dasatinib (TRAD) study.

Multiple studies have reported a significant treatment-free remission (TFR) rate of 50%-60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re-initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should be switched for re-therapy in patients who failed the first TFR (TFR1) attempt. Our study attempted to determine whether dasatinib therapy after TFR1 failure post-imatinib discontinuation could improve the likelihood of TFR2. Of 59 patients who lost molecular response after imatinib discontinuation for TFR1, 55 patients (93.2%) were treated with dasatinib, of whom 49 (89.1%) regained MR4.5 or deeper response, with a median time of 1.85 months to achieve MR4.5. Dasatinib was discontinued in 35 patients for TFR2 attempt, of whom 26 patients (74.28%) lost MMR and 6 (17.14%) MR4. Risk factor analysis for the TFR2 after dasatinib discontinuation suggested three significant factors: (1) doubling time of BCR::ABL1 transcript following TFR1 attempt, (2) rapid regaining of molecular response following dasatinib therapy and (3) undetectable BCR::ABL1 transcript prior to TFR2 attempt. The present study showed that dasatinib does not increase the TFR2 rate in general, but a selected group of patients could benefit from this approach.

Risk of progression in chronic phase-chronic myeloid leukemia patients eligible for tyrosine kinase inhibitor discontinuation: Final analysis of the TFR-PRO study.

Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP-CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD-eligible patients, we conducted TFR-PRO, a cohort retro-prospective study: 870 CP-CML patients eligible for TD formed a discontinuation cohort (505 patients) and a reference one (365 patients). The primary objective was the time adjusted rate (TAR) of progression in relation to TD. Secondary endpoints included the TAR of molecular relapse, that is, loss of major molecular response (MMR). With a median follow up of 5.5 years and 5188.2 person-years available, no events occurred in the TD cohort. One event of progression was registered 55 months after the end of TD, when the patient was contributing to the reference cohort. The TAR of progression was 0.019/100 person-years (95% CI [0.003-0.138]) in the overall group; 0.0 (95% CI [0-0.163]) in the discontinuation cohort; and 0.030 (95% CI [0.004-0.215]) in the reference cohort. These differences are not statistically significant. Molecular relapses occurred in 172/505 (34.1%) patients after TD, and in 64/365 (17.5%) patients in the reference cohort, p < .0001. Similar rates were observed in TD patients in first, second or third line of treatment. CML progression in patients eligible for TD is rare and not related to TD. Fears about the risk of disease progression among patients attempting TD should be dissipated.

Lineage-specific detection of residual disease predicts relapse in patients with chronic myeloid leukemia stopping therapy

AbstractPatients with chronic myeloid leukemia who are eligible for treatment-free remission (TFR) may still relapse after tyrosine kinase inhibitor (TKI) cessation. There is a need for accurate predictors of outcome to enable patients with a favorable profile to proceed while avoiding futile attempts. Sensitive detection of residual disease in total leukocytes at treatment cessation is associated with relapse but is not highly discriminatory, likely because it is a composite measure of residual leukemia derived from different cell lineages, whereas only some lineages are relevant for relapse. We prospectively measured BCR::ABL1 DNA as a predictive yes/no binary test in 5 cellular fractions from 48 patients meeting conventional criteria for TKI discontinuation. The median BCR::ABL1 DNA level was higher in granulocytes and T cells, but not in other lineages, in patients who relapsed. Among the 40 patients undergoing their first TFR attempt, we defined 3 groups with differing relapse risk: granulocyte-positive group (100%), granulocyte-negative/T-cell–positive group (67%), and granulocyte-negative /T-cell–negative group (25%). These data show the critical importance of lineage-specific assessment of residual disease in the selection of patients who can attempt to achieve TFR with a high expectation of success and, concurrently, defer patients who have a high probability of relapse.

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.

The Success of Treatment Free Remission in Chronic Myeloid Leukaemia in Clinical Practice: A Single-Centre Retrospective Experience from South Africa.

Chronic myeloid leukaemia (CML) management has evolved from a disease once considered to be incurable just over 2 decades ago to that of one of a "functional cure" as defined by the sustained molecular response on stopping tyrosine kinase inhibitor(TKI) therapy. The next goal of CML management has been treatment-free remission (TFR). The past 4 years have seen much international data on TFR attempts in CML in clinical practice. However, Africa as a continent has lagged behind the rest of the world, in keeping up with the latest trends in CML management, and so this study aims to address this gap by assessing the outcome of TFR in CML in a single centre in South Africa (SA). We conducted a retrospective cohort study in 12 CML patients in the chronic phase to assess the success of TKI discontinuation. The patients were treated in King Edward VIII Hospital (KEH), a tertiary, academic hospital in KwaZulu-Natal, South Africa, and the study period was from June 2020 to May 2022. Patients included had to have been on TKI therapy for a minimum of 5 years and achieved a deep molecular response (DMR) for a minimum period of 3 years. The overall TFR cohort showed a success rate of 75% at a median follow-up of 12 months. All patients who failed TFR, defined as a loss of major molecular remission (MMR), failed within 6 months of stopping TKI therapy. All patients who failed TFR regained DMR after retreatment with TKI, with no disease progression reported. The only factor influencing the success of TFR was the total period of TKI therapy. Despite our study having a small cohort of patients, this study demonstrated that TFR in CML is an attainable goal, even in a resource-limited setting.

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.

Myelofibrosis at diagnosis is associated with the failure of treatment-free remission in CML patients.

The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor associating with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (α-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and BCR::ABL1 mRNA levels, while α-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Analysis of human CML-vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, whereas this was only the case in 25% of patients with achieved TFR, further supporting the link between fibrosis and LSC persistence.

Prospective monitoring of chronic myeloid leukemia patients from the time of TKI discontinuation: the fate of peripheral blood CD26+ leukemia stem cells.

Introduction: In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR. Methods: CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation. Results: After a median observation time of 33months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found (p = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib (p = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss. Discussion: Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of "fluctuating" values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs "burden" playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs' ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing.

A long-term follow-up of observation in treatment-free remission in patients with chronic myeloid leukemia

Introduction. The option of observation without therapy with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients is already included in Russian and international clinical guidelines. Evaluation of long-term follow-up results of treatment free remission (TFR) in CML patients is relevant for the introduction of this approach into routine clinical practice. Aim — to demonstrate the outcomes in a long-term follow-up of CML patients who discontinued TKI therapy in the RU-SKI trial. Patients and methods. The prospective study included 98 CML patients with TKI therapy duration ≥ 3 years and a deep molecular response (DMR, BCR::ABL1 ≤ 0.01 %) duration ≥ 2 years. TKI therapy was resumed with the loss of a major MR (MMR, BCR::ABL1 &gt; 0,1 %). Results. Median time of follow-up after TKI discontinuation was 64 months (range of 51–86 months). Survival without MMR loss at 3 and 5 years after TKI discontinuation was 51 % (CI 41–61 %) and 46 % (CI 36–57 %) respectively. From 3 to 5 years of follow-up without therapy, the loss of MMR occurred in 2 (4 %) patients. There was no MMR loss observed after 5 years of follow-up. In patients with first and second treatment discontinuation, survival without MMR loss was 50 % versus 12,5 %(р = 0,039). All 50 patients with molecular relapses regained MMR and MR4 after TKI therapy resumption. BCR::ABL1 level fluctuations 0,01–0,1 % were in 62 % (n = 29) patients, who were in TFR at the time of analysis. Loss of MR4 was observed in 38 (42 %) from 90 patients with first TKI discontinuation. Survival without MMR loss from MO4 loss was 24 % at 5 years after TKI discontinuation. Loss of MO4 in the first 3 months after TKI cessation was associated with a high probability of further MMR loss (8 % versus 54 % in patients with loss of MO4 for &gt; 3 months, p = 0.00015). Conclusion. The low frequency of late relapses (4 % after 3 years of follow-up) and the possibility of long-term persistence of minimal residual disease (MRD) after discontinuation of therapy determine the need to optimize the timing of molecular monitoring, taking into account the MRD status of patients.

SOHO State of the Art Updates and Next Questions | Update on Treatment-Free Remission in Chronic Myeloid Leukemia (CML).

Tyrosine kinase inhibitor (TKI) discontinuation, also known as treatment-free remission (TFR) is currently one of the main goals of chronic myeloid leukemia (CML) therapy. TKI discontinuation should be considered in eligible patients for several reasons. Specifically, TKI therapy is associated with reduced quality of life, long-term side effects, and a heavy financial burden on both the patients and society. TKI discontinuation is a particularly important goal for younger patients diagnosed with CML because of the treatment's effects on their growth and development in addition to potential long-term side-effects. Numerous studies with thousands of patients have demonstrated the safety and feasibility of attempting TKI discontinuation in a select group of patients who have achieved a sustained deep molecular remission. With current TKIs, approximately 50% of patients will be eligible for attempting TFR of which only 50% will achieve a successful TFR. Therefore, in reality, only 20% of patients with newly diagnosed CML will achieve a successful TFR, and the majority of patients will need to continue TKI therapy indefinitely. However, several ongoing clinical trials are investigating treatment options for patients to achieve deeper remission with the ultimate goal of a cure, which is defined as being off drug with no evidence of disease.

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.

Abstract 2181: Treatment-free remission after discontinuation of ALK tyrosine kinase inhibitors (TKIs) in patients with ALK-positive anaplastic large cell lymphoma (ALCL)

Abstract Introduction: ALK-positive ALCL accounts for 0.8% of Korean lymphoma patients. ALK TKIs are effective and durable, but clinical outcomes after treatment discontinuation are unknown. We analyzed outcomes and minimal residual disease (MRD) in adult ALK-positive ALCL patients who discontinued ALK TKIs after achieving treatment-free remission. Methods: Six patients who achieved responses to crizotinib (N=5) and ceritinib (N=1) were analyzed. RNA extracted from the blood or tissues before TKI treatment were subjected to multiplex PCR-based next generation sequencing (NGS) using ARCHER® RNA Fusionplex® to detect NPM-ALK fusion. MRD was assessed by droplet digital PCR (ddPCR) of peripheral blood mononuclear cells (PBMCs) after the treatment discontinuation. Undetectable MRD was defined as less than one lymphocytic cell per 10,000 leukocytes (10-4) in peripheral blood. Results: Patients received ALK TKIs as second line (N=3) or third line and beyond (N=3). All achieved complete metabolic responses after median 28.5 months (range, 1.7-93.9) of treatments (Table 1). Before TKI, LY1 patient had no morphologic evidence of bone marrow involvement, but NPM1-ALK fusions were detected by NGS and ddPCR in blood, bone marrow, and tissue. LY1 patient remained in remission at 27.8 months after crizotinib discontinuation. In all patients, NPM1-ALK fusion were not detected in the PBMCs after discontinuing ALK TKIs for median 38.2 months (range, 0-61.9). No patient re-initiated anti-lymphoma therapies. Conclusion: Out data demonstrated that treatment-free remission was durable for more than two years in ALK-positive ALCL patients following the cessation of ALK TKIs. MRD-guided discontinuation decision may be considered for ALK-positive ALCL patients treated with ALK inhibitors who had undetectable MRD. Table 1. Summary of patient characteristics and outcomes of ALK TKI discontinuation No. Sex Age at diagnosis Ann Arbor stage ALK TKI Lines of prior therapy Treatment duration of ALK TKI (months) Reason for cessation Duration of ALK TKI cessation (months) Best response to ALK TKI Time of MRD assessment after TKI cessation MRD after TKI cessation 1 M 22 IIB Crizotinib 3 93.9 Fertility 27.8 CR 5.6 Negative 2 F 20 IVB Crizotinib 1 90.9 Fertility 25.9 CR 0.0 Negative 3 M 23 IV Ceritinib 1 42.7 Adverse event 61.9 CR 61.9 Negative 4 F 58 IV Crizotinib 3 1.7 Cost 86.6 CR 72.1 Negative 5 F 64 IVB Crizotinib 1 13.6 Cost 31.0 CR 14.4 Negative 6 M 75 IV Crizotinib 2 11.7 Cost 80.2 CR 62.0 Negative Citation Format: Jinyong Kim, Soyeon Kim, Tae Min Kim, Jeonghwan Youk, Miso Kim, Bhumsuk Keam, Dong-Wan Kim, Dae Seog Heo. Treatment-free remission after discontinuation of ALK tyrosine kinase inhibitors (TKIs) in patients with ALK-positive anaplastic large cell lymphoma (ALCL) [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 2181.

Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment-free remission period after imatinib discontinuation: Results of the French Nilo post-STIM study.

Molecular recurrence (MRec) occurs in about half of all patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitors (TKI) in sustained deep molecular response. A second TKI discontinuation has been attempted in some patients who regain the discontinuation criteria after resuming treatment. Nilotinib treatment affords faster and deeper molecular responses than imatinib as first-line therapy. We prospectively evaluated the efficacy and safety of nilotinib (300 mg twice daily) in chronic-phase CML patients who experienced MRec, after imatinib discontinuation and analysed the probability of TFR after a new attempt in patients treated for 2 years with sustained MR4.5 for at least 1 year. A total of 31 patients were included in the study between 2013 and 2018. Seven (23%) patients experienced serious adverse events after a median of 2 months of nilotinib treatment leading to discontinuation of treatment. One patient was excluded from the study for convenience. Among the 23 patients treated for 2 years with nilotinib, 22 maintained their molecular response for at least 1 year (median: 22 months) and stopped nilotinib. The TFR rates at 24 and 48 months after nilotinib discontinuation were 59.1% (95% confidence interval [CI]: 41.7%-83.7%) and 42.1% (95% CI: 25%-71%) respectively (NCT #01774630).

DNA Damage Response (DDR) Is Associated With Treatment-free Remission in Chronic Myeloid Leukemia Patients.

DNA Damage Response (DDR) Is Associated With Treatment-free Remission in Chronic Myeloid Leukemia Patients.

Study progress of tyrosine kinase inhibitor discontinuation in children with chronic myeloid leukemia

Study progress of tyrosine kinase inhibitor discontinuation in children with chronic myeloid leukemia