Sustained MR4 Research Articles

Successful Treatment-Free Remission After Ponatinib Discontinuation in Pretreated Patients with Chronic Myeloid Leukemia in Chronic Phase

IntroductionThe discontinuation of third-generation BCR::ABL1 tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is not well understood. We aim to evaluate treatment-free remission in patients with CML-CP who discontinue ponatinib. MethodsWe retrospectively reviewed 361 patients who attempted TKI discontinuation between November 2005 and February 2024 and identified those receiving ponatinib at the time of discontinuation. Molecular relapse-free survival (MRFS) was calculated from the time of ponatinib discontinuation to the date of loss of major molecular response (MMR) or last follow-up. ResultsEleven patients discontinued ponatinib. Before ponatinib discontinuation, patients were on TKI therapy for a median of 146.6 months and on ponatinib for a median of 67.5 months. The median number of TKIs prior to starting ponatinib was 2 (range, 1-3). The median durations of sustained MR4 and MR4.5 before ponatinib discontinuation were 32.8 and 29.4 months, respectively. After a median follow-up of 60.3 months, the 60-month MRFS rate was 53%. Five patients lost MMR; their median MR4.5 duration was 5 months before ponatinib discontinuation. ConclusionPonatinib discontinuation is feasible in patients with CML-CP failing prior TKIs. Patients who achieve sustained MR4.5 for at least 2 years have the highest likelihood of remaining in treatment-free remission following ponatinib discontinuation. Micro-abstractWe aim to evaluate treatment-free remission in patients with chronic myeloid leukemia in chronic phase (CML-CP) who discontinue ponatinib. We identified 11 patients who failed prior tyrosine kinase inhibitors (TKIs) and were receiving ponatinib at the time of discontinuation. The median durations of sustained MR4 and MR4.5 before ponatinib discontinuation were 32.8 and 29.4 months, respectively. Five patients lost MMR; their median MR4.5 duration was 5 months before ponatinib discontinuation. In summary, ponatinib discontinuation is feasible in patients with CML-CP failing prior TKIs. Patients who achieve sustained MR4.5 for at least 2 years have the highest likelihood of remaining in treatment-free remission following ponatinib discontinuation.

International, Prospective Study Comparing Nilotinib Versus Imatinib with Early Switch to Nilotinib to Obtain Sustained Treatment-Free Remission in Patients with Chronic Myeloid Leukemia (SUSTRENIM trial): Analysis of the Eligibility to Treatment Discontinuation

Background. Treatment free remission (TFR) is one of the most important aims of CML treatment but, so far, the best treatment strategy to obtain a durable deep molecular response (DMR) and the overall rate of patients able to achieve a successful TKI discontinuation based on intention-to-treat principle from CML diagnosis are still debated. In November 2016 we launched an international, prospective, randomized, two arms study to evaluate both the depth of the molecular response and the rate of TFR in newly diagnosed CP-CML patients treated with a second generation TKI (Nilotinib, NIL) or with imatinib (IM) followed by switching to NIL in absence of optimal response (Clinical Trial number 02602314). Patients were randomized 1:1 between NIL and IM, stratifying on the Sokal score. All the patients achieving a MR4.0 or better by three years and maintaining this level of response up to the end of the fourth year of therapy were qualified for the discontinuation phase. We recently reported that patients enrolled in the NIL arm had a rate of MR4.5 at two years (primary co-endpoint of the study), significantly higher than those in the IM arm (32 vs 22%, p = 0.023 Pane F. et al, EHA 2022). The aim of the present analysis is to assess, in both arms of the trial, the percentage of patients achieving the eligibility to treatment discontinuation, defined as a MR4 maintained in 4 consecutive MRD analysis within the fourth year of therapy. Methods. In this pilot analysis, we first examined the rate of patients eligible to discontinuation and their baseline features (i.e. age, gender, ELTS and Sokal risk, BCR::ABL1 isoform) compared to patients without sustained MR4, using Fisher's exact test or Wilcoxon according to variable type. In patients discontinuing TKIs at 48 months, the successful TFR probability at 12 months after TKI withdrawal was computed with the Kaplan Meier method. Molecular relapse, defined as the loss of MMR or confirmed loss of MR3.0, progression, or death were considering as event in the event-free survival curve. Results. Of the 448 randomized patients, 289 had at least 48-month observation at the time of the present analysis and were evaluated for TFR eligibility, 141 in the IM arm and 148 in the NIL arm, respectively. Ninety-three patients (32%) showed a sustained MR4 in the fourth year and were deemed eligible for treatment discontinuation, 45 in the IM arm (32%) and 48 in the NIL arm (32%). Of the remaining 196 patients, 59 did not have the criteria to discontinue treatment and 137 previously went off study for failure, progression, toxicity, death, or other causes (66 in the IM arm and 71 in the NIL arm, respectively). We found that sustained MR4 achievement was significantly associated with low disease risk, according to both ELTS (81.7% vs 47.2% p<0.0001) and Sokal scores (50.5% vs 34.2%, p=0.008). There is a weak correlation to the age, being those eligible younger (median 52.5 vs 55 years, p=0.037), while no differences in gender and BCR::ABL1 isoform distributions were observed. Within the IM arm, patients who switched to NIL were 60/141 (43%), 44 within the first 12 months and 16 after the first year; those patients had a lower probability of starting the TFR phase compared to patients continuing IM (22% vs 40%, p=0.025). The median follow-up of the 93 patients who attempted treatment discontinuation at 48 months is 9.9 months (IQR: 5.3-12.1). The percentages of those patients in TFR were 82.9% (95% CI:74.8-91.8) at 6 months and 74.3% (95% CI:63.9-86.4) at 12 months. The analysis per random was considered premature given the short follow-up and the proportion of patients not yet evaluable for the discontinuation. Conclusions Although the results are still preliminary to draw definitive conclusions on the rate of sustained DMR and stable TFR , our data indicates that despite higher 24-month rates of MR4.5 in the NIL arm, the probability of reaching criteria for TFR attempt may be not different in the two study arms: one third of patients attempted discontinuation and the majority of them appear to be free of relapse after a median of 10 months from the therapy discontinuation. Among patients of the IM arm, patients switching to NIL due to absence of optimal response had a lower probability to attempt discontinuation. Noteworthy, as for the MR4.5 rate at 24 mo. of therapy, patients at low ELTS risk score are those with the highest probability to achieve sustained MR4 and being eligible for the treatment discontinuation.

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

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

Phase 2 Study of Dasatinib with and without Venetoclax in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECP-CML)

Background Treatment-free remission (TFR) is a therapeutic goal for patients with ECP-CML once patients maintain a deep molecular remission (DMR) on tyrosine kinase inhibitors (TKIs). Only a fraction of patients (pts) achieved sustained (3+ years) molecular remission with 4.0- to 4.5-log reduction (MR4.5). Preclinical studies showed that BCL-2 is a key survival factor for CML stem/progenitor cells. Therefore, the combination of TKIs and venetoclax, targeting BCR::ABL1 and BCL-2, has the potential to significantly improve DMR and subsequently the rates of TFR. The aim of this study is to evaluate the safety and efficacy of the combination. Methods Patients with ECP-CML or accelerated phase (AP; defined by clonal evolution only) were eligible; pts with < 1 month of prior TKI therapy were eligible. Pts received single-agent dasatinib 50 mg/d for the first 3 months. From Month 4 and onwards, venetoclax was administered from Days 1 to 14 each month concomitantly with dasatinib for a total of 3 years. The first 16 patients received venetoclax 200 mg/d, with a rapid ramp-up starting 50 mg on Day 1, then 100 mg on Day 2, then 200 mg daily on Day 3 and onwards. Due to neutropenia observed with continuous dose of venetoclax 200 mg/d, the protocol was ameded: from patient #17 and onwards, venetoclax was administered at 200 mg/d for 14 days per month and upon achievement of MR4.5, venetoclax was reduced to 100 mg/d for 7 days per month. After 3 years of combination, patients received single-agent dasatinib. TFR was offered after ≥ 3 years of DMR. The primary endpoint was the rate of major molecular response (MMR) by 12 months of the combination. The secondary endpoints were the 12-month rate of MR4.5 and the cumulative overall rate of MR4.5; the rates of MR4.5 at 6-, 12-, 18-, 24, and 36-months of the combination; the proportion of patients with sustained MR4.5 of 3 years and more; the TFR rate; overall survival; and the safety of the combination. Cumulative response rates were calculated with treatment failure as a competing event. Failure-free survival (FFS) was calculated from the initiation of therapy to loss of major cytogenetic response (MCyR), transformation to AP or blast phase, discontinuation of therapy for any reason except of TFR, or death. Results Sixty-five pts were enrolled and treated between April 2018 and August 2021. The median age at treatment initation was 46 years (range, 23-73) and 57% of the pts were females. Twenty-one (32%) pts had splenomegaly, 46 (71%) had low Sokal risk disease and 3 (5%) had high Sokal risk disease (Table 1). By 12 months of the combination, 85% of the pts had achieved MMR or deeper response. The median time to MMR, MR4, and MR4.5 were 6.2 months, 13 months, and 23.9 months from the time of TKI start, respectively. After a median follow-up of 25.7 months (range, 8.7-48.1), two pts discontinued therapy due to adverse events (GI intolerance, and pleural effusion); the 2 -year FFS was 96%. One pt switched TKI therapy due to the lack of 18-month complete cytogenetic response (CCyR); no loss of CCyR, transformation, or death was observed. We then compared the outcomes with the combination to the outcomes of 85 pts treated with single-agent dasatinib. From the start of TKI therapy, the 12-month cumulative MMR rates were 78% and 79% in the dasatinib single-agent and dasatinib + venetoclax groups, respectively. The cumulative 24-month rates of CCyR, MMR, MR4, and MR4.5 are summarized in Table 2. In the dasatinib single-agent group, 3 pts switched TKI therapy due to the lack of 12-month MCyR, 18-month CCyR, and the acquisition of ABL1 mutation (1 each); 3 pts switched TKI therapy due to loss of CCyR; 2 pts died during therapy (deaths unrelated to CML). Within one year of therapy, the incidence of grade 1/2 neutropenia (absolute neutrophil count, below lower range of normal to 1,000 x10 9/L) was 21% and 52% in the dasatinib single agent and dasatinib + venetoclax groups, respectively ( P<0.001); the incidence of grade 3/4 neutropenia (absolute neutrophil count, below 1,000 x10 9/L) was 8% and 17%, respectively ( P<0.001). There was no incidence of neutropenic fever in the dasatinib + venetoclax. Conclusion The combination of dasatinib 50 mg/d and venetoclax is safe and effective in pts with ECP-CML. With a median follow-up of 2 years, the cumulative resposne of dasatinib + venetoclax is similar to that of dasatinib single-agent without adding significant toxicities. Further follow-up is needed for the evaluation of TFR.

Improvement of Treatment-Free Remission Rate Following Discontinuation of BCR::ABL1 Tyrosine Kinase Inhibitors in Chronic Phase, Chronic Myeloid Leukemia

Backgrounds: Several studies have shown that approximately one-half of patients with chronic phase chronic myeloid leukemia (CP-CML) who receive sufficient tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. The main factors affecting Treatment free remission (TFR) are the duration of TKIs treatment and the duration of DMR maintenance during TKI treatment. Aims: To investigate impact of longer duration of DMR, we analyzed the outcome of patients with CP-CML who maintained DMR for more than 6 years during TKIs treatment and discontinued TKIs. The clinical and molecular immunological application criteria were also investigated for safer and more successful TFR. Methods: Among patients newly diagnosed with CP-CML and treated at least one of TKIs (Imatinib, Nilotinib, Dasatinib, Bosutinib, and Radotinib) as the first treatment, patients who maintained MR4.5 (BCR::ABL1 IS ≤0.0032%) continuously for at least 6 years through qRT-PCR tests were enrolled in this study. After discontinuation, molecular responses were monitored for up to six months per month, up to 12 months every two months, and every three months thereafter using the qRT-PCR method. In the case of relapse, defined as loss of major molecular response (MMR), the last TKI therapy was reintroduced and molecular responses after resumption were monitored monthly until achievement of MMR using qRT-PCR. Results: Altogether 116 patients (50 males and 66 females) discontinued TKI. Median age at diagnosis was 43.0 years (range, 40.8-45.3) and the percentages of patients with low, intermediate and high Sokal risk scores ware 58 (50.0%), 35 (30.2%) and 18 (15.5%) patients, respectively with unknown Sokal risk scores in 5 (4.3%) patients. Prior to discontinuation, all patients received TKIs for a median of 120.6 months (range, 113.9-127.3), and the duration of sustained MR4.5 was 75.0 months (range, 70.7-79.3). At the time of discontinuation, 93 patients (80.2%) were receiving their first TKI (70 imatinib, 13 nilotinib, 6 radotinib, and 4 dasatinib) while 13 (11.2 %) and 10 (8.6%) patients were receiving their second and more than three TKIs respectively. All patients who received more than one TKI had changed to adverse events. After a median follow-up from treatment discontinuation of 42.2 months (range, 35.3-49.1), 28 (24.1%) patients have lost their response at a median of 8.4 months (range, 4.9-11.9) after discontinuation; 18 (64.3%) patients had molecular relapse within 6 months of TKI discontinuation and 7 (25.0%) patients lost MMR after 12 months from discontinuation. TFR rates at 12, 24, and 48 months were 81.9%, 76.0%, and 71.0%, respectively. No progression toward advanced-phase CML occurred, and when 28 patients who lost MMR were retreated with same TKI, 26 patients (92.9%) re-achieved MMR with a median of 5.6 months (range, 4.0-7.2). By univariate analysis, a TKI treatment duration of 10 years or more was the only significant predictor for maintained response (P<0.048). Conclusion: Our result demonstrates that TFR rate can be improved in patients who received TKI treatment for approximately 10 years and maintained DMR for more than 6 years regardless of the type of TKI. Based on results, we can confirm one of important factors for safer TFR in CP-CML patients.

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.

Economic Impact Analysis of Treatment-Free Remission in Chronic Myeloid Leukemia Patients with Sustained Deep Molecular Response in the AST-2018 Trial

Introduction: The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of chronic myeloid leukemia (CML), bringing the life expectancy of patients close to that of the general population. However, TKI treatment is associated with adverse events, some of them serious or affecting quality of life. In addition, drug costs have a high economic impact, especially in low-income countries. Treatment-free remission (TFR) is an emerging goal for CML patients and it has been associated with cost savings in different country analyses. Main Objective: Assess the economic impact of TKI discontinuation in patients included in the AST2018 Trial. Secondary objective: Estimate the long-term saving in patients included in the AST2018 Trial, considering Argentinian life expectancy. Methods: AST2018 is a multicentric, prospective trial that recruited aged >18 years CML chronic phase patients, with confirmed typical BCR-ABL1 transcripts b3a2 and/or b2a2, under TKI treatment for at least ≥ 4 years and sustained MR4.0 for ≥ 2 years. Molecular tests were centralized in 2 harmonized laboratories and performed monthly for the first 6 months, every 2 months until the 1st year, and every 3 months until month 24. TKI was restarted at confirmed loss of major molecular response (MMR). The economic impact was evaluated by an Excel-based budget impact model, in order to estimate the costs of the patients in first-line pharmacological treatment for CML. We considered the costs of TKI-treatment, PCRs performing and medical visits as money flow. We calculated the present value of savings, in US dollars, in patients who discontinued treatment during the trial. Results: Between February 2018 and March 2022, we evaluated 50 CML patients in the AST2018 trial, 46 were enrolled from 7 centers in Argentina, and were included in this economic analysis. The median patients’ age was 57.5 years (24-85). TKI treatment before discontinuation was Imatinib 34/46 (74%), Nilotinib 4/46 (9%) and Dasatinib 8/46 (17%). After 24 months since first patient was enrolled, 30/46 (65%) patients continued free from TKI, Imatinib 21/34, Nilotinib 2/4 and Dasatinib 7/8, with a median follow-up of 31.3 months (range 25.9 - 38.1). Treatment was restarted after losing MMR in 16/46 (35%) patients. We considered the costs of TKI treatment, PCR performing and physician visits, and we calculated the estimated cost saving per patient at 24 months on TFR: Imatinib US$ 78,433; Dasatinib US$ 102,817 and Nilotinib US $106,161. For the 30 patients who persisted in TFR for 24 months, total cost saving was US$ 2,579,137. For 17 patients who lost MMR, US$ 335,043 dollars were saved previously to TKI reinitiation. Adding up both amounts, the total economic saving in AST2018 was US$ 2,914,181. We performed an analysis of the potential cost savings of remaining in TFR beyond 24 months and according to life expectancy in Argentina (76 years), median age of patients in this trial and cost per patient/year on TKI treatment, the estimated cost saving per patient was US$ 714,512. Conclusions: This is the first economic analysis of the AST2018 trial on TKI discontinuation in CML patients with sustained deep molecular response in Argentina. Our analysis shows that, in spite of the PCR spending, there is a considerable saving in patients on TFR. A careful approach for patients participating in TFR trials or programs will decrease the risk of relapse and make TFR a reality in our region. Potential advantages of TFR will not only impact in patients’ quality of life but also show considerable reduction in the use of economic resources. In developing countries, where lack of molecular monitoring is still an issue outside academic centers, these savings could be redirected to this unmet need making TFR feasible and a goal for the patient and the healthcare system. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Real-World Study to End Tyrosine Kinase Inhibitor in Chronic Myeloid Leukaemia (EnTIC) in Malaysia: One Year Follow-up of Multicenter Study in Malaysia

Introduction The practice of indefinite tyrosine kinase inhibitor (TKI) provision for Chronic Myeloid Leukaemia (CML) has remained unchallenged and the ability of TKIs to eradicate the CML clone is still largely unknown. Hence, a multicentre observational study involving major hospitals in Malaysia to observe the clinical practice to End TKI In CML (EnTIC) was performed. This study aims to determine the molecular response to TKI cessation in CML patients by close monitoring of BCR-ABL1. Materials and Methods A total of 88 adult patients diagnosed with CML in chronic phase and receiving first line TKI (imatinib, nilotinib or dasatinib) for at least four years with sustained MR4 (IS: 0.01%) for at least 2 years were recruited from January 2021 till July 2022. Close clinical review, and monthly BCR-ABL1 quantification analysis using real-time polymerase chain reaction for molecular monitoring were carried out. Results Eighty-eight patients with equal gender distribution (44 male and 44 female) and a median age of 41 years old (range, 31.5-53.5 years old) were included in the analysis. Chinese (60.2%, n =53) were the most prevalent ethnic group, followed by Malay (33%, n =29), and Indian (5.7%, n=5). 82.8% (n=64) of the patients had high presenting white blood cell count (>30x10⁹/L), with a median presenting white blood cell count of 102x109/L. Of the 64 patients, 38 of them (59.3%) had thrombocytosis (>450x10⁹/L). Majority of these patients (71.2%, n=37) presented with low Sokal score. First-line TKIs were administered to all patients throughout the course of treatment, with a median duration of 9 years (range: 7-13 years) and a median of 4 years for sustained deep molecular response (DMR) (range 3-6 years) was achieved. With a median follow-up of 14 months (range, 1-18 months) after stopping TKI, 57 patients (64.8%) remain in treatment-free remission (TFR). Thirty-one patients failed TFR, with a median duration of 2 months (range 1-5 months). Patients who remained in TFR at 166 days (5.5 months) and beyond were likely to achieve long term TFR in the following months (Fig 1). Conclusion The preliminary findings of EnTIC study demonstrate that a clinically significant percentage of patients were able to remain in MMR after stopping TKI. We observed the likelihood of breakthrough MMR during TFR trial is most often within the first 6 months of stopping TKI. Nonetheless, a longer follow-up duration and analyses of TFR data in EnTIC will be important to further evaluate the patients, and identifying clinically significant characteristics to predict disease relapse before stopping treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Asciminib As Initial Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)-H. Jean Khoury Cure CML Consortium Study

Background: Although tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients with CML, there remains need for improvement as less than 50% achieve sustained MR4.5 by 10 years (sine qua non for treatment discontinuation) and approximately 40% need change of therapy within 5 years because of lack of efficacy or unacceptable toxicity. Asciminib is a potent allosteric inhibitor of BCR::ABL1, effective in vitro against BCR::ABL1 mutations that confer resistance to ABL-competitive tyrosine kinase inhibitors (TKIs). Asciminib has potential to combine with TKIs to prevent the emergence of resistant clones, potentially increasing the depth of molecular response in a greater number of patients compared with single-agent treatment. In a phase I study of asciminib, 48% of patients with CP-CML resistant to or intolerant of multiple prior TKIs achieved a major molecular response. The significant efficacy of asciminib in this setting suggests it might be more effective than other available options in achieving deep early responses in patients with newly diagnosed CML. Our goal in this study is to evaluate the role of asciminib in the treatment of patients with newly diagnosed CML-CP. Study Design and methods: This study is a multicenter phase 2, non-randomized open-label single-group study of asciminib in patients with newly diagnosed CP-CML (NCT05143840). The primary outcome is to evaluate the proportion of patients attaining MR4.5 within 12 months of therapy. In addition, patient reported outcomes will be collected at multiple timepoints. Patients will receive asciminib 40 mg orally twice daily. Peripheral blood BCR::ABL1 by RQ-PCR will be monitored in a central lab. Patients who do not achieved MR4.5 after 24 months of single agent asciminib will be offered the addition of nilotinib with the goal to attain MR4.5. In those instances, nilotinib will be started at 300 mg BID added to asciminib. Patients will discontinue study treatment if they experience disease progression, treatment failure according to ELN criteria or unacceptable toxicity. Patients who, after three years of asciminib +/- nilotinib, achieve sustained MR4.5 for at least 2 years may discontinue study treatment for an attempt at treatment-free remission. Sustained MR4.5 is defined as BCR::ABL1<0.0032% for approximately 2 years or more on at least 4 tests performed approximately 3 months apart. The primary objective of this study is to determine the rate of deep molecular response (DMR), defined as BCR::ABL1 <0.0032% IS by RQ-PCR at 12 months with asciminib compared to historical second generation TKI. With a total of 50 subjects, the study will have a 90% power to detect a 13.5% difference with an improvement of DMR at 12 months from 5% (based on historical experience with second generation TKIs used in frontline setting) to 18.5%. The exploratory endpoint of evaluating the rate of DMR after adding nilotinib at 24 months for patients not in DMR will be assessed at 36 months (after 12 months on combination therapy) and compared to the historical rate of 25% DMR with single agent nilotinib at 36 months. The study will have a 82% power to detect a 10% difference, 95% power to detect 15% difference and 99% power to detect a 20% difference.

Treatment-Free Remission in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line, in Real-Life Conditions: Influence of Switching to Another TKI Prior to Cessation.

Nilotinib (NIL) as front-line therapy in newly diagnosed chronic phase (CP) CML patients (pts) is able to induce high rates of sustained deep molecular response and high possibilities of treatment-free remission (TFR). However, the identification of factors influencing successful TFR in this population remains imprecise. This observational study retrospectively analyzed TFR rates, outcome, and tried to identify factors related to successful TFR in in- and out-study 221 pts treated in this setting with NIL 600 mg, in "real-life" conditions. All pts with newly diagnosed adult CP-CML receiving NIL 300 mg BID alone front-line between 10/2007 and 06/2022, were eligible. Data were retrospectively collected according to the national regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2006→2020 along treatment and to the recommendations of the Fi-LMC (D. Rea et al., Cancer 2018, i. e. 2 years of sustained MR4.5) in case of TFR. In this regard, a TKI was resumed if loss of MMR on one instance. BCR::ABL1 assessments were performed in the 2 reference laboratories, standardised, and expressed in % (IS) with ≥32,000 copies of ABL1 as control. The primary endpoints were the rate of successful TFR on NIL first-line. Secondary endpoints were the kinetics of molecular response, factors influencing outcome, survival, and safety of NIL. Two hundred and one patients were enrolled with 56% males with a median age at diagnosis of 50 (17.5-83) years, and 26% of them had cardiovascular risk factors at onset (tobacco abuse 10%, hypercholesterolemia 9.55%, diabetes 1.36%, none with history of cardiovascular events [CVE]). ELTS scores were high in 13%, intermediate in 30% and low in 53% of pts, unknown in 4% of pts. Twenty-six (12%) pts harboured additional chromosomal abnormalities (ACA) at diagnosis. The median follow-up after NIL initiation was 85.16 (5.72-174) months. After a median of 37.7 months, 119 pts (58%) were not on NIL anymore for toxicities, resistance or TFR. Sixty-eight (31%) pts obtained the TFR criteria and stopped NIL after a median of 66.7 (27-132) months. The median time between first MR4.5 datapoint and TFR was 39 (15.31-120) months. With a median follow-up of 20.3 (0.03-108) months after NIL cessation, the survival without MMR loss after NIL cessation (figure 1.) is 64.38% (95% CI: 53.35- 77.69). Interestingly, no CVE occurred after NIL cessation, as well as no blast crisis. Two patients died in TFR from competitive events (2 solid tumours). We went on comparing the TFR group vs the non-TFR group. The median age at TFR was 56 (30-87) years with no difference at CML diagnosis in terms of age (49 vs 50 years, p=0.096), ELTS (p=0.276), ACA (15% vs 11%, p=0.483) between the 2 groups. In contrast, there was a difference in favour of female vs male gender in the TFR group (56%) vs non-TFR group (39%, p=0.031), and the median time to reach MMR was shorter in the TFR group 5.04 vs 10.2 months, p<0.001; as well as the median time to reach MR4.5 in the TFR group 18.2 vs 36.1 months, p<0.001. We finally compared the successful vs the unsuccessful TFR pts requiring TKI-rechallenge, in univariate analysis and multivariate analyses. The univariate analysis identified pts that have switched to another TKI before TFR for whatever reasons was a risk factor for subsequent loss of MMR [HR: 3.09 (95% CI: 1.30-7.34), Cox p-value=0.011]. This was confirmed by the log-rank survival curves of TFR in patients with or without switch (figure 2., log-rank p=0.008). Surprisingly, neither the duration of NIL before TFR [HR: 0.98 (0.96-1.00), Cox p-value=0.072], nor the duration of MR4.5 prior to NIL cessation [HR: 0.98 (0.95-1.01), Cox p-value=0.15] were found to have an impact. Additionally, the prognostic scores did not influence TFR success on NIL. The multivariate analysis confirmed that switching to another TKI was an unfavourable risk factor for molecular relapse [HR: 2.87 (1.20-6.84), p-value=0.018], and that the lack of impact of the duration of MR4.5 [HR: 0.98 (0.95-1.01), Cox p-value=0.218] had no significant influence. NIL first-line is able to induce high rates of successful TFR in newly diagnosed CP CML patients and switching to another TKI for toxicity and/or resistance, prior to TFR, represents an unfavourable risk factor for the success of TKI cessation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Importance of the Duration of TKI Treatment in Treatment-Free Remission of Chronic Phase Chronic Myeloid Leukemia: Results of D-Free Trial

Importance of the Duration of TKI Treatment in Treatment-Free Remission of Chronic Phase Chronic Myeloid Leukemia: Results of D-Free Trial

Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Following the Discontinuation of Tyrosine Kinase Inhibitors

Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Following the Discontinuation of Tyrosine Kinase Inhibitors

The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Treatment Free Remission in Patients with Chronic Phase CML: A Single Center Experience

Treatment Free Remission in Patients with Chronic Phase CML: A Single Center Experience

First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

The Importance of Bone Marrow Lymphocyte Subtypes As Predicting Factors for Molecular Recurrence in Patients with Chronic Myeloid Leukemia after Discontinuation of Imatinib

Introduction: in recent years the feasibility of the discontinuation of tyrosine kinase treatment in chronic myeloid leukemia (CML) has been proven, and several clinical factors influencing the duration of treatment-free remission (TFR) after discontinuation have been studied.Aim: we analyzed the influence of bone marrow (BM) lymphocyte subsets on the molecular recurrence after discontinuation of Imatinib (IM) in CML.Methods: in a recent discontinuation study performed at our Institution (EDI-PIO trial) we assessed BM lymphocyte subsets before and after introduction of pioglitazone which was given 3 months before discontinuation of IM. Criterias for discontinuation were: patient in chronic phase at diagnosis, a minimum of 3 years on TKI and sustained molecular remission MR4.5 for at least 2 years. Lymphocyte populations studied: B, TCD8, TCD4, T CD4+CD8+ and T CD4- CD8- besides T naïve and memory, TCRαβ, TCRγδ, NK-t and NK cells. The influence of Sokal score at diagnosis, the duration of imatinib treatment together with the BM lymphoid subsets on the time of treatment-free remission (TFR) were examined by uni- and multivariate Cox regressions.Results: we studied 30 out of 32 patients diagnosed between 1998 and 2013 that reached criteria for discontinuation that were included in EDI-PIO trial: 13 male and 17 female. Median age at diagnosis: 41 years (22-65). Median time of IM treatment: 116.3 months (38.2-209.3); 11 patients (36%) had a molecular recurrence in a median of 5,17 months (2.4-29.4). For patients remaining in TFR the median time of follow-up was 46 months (26.3-55.9). Median overall time of IM treatment (IM-Tr) was 65 months for patients recurring and 124 months for those remaining in TFR. In the univariate Cox regression a significant value was found for IM-Tr, higher percentages of T CD4+CD8+ and lower ones of TCRγδ lymphocytes at discontinuation. In the multivariate model only the T CD4+CD8+ remained.Conclusion: discontinuation of IM is feasible in patients remaining in continuous MR4.5 for more than 2 years. A longer time of IM treatment and higher values of BM T CD4+CD8+ predict a lower risk of relapse.Key words: chronic myeloid leukemia, imatinib, discontinuation, lymphocytes, pioglitazone DisclosuresPagnano: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pintpharma: Other: Lecture; EMS: Other: Lecture; Jansenn: Other: Lecture.

Treatment-Free Remissions in Newly Diagnosed CP CML Patients Treated with the Combination of Nilotinib + Pegylated Interferon Alpha 2a Versus Nilotinib Alone in the National Phase III Petals Trial

Treatment-Free Remissions in Newly Diagnosed CP CML Patients Treated with the Combination of Nilotinib + Pegylated Interferon Alpha 2a Versus Nilotinib Alone in the National Phase III Petals Trial

Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: A Study from the International Registry of Childhood CML.

Simple SummaryAbout 50% of adults with chronic myeloid leukemia (CML) in sustained deep molecular response (DMR) to tyrosine kinase inhibitors (TKI) could discontinue the treatment permanently without molecular relapse. Recommendations regarding discontinuation apply only for adults because childhood CML is a very rare disease and represents a separate entity. The aim of our retrospective study was to assess within the International Registry of Childhood CML, the rate of children remaining in molecular response after discontinuation of imatinib in a context of DMR defined as BCR-ABL1/ABL1 < 0.01% (MR4) for at least two years. Eighteen patients less than 18 years old at diagnosis of CML exhibiting a sustained DMR followed by imatinib discontinuation were identified. After discontinuation, the molecular free remission rate was 61%, 56% and 56% at 6, 12 and 36 months, respectively. Our findings represent the basis of recommendation regarding discontinuation for physicians involved in the pediatric CML field.Within the International Registry of Childhood Chronic Myeloid Leukemia (CML), we identified 18 patients less than 18 years old at diagnosis of CML who were in the chronic phase and exhibiting a sustained deep molecular response (DMR) to imatinib defined as BCR-ABL1/ABL1 < 0.01% (MR4) for at least two years followed by discontinuation of imatinib. Before discontinuation, the median duration of imatinib was 73.2 months (range, 32–109) and the median duration of MR4 was 46.2 months (range, 23.9–98.6). Seven patients experienced loss of major molecular response (MMR) 4.1 months (range, 1.9–6.4) after stopping and so restarted imatinib. The median molecular follow-up after discontinuation was 51 months (range, 6–100) for the nine patients without molecular relapse. The molecular free remission rate was 61% (95% CI, 38–83%), 56% (95% CI, 33–79%) and 56% (95% CI, 33–79%) at 6, 12 and 36 months, respectively. Six of the seven children who experienced molecular relapse after discontinuation regained DMR (median, 4.7 months; range, 2.5–18) after restarting imatinib. No withdrawal syndrome was observed. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment and DMR durations before discontinuation had no influence on treatment free remission. These data suggest that imatinib can be safely discontinued in children with sustained MR4 for at least two years.

Long-Term Outcome of CML Patients Treated with Second-Generation Tyrosine Kinase Inhibitors in the Second Line: A Single Center Experience

Background: Since the introduction of tyrosine kinase inhibitors (TKI), most patients (pts) with chronic myeloid leukemia (CML) have a favorable outcome with their initial therapy. However, some pts experience resistance or intolerance. Second generation TKI dasatinib, nilotinib and bosutinib are effective (and approved) for pts with failure to one prior TKI. In the absence of specific mutations or patient comorbidities driving the selection of a specific TKI, selecting the next TKI remains at the physician discretion, especially in the lack of randomized data comparing 2nd generation TKI. Methods: We analyzed the outcomes of 621 consecutive patients with CML treated at a single institution with 2nd generation TKI in the 2nd line following failure of frontline TKI. For this analysis we focused on the 572 pts that received dasatinib, nilotinib or bosutinib as 2nd line TKI (not including 49 pts treated with ponatinib, imatinib or investigational TKI). Results: The median age at diagnosis was 47 years (range, 12-86) and 49% were male. 516 pts received TKI as frontline treatment and 105 had other therapies (interferon, chemotherapy) prior to TKI. Pts were switched to a 2nd generation TKI for resistance (n=337; 54%) or intolerance (n= 279; 45%). The median time from diagnosis to start of 2nd line TKI was 32 mo (0 to 206 mo). Dasatinib, nilotinib and bosutinib were used as 2nd line TKI in 338 (54%), 194 (31%), and 40 (6%) pts, respectively. Overall, out of 572 pts who received one of these three TKIs, 401 had cytogenetic evaluation of which 323 (81%) achieved major cytogenetic response (34 (8%) partial (PCyR) and 289 (72%) complete (CCyR)). Out of 428 who had a molecular evaluation, 75% achieved molecular response (94 (18%) MMR, 52 (6%) MR4, 217 (51%) MR4.5). The rates of major cytogenetic response (MCyR) were, with dasatinib 85% (76% CCyR), nilotinib 76% (70% CCyR), and bosutinib 67% (50% CCyR) (p=0.015). Rates of molecular response (MMR or better) were with dasatinib 72% (55% MR4.5), nilotinib 65% (46% MR4.5), and bosutinib 55% (39% MR4.5), (p=0.07). At a median follow-up from diagnosis of 96 mo (range, 4-283), 39 (7%) pts transformed either to accelerated (n=26, 5%) or to blast phase (n=13, 2%) while on 2nd line TKI. Median overall survival (OS) and transformation-free survival (TFS) were not reached and the median event-free survival (EFS) was 121 mo. Seven-year probabilities of OS, TFS and EFS were 66%, 91% and 55%, respectively. Higher OS, TFS, and EFS were found in patients who received frontline TKI (7-yr 70%, 92% and 59%, respectively) vs those who failed another treatment prior to any TKI (49%, 83%, and 38%, respectively) (p Conclusion: This analysis shows that dasatinib, nilotinib and bosutinib remain largely effective in inducing cytogenetic and molecular response when used as a 2nd line TKI with similar OS, TFS and EFS in the overall pts population. A multivariate analysis to identify predictors of long-term outcome, including specific TKI as a variable, is ongoing. Disclosures Kantarjian: Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Delta-Fly Pharma: Research Funding; Pfizer: Research Funding. DiNardo: Daiichi-Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Daver: Bristol-Myers Squibb Company: Consultancy, Research Funding; Incyte Corporation: Honoraria, Research Funding; Pfizer Inc.: Consultancy, Research Funding; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Immunogen: Research Funding; Kiromic: Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Pemmaraju: Incyte Corporation: Consultancy, Honoraria; cellectis: Research Funding; novartis: Consultancy, Honoraria, Research Funding; abbvie: Research Funding; roche diagnostics: Consultancy, Honoraria; affymetrix: Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding. Burger: Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Jabbour: Bristol-Myers Squibb: Consultancy. Cortes: Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; Sun Pharma: Research Funding; Teva: Research Funding.