Treatment-free Remission Rate Research Articles

Outcomes of pregnancy in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

Young female patients with chronic myeloid leukemia (CML) often face challenges becoming pregnant due to the teratogenicity of tyrosine kinase inhibitors (TKIs). The authors conducted a nationwide survey of female patients with CML who experienced pregnancy between 2002 and 2020. Information for 70 pregnancies in 49 patients was obtained. There were three types of pregnancies: CML onset during pregnancy (n=9), unplanned pregnancy mostly during treatment with a TKI (n=25), and planned pregnancy during treatment-free remission (TFR) or treatment with interferon-alpha (IFN-α) (n=36). The median duration from CML diagnosis to pregnancy in patients with planned pregnancy was significantly longer than that in patients with unplanned pregnancy (10.6 years vs. 4.1 years, p<.001). In 48 pregnancies that resulted in childbirth, TFR and treatment with IFN-α were chosen in 26 and 17 pregnancies, respectively. Sustained major or deeper molecular response was observed in 18 of 26 pregnancies with TFR. The patients who fulfilled the requirements for TKI therapy discontinuation by European LeukemiaNet recommendations achieved a TFR rate of 77% in pregnancy. Treatment with IFN-α might be effective for patients who are in complete cytogenetic response or deeper response (response rate, 76%). Pregnancy by TFR or treatment with IFN-α could be a safe and feasible way for patients with CML. However, a substantial duration of treatment with a TKI before conception may be needed for planned pregnancy. Planning and evaluation for pregnancy should be considered at the time of CML onset for female patients with childbearing potential.

The long-term efficacy of eltrombopag in children with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is the most common autoimmune disorder characterized by decreased platelet counts and impaired platelet production. Eltrombopag has been demonstrated to be safe and effective for children with ITP. It is reported eltrombopag can achieve a sustained response off treatment. However, data on its overall efficacy and safety profile are scarce in children. This study aimed to investigate the long-term efficacy of eltrombopag in children with ITP. Treatment overall response (OR), complete response (CR), response (R), durable response (DR), no response (NR), treatment free remission (TFR), and relapse rate, were assessed in 103 children with ITP during eltrombopag therapy. The OR rate, CR rate, R rate, DR rate, NR rate, TFR rate, and relapse rate were 67.0%, 55.3%, 11.7%, 56.3%, 33.0%, 60%, 36.2%, respectively. Importantly, we discovered that newly diagnosed ITP patients showed a higher DR rate, TFR rate and lower relapse rate compared to persistent and chronic ITP patients. Furthermore, the CR rate, DR rate, and TFR rate of 5 patients under six months were 100%. None of them suffered relapse. The most common adverse event (AEs) was hepatotoxicity (7.77%). Our study highlighted the critical role of eltrombopag as the second-line treatment in children with ITP who were intolerant to first-line therapy.

A Higher Neutrophil Count Is Associated with Favorable Achievement of Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Who Received Second Generation Tyrosine Kinase Inhibitor as Frontline Treatment.

ABL1 tyrosine kinase inhibitor discontinuation securely became among the therapeutic goal for chronic myeloid leukemia chronic phase patients (CML-CP). To establish successful prognostic factors for treatment-free remission (TFR), it is necessary to diagnose the patients with high-risk molecular relapse, however, a biomarker for the achievement of TFR has not been completely elucidated. Recent investigations have determined that neutrophils function crucially in cancer immunology. The research was a multicenter retrospective observational study to examine the correlation between TFR and neutrophil counts before TKI discontinuation. The investigation included patients having Philadelphia chromosome-positive CML-CP who attempted the discontinuation of TKIs after a durable deep molecular response between January 2012 and July 2021 at four institutions in Japan. 118 CML-CP patients in total discontinued TKIs and an estimated 36-month TFR rate was 65.1%. 52 patients received second-generation TKIs as frontline. Higher neutrophil count (>3210/μL) at TKIs discontinuation was determined as an independent prognostic variable for TFR in patients who received second-generation TKIs as frontline [(HR, 0.235 (95%, confidence interval (CI) 0.078-0.711); p = 0.010]. The neutrophil-mediated immunomodulation can be a significant component for the effective achievement of TFR in CML supported by our clinical observation.

Treatment-free remission after a second TKI discontinuation attempt in patients with Chronic Myeloid Leukemia re-treated with dasatinib – interim results from the DAstop2 trial

Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61, 56 and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.

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&amp;lt;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 &amp; Method: We have retrospectively analyzed the outcome of adult pts with CML in chronic phase treated with NIL frontline therapy and achieved sustained MR4 ( BCR::ABL1 transcript ≤0.01%IS). From the pts treated with NIL frontline therapy, we identified the cases attempted NIL de-scalation after achievement of MR4. The molecular response after NIL de-escalation was closely monitored every 3 months using BCR::ABL1 qPCR. Molecular recurrence was defined as an increase in BCR::ABL1 transcript levels above MR4 on at least two consecutive occasions or a single increase in BCR::ABL1 transcript level above MR3 ( BCR::ABL1 transcript ≤0.1%IS). At any time, pts who lost MR3 had returned Nilotinib dose to 300 mg BID. Primary endpoint of the study was event-free survival (EFS) following NIL de-escalation, which was defined from NIL DESC starts to molecular recurrence or death from any cause. Results: We have identified 52 pts who started NIL as first line therapy for CML-CP under clinical practice. With median follow-up duration of 9 years (range:2-12 years), 33 patient (64%) remains on NIL at the last follow-up visit. In 33 pts on NIL treatment, with a median follow up duration of 8 years (range;2-12), 25 (76%) had attempted NIL DESC at median of 6 years (range; 1-10 years) after frontline NIL therapy start, of whom the median time from NIL start to MR4 achievement was 12 months (range: 5-50 months). The median time from first achievement of MR4 to NIL DESC starts was 50 months (range: 3-105 months), while the median time from NIL start to NIL DESC was 77 months (range: 13-121 months). At the latest follow up, only one patient experienced molecular recurrence at 3 months after DESC but regained MR3 in 9 months after re-escalation of NIL to 300mg BID. One patient died of cardiac arrest at 80 months after NIL DESC with other comorbidities of coronary artery disease, hypertension and diabetes. One patient discontinued NIL at 51 months post DESC and has sustained MR4 till last follow up. In the DESC group, the EFS at 3 years, 95% (69.5-99.3%). There is another case developed myocardial infarction while on DESC dose of NIL, who switched the treatment to Asciminib. Conclusion: Achieving early and sustained MR4 with frontline NIL treatment facilitates DESC approach without compromising molecular response and might promote the TFR rate by extending MR4 duration. This DESC strategy can bridge CML pts on NIL frontline therapy prior to NIL discontinuation for TFR attempt.

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&amp;lt;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.

Single-Cell Analysis of Immune Recognition in Chronic Myeloid Leukemia Patients Following Tyrosine Kinase Inhibitor Discontinuation

Background: Modern treatment goal for patients with chronic myeloid leukemia (CML) is to maintain treatment-free remission (TFR) following tyrosine kinase inhibitor (TKI) discontinuation. The control of residual leukemia cells may occur with immunological mechanisms as several studies have shown that a higher proportion of CD56 dim NK cells before TKI discontinuation is associated with a better probability of TFR. In addition, CD8+ T cell abundances and phenotypes have been associated with responses to TKIs. However, the more detailed phenotypes and mechanisms and how to translate these findings to increased TFR rates have remained unknown. Methods: We analyzed 55 single-cell RNA and T cell receptor (TCR) sequenced (scRNA+TCRαβ-seq) samples from patients with CML ( n=13, N=25), other cancers (AML n=11, CLL n=13, solid tumors n=4), and healthy ( n=7). Additionally, we profiled 90 CML and 786 healthy TCRβ-seq samples, and sorted T cells specific to leukemia-associated antigen PR1 and matched these back to the scRNA+TCRαβ-seq and TCRβ-seq data. To validate and refine our findings, we performed co-culture of primary and expanded NK cells with CML cell lines (K562 and LAMA84) with a multiplexed scRNA-seq readout. Results: In the pan-cancer scRNA+TCRαβ-seq comparison of &amp;gt;250,000 cells, CML was separated from other cancers and healthy by the high number and active phenotype NK cells. The other phenotype more pronounced in CML was CD8+ T EM/T EMRA phenotype. Most NK cells in CML had an active CD56 dim phenotype with high expression of GZMA/B, PRF1, CCL3/4 and IFNG. In the off-TKI samples from patients with TFR, these NK cells upregulated NK cell activation genes such as TNFRSF4/OX40, TNFRSF9/4-1BB, and TNFRSF18/GITR. The most important predicted interactions between NK cells and CD34+ leukemic cells were inhibitory LGALS9- TIM3 and PVR- TIGIT interactions. Following TKI discontinuation, the inhibitory markers HAVCR2/TIM3 and TIGIT decreased in patients with TFR, which was not seen in patients with relapse following TFR. Accordingly, in our co-culture data of NK cells with CML cell lines, we noted activation of NK cells to a similar phenotype as noted in ex vivo off-TKI samples. In co-culture with CML target cells, NK cells gained an activation by upregulation of genes like TNFRSF4/OX40, TNFRSF9/4-1BB, TNFRSF18/GITR and the inhibitory markers HAVCR2/TIM3 and TIGIT. In co-culture with NK cells, CML target cells upregulated the IFN-γ response pathway including elevated HLA-expression and accordingly, upregulation of LGALS9 and PVR. The CD8+ T EM/EMRA cells that were expanded in CML diagnosis were suppressed following TKI treatment and decreased following TKI discontinuation. To track anti-CML T cells, we created a classifier to identify TCRs targeting leukemia-associated antigen PR1 from the TCRb-sequenced samples. As a validation of our classifier, we noticed that anti-PR1 T cells were more prevalent in CML than in healthy ( P adj&amp;lt;0.0001) or melanoma ( P adj&amp;lt;0.0001), more expanded than similar anti-viral T cells ( P adj&amp;lt;0.0001) and enriched in bone marrow samples compared to peripheral blood ( P adj&amp;lt;0.0001). From different TKIs, dasatinib expanded anti-PR1 T cells the most ( P adj&amp;lt;0.01). In the scRNA+TCRαβ-seq data, anti-PR1 T cells were enriched in the mature, cytotoxic CD8+ T EMRA phenotype ( P adj&amp;lt;0.0001). In a patient maintaining TFR, anti-PR1 T cells had a highly cytotoxic profile ( GZMB, PRF1) throughout the therapy with upregulated NK receptors like FCGR3A/CD16 and KIR2DL2, even more so than T cells targeting other targets e.g., different viruses. In comparison, the anti-PR1 T cells in a patient with early relapse had an exhausted profile with upregulation of memory marker GZMK and exhaustion markers like LAG3 and HAVCR2/TIM3. Conclusions: With our in-depth analysis of cellular and molecular immune responses in CML, we identified the active NK cells and anti-PR1 T cells that could help maintain TFR in patients discontinuing TKI treatment. Different immune-checkpoint blockade therapies such as anti-TIM3 could be considered as future strategies to improve the TFR rates.

T rial of Imatinib after Ponatinib Induction (TIPI) in the Front-Line Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Setting. Report of the First Therapeutic Sequence

Introduction: The prevention ofdisease transformation which typically occurs during the first years of treatment, is one of the critical goals of the treatment of CP-CML with TKI. In addition, treatment free remission (TFR) represents now another major challenge. In vitro data show that ponatinib is one of the most powerful inhibitors of wild-type as well as mutated BCR::ABL1 TK and this has been translated in heavily pre-treated CML patients (pts) intolerant or resistant to other compounds. In this trial we assessed the safety and efficacy of a 6-months debulking strategy using ponatinib as front-line therapy in newly diagnosed CP-CML, followed by a maintenance with imatinib, in order to bring a high proportion of pts in TFR. Methods: This open-label phase II national academic trial (Clinical Trial: NCT04070443) enrolled newly diagnosed adult CP-CML pts ≤65 years, with a major BCR::ABL1 transcript and no significant underlying cardio-vascular disease, uncontrolled hypertension or diabetes with target organ damage, QTc prolongation and with adequate organ functions. They were stratified according to the ELTS score. The primary endpoint is the impact of ponatinib induction on the rate of pts reaching TFR criteria as defined by our group (Rea et al. Cancer, 2018) at M36. Secondary endpoints were the safety and clinical activity of this strategy, ponatinib pharmacokinetics (PK), QoL under both inhibitors and compliance. Pts were treated with ponatinib 30 mg QD for 6-months, followed by imatinib 400 mg QD until TFR criteria (i. e. MR4.5 ≥2 years) would been reached before M60. All molecular assessments were centralised and BCR::ABL1 transcripts were expressed in % on the international scale (IS). This analysis relies on the intention-to-treat principle. Results: One hundred and seventy-eight pts were screened, 170 enrolled and 169 treated between November 2019 and October 2022. Median age was 48 (18-65) years, 113 pts were males (67%). One pt had a cryptic Ph, and 15 (9%) pts harboured additional chromosomal abnormalities (ACA). Eighty-four (51.5%) pts had b2a2 and 99 (61%) b3a2 transcripts knowing that they could harbour both. ELTS were low for 67 (40%) pts, intermediate for 73 (44%) and high for 27 (16%). For 2 patients it could not be calculated (1 splenectomy, 1 no spleen assessment). European Society of Cardiology (ESC) score was &amp;lt;2% in 158/167 (93%) evaluable pts, 3-9% in 8 (5%) pts and &amp;gt;10% in 1 (2%) pt. One hundred and one (60%) pts never smoked, 46 (27%) were past smokers. The median follow-up at database lock was 18 (3-33) months. Only induction data are presented here. The median number of days on ponatinib is 172 (1-193) and the median dose of ponatinib delivered is 30 (16.5-32) mg daily. Overall, 135 grade 3-5 AEs occurred after a median of 51 (0-186) days: 123 (91%) grade 3, 11 (8%) grade 4 and 1 fatal AE; 49 (36%) were hematologic, and 86 (64%) non-hematologic, and 109 (81%) were considered as related to study treatment. Seven pts (5%) discontinued permanently ponatinib, and 56 (41.5%) received the full planned dose. Six (4.5%) Grade 3-5 cardiac events (1 fatal cardiac arrest) and 17 (12.5%) vascular events (15 newly hypertensive pts, 1 pulmonary embolism? 1 carotid stenosis) occurred. Their cumulative incidence is shown in Figure 1A. Digestive &amp; clinical hepato-biliary events occurred in 10 (7.5%), infections in 7 (5%), lipase elevation in 15 (11%) and liver enzymes elevation in 20 (15%) pts. Eye, skin and neurologic events occurred in less than 2% of pts. Regarding efficacy, 147 evaluable pts/158 (93%) were in CHR at M1, 115 in CCyR (70.5%) at M3 and 158/163 (97%) in EMR. The median halving time (calculated with ABL1 as a reference gene) was 13.5 (11.5-17.5) days. The cumulative incidence of molecular response is shown in Figure 1B. Fourty-seven pts over 157 assessable (30%) were in deep molecular response at M6. One (0.6%) pt transformed into myeloid blast crisis, alive in CR before transplant. PK data and their relationship with safety and efficacy will be presented. Univariate analysis identified the halving time as the only factor impacting on MR4.5 at M6. Conclusions: Ponatinib displays high anti-leukemic activity as front-line therapy in selected newly diagnosed CP-CML pts with high early molecular response rates with non-negligible severe -in particular cardio-vascular- toxicity at 30 mg QD. Whether or not this will be translated into substantial TFR rates will be determined at later time points.

Treatment Free Remission (TFR) “for” Pregnancy. Overview and Outcome of Pregnancies Reported in the Italy-Tfr Registry

TFR is a consolidated practice and the goal to be reached for all CML patients. In Italy only a few centers participate in TFR clinical trials, while, in clinical practice, many patients discontinue TKIs for intolerance, pregnancy, or other reasons. A cohort of 467 Italian patients who underwent discontinuation outside of clinical trials were collected in the Italy TFR registry. This cohort showed a mean TFR rate of 73% at 12 months. Italy-TFR is an observational study, both retrospective and prospective, with the purpose of collecting data on patients with Ph+, chronic phase CML who discontinue TKIs in an off-protocol setting. Eligibility criteria include patients treated with TKI monotherapy or in association with other drugs (IFN, BCR:;ABL1 peptidic vaccine, and others) and those who discontinued therapy for any reason. Deep Molecular Response (DMR) defined as MR4 (BCR::ABL ratio ≤ 0.01% IS), MR4.5 (≤ 0.0032%) or MR5 (≤ 0.001%) was confirmed at least three times before TKI discontinuation. Data from patients discontinuing in less than DMR were collected and analyzed separately. Molecular responses were assessed by qPCR; tests were performed by the GIMEMA Laboratories Network (LabNet). TFR was assessed using the Kaplan-Meier method and 95% confidence interval, from the date of TKI discontinuation to the date when therapy was reinitiated. Patients discontinuing for pregnancy were analyzed in this sub-analysis. Thirty patients and 33 pregnancies (3 patients had 2 pregnancies) were entered from 8/32 participating centers. Main data are reported in Table 1. Median age at diagnosis was 28 years (range 19-36), and 35 years at pregnancy (range 29-41). Fifteen patients switched from 1st to 2 ndG TKI before pregnancy due to intolerance or resistance/unsatisfactory responses. Only one patient switched to another TKI to deepen the response before attempting a second pregnancy (imatinib to nilotinib). Not all patients at TKI interruption were in DMR, however, they were all treated with the last TKI for a median of 60 months (range 18-151), and exposed to any TKI for a median of 89 months (range 44-186). Specifically, 9/33 pregnancies started in MMR (≤0.1% transcript), 13 in MR4, 6 in MR4.5, and 5 in MR5. Three patients stopped TKI therapy before conception, two at 5 months and 1.5 months, respectively, before pregnancy. The third patient, in TFR after the first pregnancy, conceived a second child while still in TFR. These 3 patients were in TFR for 9, 9 and 5 years after treatment stoppage. During pregnancy 4 patients were treated after losing MMR. One patient, in MR5 with imatinib for 4 years rapidly lost MMR and was treated with a peptidic vaccine, maintaining complete cytogenetic remission until delivery; 2 patients were treated with IFN, and 1 restarted nilotinib at 23 weeks. All 33 pregnancies were carried to term, with unremarkable outcomes for mothers and babies. No CML progression was recorded. Breastfeeding was allowed for patients with stable transcript levels. With a median follow-up of 40 months, 11 patients were still in TFR (33%; 48% at 12 months), with no differences for patients treated with imatinib or a 2 ndG TKI. The lower number of patients maintaining TFR compared with the general population of patients studied can be explained by 3 main considerations. First, 9/33 pregnancies started in MMR, which is not a criteria that allows for discontinuation, the kinetics of transcript rise are often not correlated with molecular remission. Second, the biological clock in women can rush conception attempts before the appearance of a consolidated response (also resistant patients). Third, as demonstrated in the main study, older age is the only statistically significant positive prognostic factor, with a higher risk of relapse for younger patients. Indeed, all patients restarting treatment regained at least MMR within 3 months. Except for the patient described earlier, and a patient who had a suboptimal response to the 2nd line and switched to bosutinib 3rd line, patients recommenced the same TKI discontinued before pregnancy. There was no significant difference in TFR between patients who discontinued imatinib 1 st versus 2 nd lines (Fig.1) and also in patients who discontinued 2 ndG TKI frontline versus 2 nd line for intolerance/resistance unsatisfactory response. The Italy-TFR protocol is still enrolling in the prospective cohort and updating. We plan to include more cases and present an exhaustive analysis.

Long-Term Follow-up of the AST Trial of Treatment-Free Remission in Chronic Myeloid Leukemia Patients

Background: Treatment-free remission (TFR) is a new goal for chronic myeloid leukemia (CML) patients who achieved a long deep molecular response (DMR) with better quality of life, reduced adverse events and high economic impact. The primary objective of the AST trial was to estimate molecular relapse rate at 24 month in CP-CML patients who discontinued TKI. Secondary objective to explore predictive markers for sustained TFR through clinical and immunological analysis ( innate inmune response). This update provides longer follow-up data and includes a new cohort of patients. Patients and Methods: AST-Argentina Stop Trial (NCT05926128) is a multicenter prospective study that included patients from 15 centers. Recruited patients ≥ 18 years, treated with TKI for at least 4 years, sustained MR 4.0 for ≥ 2 years and confirmed typical BCR-ABL1 b3a2 and/or b2a2 transcripts. Molecular studies were centralized in 2 internationally standardized laboratories and were performed monthly during the first 6 months, every 2 months until the first year, and every 3 months during the second year. TKI was restarted due to loss of major molecular response (MMR). Expression of multiple NK cell immunophenotypic markers(CD3-CD56+) was analyzed by flow cytometry at discontinuation time and 3 months later. The nonparametric Mann-Whitney test was used to compare the differences between relapsed and responding patients. Molecular relapse-free survival was estimated using the Kaplan-Meier method and optimal cut-off points were obtained using ROC curves. Comparisons between survival curves were made using the Log rank test method. The differences were considered statistically significant with p-values less than 0.05. Multivariate analysis was performed using the COX regression model. Results: A total of 81 patients divided into 2 cohorts were evaluated: 46 patients recruited between February 2018 and July 2020 (1st cohort) and 35 patients recruited between July 2022 and April 2023. Between these two periods, recruitment was stopped due to the COVID19 pandemic. This analysis focuses on the 1st cohort that has completed 24 months in the study. The median age was 57.5 years (24-86), median duration of treatment before discontinuation was 10.5 years (4.2-20). TKI treatment prior to discontinuation was as follows: Imatinib in 34 (73%) patients, Dasatinib 8 (17%), and Nilotinib 4 (9%). According to Sokal risk score: 22 (48%) were low risk, 14 (30%) intermediate, and 10 (22%) high risk. Seventeen patients (37%) lost MMR, leading to a 63% molecular relapse-free survival rate with a median follow-up of 47 months (41-52). All patients who lost MMR recovered it after restarting the same TKI, with a median time to response of 2.8 months (1-7). With a prolonged follow-up, 2 late relapses were observed (18 and 42 months) (Fig 1). For a univariate analysis, the continuous variables were dichotomized seeking to maximize the difference between the different cohorts. The differences were significant in the variables time in DMR (cut-off point: 51 months, p=0.0166)(HR=0.97 (0.94 - 0.99); p=0.013). Two of the NK cell markers showed significant differences between groups at month 3 after starting treatment, PD1 (Mann-Whitney p=0.035; Log-Rank test p=0.033) and NK-p44 (Mann-Whitney p=0.015; Log -Rank test p=0.020). Multivariate analysis using the Cox model that included variables as gender, age at diagnosis, time in DMR, time in TKI prior to discontinuation, Sokal score, and type of inhibitor, the clinical predictor of time in DMR was the only predictor, significantly associated with a higher rate of TFR, (HR = 0.97 (0.95 - 0.99); p=0.020). No patient experienced disease progression to advanced stages or death for any reason. Conclusion:This is the first multicenter study of TKI discontinuation in CML patients in Argentina showing that TKI can be safely discontinued in those who achieve and maintain a DMR before discontinuation. Molecular relapse-free survival rate was slightly higher than that reported in the international literature, and longer follow-up confirmed the sustained response. DMR before discontinuation showed to be a robust predictor of TFR. Although the sample size was increased, longer follow-up is needed to validate these findings in the second cohort. Potential advantages of TFR will not only impact in patients' quality of life but also show considerable reduction in the use of economic resources.

Outcomes of Adolescents and Young Adult Patients with Chronic Myeloid Leukemia in the Era of Second-Generation TKIs and Treatment-Free Remission

Background: While chronic myeloid leukemia (CML) is most often diagnosed in older adults, it is frequently diagnosed in adolescents and young adults (AYA). Defined by the NCI as individuals between the ages of 15-39 years old, AYA CML patients have been understudied by comparison to their older counterparts, with little known about their outcomes in the United States (US) in the era of second-generation tyrosine kinase inhibitors (TKIs) and treatment-free remission (TFR). We sought to determine the clinical outcomes of AYA patients with CML at our institution, a CML specialty center. Methods: We performed a single-center, retrospective cohort study of patients with CML who were diagnosed between the ages of 15-39 years old and seen in our adult hematology clinic between January 2012 and December 2022. Patients were identified by ICD-9 and ICD-10 codes from the electronic medical record and chart review. Descriptive statistics were used to summarize the data. Outcomes evaluating second-generation TKIs (2G-TKIs) started with patients diagnosed in June 2010. Outcomes evaluating molecular response included BCR-ABL1 PCR testing conducted after implementation of the International Scale (IS) in 2012. Molecular treatment milestones were defined per the 2023 NCCN guidelines for CML. Results: Of 396 CML patients evaluated at our institution, 136 (34.3%) were diagnosed as AYA at a median age of 31 years (range 15-39). The majority were male (62.5%; n=85/136) and English speaking (94.1%; n=128/136). The most frequently cited race/ethnicities were Caucasian (40.4%; n=55/136), Asian (20.6%; n=28/136), and Hispanic (19.1%; n=26/136). At time of diagnosis, 91.2% (n=124/136) were in chronic phase (CP), followed by 4.4% (n=6/136) in accelerated phase (AP) and 4.4% (n=6/136) in blast phase (BP). Of those diagnosed in advanced phase, 91.7% (n=11/12) were male and 66.7% (n=8/12) were Asian or Hispanic. Of CP patients evaluated, 75.8% (n=94/124) started treatment in the 2G-TKI era. Most CP patients were first prescribed dasatinib (61.7%; n=58/94), followed by imatinib (28.7%; n=27/94), and nilotinib (8.5%; n=8/94). Of 62 patients in CP with available molecular data after 2012, 64.5% (n=40/62) met a transcript level &amp;lt;10% at 3-months and 80.6% (n=50/62) met a transcript level &amp;lt;1% at 12-months. Major molecular response (MMR) was achieved and maintained in 59.7% (n=37/62) of these patients, with 25.8% (n=16/62) losing MMR and 14.5% (n=9/62) never achieving MMR. Reasons for loss of MMR included TFR attempts (31.3%; n=5/16), non-adherence from side effects (25%; n=4/16), lack of health insurance/inability to afford medication (18.8%; n=3/16), lack of response (18.8%; n=3/16), and pregnancy attempts (6.3%; n=1/16). Fertility was a notable issue for AYA patients, with 16 females (31.4%; n=16/51) and 18 patients overall (13.2%; n=18/136) interrupting or delaying start of TKI because of pregnancy/fertility. For patients who attempted TFR, 48.1% (n=13/27) remained off TKI in MMR at time of last follow-up. Of 130 AYA patients with CP or AP CML at diagnosis, 7.7% (n=10/130) experienced disease transformation, including 3.2% (n=3/94) of CP patients in the 2G-TKI era. Of 14 patients who presented or transformed into BP, 42.8% (n=6/14) underwent allogeneic stem cell transplantation and 64.3% (n=9/14) died. Of the entire cohort, 9.56% (n=13/136) patients died at a median age of 35 years old, including 5.4% who presented in CP (n=7/124) and 50% (n=6/12) of those who presented in AP/BP. Of the 13 who died, 11 (84.6%) died from CML-related complications. Conclusions: This represents the largest analysis of NCI-defined AYA CML patients in the US in the 2G-TKI era. Molecular response, progression and successful TFR rates in AYA CP CML patients appear to approximate those reported in prior large clinical trials that compared 2G-TKIs with imatinib. AYA patients can experience unique challenges that impact their management, including pregnancy/fertility and adherence, which can affect clinical outcomes. Patients may also present with aggressive advanced phase disease leading to mortality despite transplantation. Further study is warranted to better support the needs of this patient population. Evaluation of CML patients ≥ 40 years old at diagnosis at our institution is ongoing. A formal comparison between these groups will be presented.

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.

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.

Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: Final 5-year analysis of DASFREE.

Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.

Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study.

TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate.

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

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

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

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

Treatment Free Remission after Combination Therapy with Asciminib (ABL001) Plus Imatinib in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed after a Prior Attempt at TKI Discontinuation-H Jean Khoury Cure CML Consortium Study

Successful tyrosine kinase inhibitor (TKI) discontinuation is currently one of the main goals of CML therapy. Patients who are in sustained deep molecular remission can attempt TKI discontinuation; approximately 50% of such patients will achieve a successful treatment free remission (TFR) and the other 50% will have molecular recurrence , warranting reinitiation of TKI therapy. Molecular recurrence is defined as loss of major molecular response (BCR-ABL1 International Scale ratio >0.1%) . With a goal to increase the ultimate fraction of successful TFR, inquiry has begun into the rate and optimal approach to TFR after a second attempt at TKI discontinuation in patients with molecular recurrence after their first attempt. Molecular recurrence, is suspected to be driven by CML progenitor element(s) capable of, permitted to, and/or signaled to proliferate; different approaches to eradicate such a compartment have been proposed. One such potential means may be through alternative and synergistic BCR::ABL1 inhibition with the allosteric inhibitor asciminib in combination with approved TKIs for CML. Asciminib is a potent BCR::ABL1 inhibitor with a novel, allosteric mode of action. The activity of asciminib is a result of its ability to bind a vacant pocket on the kinase domain that is normally occupied by the myristoylated N-terminus of ABL, a negative regulatory element lost upon the fusion of ABL to BCR. Asciminib has an excellent selectivity profile, is several-fold more potent than current approved TKIs such as nilotinib, and in vitro was active in the low nanomolar range against a spectrum of clinically observed ATP site mutations. Asciminib demonstrated efficacy in phase I studies in resistant/intolerant chronic and accelerated phase CML, including T315I mutation positive and ponatinib pretreated patients. In a phase III trial, asciminib was more active than bosutinib in a phase III trial in patients who had received 2 prior TKIs Our primary objective in this study is to determine the 1-year TFR rate after 12 months of combination therapy with imatinib plus asciminib, followed by treatment cessation, in subjects who have previously had molecular recurrence first TFR attempt. This is a single arm phase II study that will enroll a maximum of 51 patients (NCT04838041). All subjects will have a confirmed diagnosis of CML-CP. Each subject must have previously attempted to discontinue imatinib, and were restarted on imatinib at the time of molecular recurrence in order to be eligible for this trial. This trial will use asciminib 40 mg PO daily plus imatinib at a maximum dose of 400 mg PO once daily in the combination treatment phase of this trial. All eligible subjects will be treated with asciminib and imatinib on cycle 1 day 1 of the combination therapy phase. Patients will remain on imatinib for 12 cycles. RQ-PCR to measure BCR::ABL1 transcripts in the peripheral blood at screening and at specific time points during the first 12 cycles on trial (combination therapy phase). At the end of 12 cycles, asciminib and imatinib will be discontinued in any subject who has continued in stable deep remission and thus meets criteria for TFR. This study will assess a wide range of PROs before and after stopping imatinib. These will be done in conjunction with RQ-PCR testing, though at fewer time points, utilizing online and/or phone questionnaires. The alternative hypothesis of relapse rate after second discontinuation of TKI combination treatment is 35% will be tested against a one-sided alternative of historical control of 55% relapse rate. Simon's two-stage admissible design will be used. The null hypothesis that the true TFR rate (no loss of MMR) is 45% will be tested against a one-sided alternative. In the first stage 29 patients will be accrued. If there are 15 patients or fewer who maintain TFR in these 29 patients, the study will be stopped. Otherwise, 18 additional patients will be accrued for a total of 47. The null hypothesis will be rejected if 27 or more patients maintain TFR in 47 patients. This design yields a type I error rate of 5% and power of 85% when the true TFR rate is 65%. To account for a potential dropout rate of 8% due to adverse events or loss of response, 51 patients will be enrolled to achieve the 47 patients needed.