Sustained Deep Molecular Response Research Articles

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 demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment while maintaining responses. Studies investigating TKI de-escalation before TFR, mainly in CML chronic phase (CP) imatinib-treated pts, suggested that this stepwise approach is feasible. Despite 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, prospective, multicenter DANTE study (NCT03874858) aims to shed light on frontline NIL de-escalation and successful TFR in Italian CML-CP patients. Our previously interim analysis showed that 1 year of NIL de-escalation before TFR in patients with sDMR is safe and effective. Here we present 1 year follow up results of those 40 patients who successfully completed NIL de-escalation and entered in TFR. Methods: Adults patients with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR 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 sDMR entered TFR phase and NIL was discontinued. Patients with at least major molecular response (MMR; BCR-ABL ≤0.1% IS), but without sDMR, 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 2022, at which time 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. Results: Overall, 113 pts were screened and 107 entered in consolidation phase. The baseline characteristics and the clinical outcome of the 52 patients that reached the end of consolidation phase by the first data cut-off period (February 8, 2021) have been previously reported (Breccia et al., 2021). Specifically, 47 out of 52 pts completed the consolidation phase and 40 (76.9%) of them, with sDMR, entered in the TFR phase. At 1-year data cut off, with a median duration of 12.7 months (range 1.9 - 20.6), 27 out of 40 pts (67.5 %) who entered in the TFR phase remained in MMR or better while 13 pts (32.5%) had discontinued the TFR phase (11 pts due to loss of MMR and 2 pts for subject/guardian decision). The median time spent in TFR phase until loss of MMR was 3.6 months (range 2-7 months). The median time to loss of MMR in TFR phase was not reached (Fig 1). At the data cut off, all patients except one (10/11, 90%) who lost MMR, regained MMR after NIL resumption. Overall, among the 13 patients who restarted NIL after MMR loss (2 pts from consolidation phase and 11 from TFR phase), 12 of them (92.3%) regained MMR and MR4 after a median time of 2.6 months (range 0.9 - 5.2) and 4.2 months (range 2.7- 8.0), respectively. Notably, 22/52 (42%) pts remained in DMR from consolidation phase until week 96. During the TFR phase, all grade AEs were reported in 26/40 (65%) pts. One pt (2.5%) had serious AE (pneumonia). No deaths and disease progressions were observed. Conclusions: Our finding show that approximately 68% of pts remained disease-free at 1 year after stopping NIL, indicating that de-escalation of NIL before TFR attempt in CML-CP pts with sDMR can be a successful dose optimization strategy. Reference: Breccia et al., Blood (2021) 138 (Supplement 1): 1474. https://doi.org/10.1182/blood-2021-145411 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk of Progression in Chronic Phase-Chronic Myeloid Leukemia (CML) Patients Eligible for Tyrosine Kinase Inhibitor Discontinuation: The Tfr-PRO Study

Background The possibility of treatment discontinuation (TD) in patients with Chronic Myeloid Leukemia (CML) achieving a sustained deep molecular response (DMR) became a reality in clinical practice and is recognized as one goal in the management of the disease. TD is considered successful if at least a major molecular response (MMR or MR3) is maintained. TD is generally considered safe, since MMR is achieved in almost all cases when TKI re-initiation is required. Progression to accelerated phase/blast crisis (AP/BC) after TD was considered virtually impossible for a long time. However, recent reports documented at least 8 cases of disease progression (DP) after TD, some of which were fatal. These observations raise concerns about the global safety of TD, since this practice can no longer be considered completely immune from the risk of disease progression, which drastically changes the patient situation and perspective. To obtain a numerical assessment of the risk of DP in patients (Pts) with durable DMR, independently of their decision to start TD, the TFR-PRO study was designed. Study Design and Methods This is a multicentre retro-prospective observational study which monitors CP-CML patients with stable and DMR followed at 20 centres in 5 different countries (Italy, Canada, Germany, Spain, France). Pts eligibility includes a history of at least 4 years of TKI treatment and at least 18 months of stable DMR, defined as a BCR-ABL1/ABL1 transcript level ratio lower than 1/10,000. The primary objective is to assess the risk of progression to AP/BC, expressed as time adjusted rates (TAR), and its relation to TD in the population of CML Pts who underwent a first or subsequent TD. Eligible Pts who did not discontinue TKI treatment are considered as a benchmark group. A flexible statistical approach allows to attribute Pts to the two groups according to their decision about TKI discontinuation (TD yes or no). Secondary endpoints are TAR of molecular relapse (MR, i.e. loss of MMR), Relapse Free Survival (RFS, defined as the time between eligibility or TD and MR), progression free survival and overall survival. Results The study opened on July 24th, 2020. As of July 24th 2022, 810 Pts were registered, of whom 778 patients are presently eligible, for a total of 3949 person years available for analysis. Median follow up is 6.0 years (range 0.2-15 years), median age at diagnosis was 50 years and 45% Pts are female. Sokal score (available in 406 patients) was low in 47.54%, intermediate in 33.25% and high in 19.21%. A total of 434 Pts (56%) attempted TD at some point; 35 Pts (4.40%) attempted TD twice. MR occurred in 154/434 (35.5%) Pts after TD for a TAR of 12.9/100 person years, (95% confidence interval (CI) [11-15.1]), but also in Pts who did not attempt TD (61/344, or 17.7%), with a TAR of 2.22/100 person years (95%CI [1.7-2.8], p<0.0001. A graphical representation of the estimated proportion of Pts with MR is provided in figure 1. One patient progressed to lymphoid BC 18 months from TD; he received allogeneic BMT and is presently in remission. Thus the risk of progression is 1/778 or 0.13% (95% CI [0.003-0.7]) in the entire cohort; this value goes from 1/434 or 0.23%, (95% CI 0.006%-1.3]) for Pts who attempted TD, to 0% (95% CI [0%-0.872%]) for Pts who did not attempt TD. The TAR of progression is 0.026/100 person years (95%CI [0.004-0.184]) in the entire cohort; this value ranges from 0.084/100 person years (95%CI [0.012-0.593]) for Pts who attempted TD to 0/100 person years (95%CI [0-0.11]) for Pts who did not attempt TD. Conclusions These results obtained in a real world scenario indicate that slightly more than half of 778 eligible Pts attempt TD. Pts who discontinue treatment have a significantly higher risk of losing MR3 than Pts who do not, although MR happen over time also in patients who do not discontinue, and the overall rate of MR after TD is lower than in previous studies. The risk of progression to AP/BC is estimated as 0.13% or 0.026/100 person years; this value is apparently higher for Pts who attempted TD but the 95% CI of the two groups overlap, indicating a lack of significant difference. We conclude that CML progression in Pts eligible for TD is a rare event (approximately 1 in 1000 patients or 0.026% per year in a single patient) and that its relationship with TD is possible but not proven. Additional data including 155 patients already registered but not yet analysed will be presented. Future studies will be needed to confirm our results. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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

More Than Ten Years Follow-up of Frontline Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Myeloid Leukemia

Background: Tyrosine kinase inhibitor (TKI) therapy improved survival in patients (pts) with chronic myeloid leukemia (CML). Treatment-free remission (TFR) can be considered for a minority of pts, particularly in those who achieved sustained deep molecular response (DMR). Given most pts needs TKI therapy over decades, the aim of this study is to evaluate the very long-term outcome of pts (pts) treated with frontline TKI. Methods: We analyzed 557 pts with newly diagnosed CML in chronic phase (CP) and accelerated phase (AP; based solely on the presence of clonal evolution) who were treated with frontline TKI therapy (standard-dose imatinib, 73 pts; higher-dose imatinib, 210 pts; dasatinib, 144 pts; and nilotinib, 130 pts) from July 2000 to September 2014. The presence of comorbidity was assessed by the Adult Comorbidity Evaluation-27. Responses criteria were previously defined (complete cytogenetic response, CCyR; major molecular response, MMR; molecular response with a 4-log reduction, MR4; molecular response with a 4.5-log reduction, MR4.5). Failure-free survival (FFS) was calculated from the start of therapy to the treatment discontinuation for any reason except of TFR; event-free survival (EFS), to the date of any of the events while on study as defined in the IRIS study; transformation-free survival (TFS), to the date of transformation to accelerated or blast phases during study; overall survival (OS), to the date of death from any cause at any time or date of last follow-up. We evaluated prognostic factors with univariate and multivariate Cox proportional hazard models with a p-value cutoff of 0.100 or less by univariate analysis for variable selections; cumulative incidence of response was assessed with a competing risk model. Multiple imputation was performed for missing variables to reduce bias. Time to complete cytogenetic response was analyzed as a time-dependent variable in the Cox regression Results: The median age at the start of TKI therapy was 49 years (range, 15.1-86.4). The overall median follow-up was 178 months (range, 5.3-253.9) (standard-dose imatinib, 231 months; higher-dose imatinib, 212 months; dasatinib 137 months; nilotinib 138 months) (Table 1). Overall, the 10-year cumulative incidence rates of CCyR, MMR, MR4, and MR4.5 were 91%, 87%, 76%, and 72%, respectively; among pts who responded, the median time to CCyR, MMR, MR4, and MR4.5 were 3.1 months, 5.9 months, 9.5 months, and 12.5 months, respectively. The cumulative incidence rates of CCyR, MMR, MR4, and MR4.5 were higher in the higher-dose imatinib, dasatinib, and nilotinib cohorts compared to standard-dose imatinib. The 10-year FFS rates were 48%, 52%, 67%, and 44% in the standard-dose imatinib, higher-dose imatinib, dasatinib, and nilotinib cohorts, respectively (P<0.001); the 10-year TFS rates were 84%, 98%, 98%, and 96%, respectively (P<0.001); the 10-year EFS rates were 67%, 80%, 89%, 86%, respectively (P=0.001); the 10-year OS rates were 67%, 80%, 89%, and 86%, respectively (P=0.206) (Figure 1). Backward multivariate Cox regression analysis identified older age at TKI therapy, the presence of smoking history, higher severity of comorbidity by the Adult Comorbidity Evaluation-27, higher percentage of blasts in peripheral blood, and longer time to achieve CCyR as adverse prognostic factors for survival. With the minimum median follow-up of more than 10 years in all the TKI groups, the 10-year relative survival rate was 91.4%; among pts who achieved CCyR within 1 year of frontline TKI therapy, the 10-year relative survival rate was 94.4%; MMR, 97.0%; MR4, 96.7%; MR4.5, 96.2%. Conclusion: TKI therapy has significantly improved outcomes of pts with CML-CP. Frontline second-generation TKIs achieve higher rates of DMR response than standard-dose imatinib. The assessment of comorbidity is essential assessment for the optimal selection of frontline TKI therapy. The survival of pts with CML-CP is similar to that of general population at 10 years. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Measurable residual disease in childhood B-cell acute lymphoblastic leukemia.

Measurable residual disease in childhood B-cell acute lymphoblastic leukemia.

Psychological Factors Affecting the Willingness to Accept a Possible Tyrosine Kinase Inhibitor (TKI) Discontinuation in Chronic Myeloid Leukaemia (CML) Patients.

Patients with chronic myeloid leukemia (CML) who present a sustained deep molecular response (DMR) for a stable period of time might benefit from discontinuing tyrosine kinase inhibitors (TKIs). A significant number of patients seem able to reach this stage due to the availability of TKIs. However, many patients remain reluctant about TKI discontinuation and may refuse treatment interruption. The purpose of this study was to explore the clinical and psycho-cognitive factors that may influence the decision to discontinue TKI therapy, thereby gaining a better understanding of patients' viewpoints on TKI discontinuation. One hundred and nineteen patients diagnosed with CML aged between 34 and 69 were enrolled (67 males and 52 females). Different clinical information and psycho-cognitive aspects such as attitude toward risk behaviours, risk preferences, need for cognitive closure, and tendency to resist to changes were assessed through the administration of a battery of questionnaires. A higher tendency toward risk behaviours and the tendency to focus on possible gain in the short term rather than on losses might represent important predictors for the willingness to accept TKI discontinuation. Possible relapses following interruption of the therapy are the most common reason for concern. Furthermore, lower levels of resistance to change and having previously experienced the desire to interrupt the therapy might lead patients to accept a higher probability of relapse risk when facing such a decision. TKI discontinuation appears appealing and challenging at the same time for many CML patients, and different factors may influence this decision. Psychology plays a crucial role in assisting physician-patient communication and informed decision-making.

Dose optimization of tyrosine kinase inhibitor therapy in chronic myeloid leukemia.

The therapeutic outcomes of chronic myeloid leukemia (CML) have improved dramatically since tyrosine kinase inhibitors (TKIs) became available in clinical practice. Life expectancy of patients with CML is now close to that of the general population. Patients with CML who achieve sustained deep molecular response may discontinue TKI therapy. However, most patients still require TKI therapy for long periods without sustained deep molecular response. Given the awareness of increased incidence of arterial occlusive events in patients on TKI therapy, the optimal TKI selection should be based on age, comorbidities, risk classification, and goals of treatment. Dose optimization of TKI therapy reduces the incidence of adverse events while maintaining efficacy in CML.

Withdrawal syndrome after tyrosine kinase inhibitors discontinuation in patients with chronic myeloid leukemia

Withdrawal syndrome (WS) a musculoskeletal pain after discontinuation of tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) has been described in the treatment-free remission (TFR) studies. The pathophysiological mechanisms and predisposing factors of WS have not been well established. Our aim was to evaluate clinical features and factors associated with WS in the Russian cohort of CML patients who discontinued TKI therapy. WS was evaluated in total of 183 CML patients with chronic phase and sustained deep molecular response (DMR). WS was defined as a musculoskeletal pain newly observed after TKI cessation or as a worsening of previously observed symptoms. DMR loss free survival at 36 months was 49% and 43% in prospective and retrospective groups respectively (p=0.96) with mеdian (Me) time of observation 33 months (range 1136). WS was observed in 49 (27%) patients: grade 12 was in 45 (92%) patients, grade 3 in 4 (8%) patients. Me time to WS occurrence was 2 months (range 17), Ме duration of WS was 5 months (range 135). WS was resolved in 14 of 15 patients with molecular relapse after 13 months of TKI re-initiation and was decreased in 1 patient. WS was completely resolved in 31 of 34 patients who continued remained in TFR and decreased in 3 patients. WS was resolved spontaneously or with nonsteroidal anti-inflammatory drugs in 14 (45%) and 17 (55%) patients accordingly. Older age (p0.0001), longer duration of TKI therapy (p0.0001) and presence of locomotion system diseases (p=0.022) were observed in patients with WS. No WS was observed in pregnant patients (р0.001). Survival without DMR loss at 12 months after TKI stop was 66 and 42% in patients with and without WS accordingly (р=0.095). The rate of WS was 27% that is in a good concordance with the data of the other TFR studies. A longer period of TKI exposure, older age and the history of locomotion system diseases were associated with the development of the WS. We found for the first time that WS was not observed in patients with pregnancy. There was no association of WS development and the rate of molecular relapses.

The prognostic role of NKG2A expression for patients with chronic myeloid leukemia after treatment discontinuation

This study aims to evaluate the possibility of tyrosine kinase inhibitors (TKIs) discontinuation in chronic myeloid leukemia (CML) patients who obtained sustained deep molecular response (DMR) and to explore the prognostic role of NK cells in treatment-free remission (TFR). Sixty CML patients who discontinued TKI treatment were enrolled, and we also investigated the immune profiles in 27 CML patients after TKI cessation. Of the 60 patients, the estimated TFR rate was 60.8% [95% CI: 49.5–74.8%] at 12 months. Patients who had longer TKI duration, major molecular response, and DMR maintenance time had a significantly higher TFR rate. And a higher percentage of NKG2A+NK cells and NKG2A+CD56brightCD16−NK cells were independent prognostic factors of TFR in multivariate analysis. These results indicate the practicality of the cessation of TKIs and patients with stable NK cell counts accompanied by higher cytotoxicity and increased killing capacity are more inclined to get sustained treatment-free survival.

Influence of cytochrome P450 and glutathione S transferase polymorphisms on response to nilotinib therapy among chronic myeloidleukemia patients from Pakistan

BackgroundCytochrome P450 (CYP) and glutathione S transferases (GSTs) are important biotransforming enzymes responsible for detoxification of anticancer drugs and carcinogens. Polymorphisms in these enzymes may greatly influence the susceptibility to CML and overall efficacy of tyrosine kinase inhibitors. This study was aimed to estimate the possible influence of the polymorphisms of GSTs and CYP in the occurrence of CML as well as in predicting therapeutic outcome of nilotinib therapy in Pakistani CML patients.MethodsThe polymorphic variability in CYP 1A1*2C, GSTP1 (A3131G), GSTT1 and GSTM1 was assessed either by RFLP or multiplex PCR. The BCR ABL1 transcripts were quantified by qPCR to monitor response to nilotinib.ResultsThe CYP1A1*2C heterozygous and GSTP1 homozygous polymorphisms seemed to be a contributing factor in developing CML. Altogether, there were 12 non-responders, 66 responders and 21 partial responders. The most frequent genotype was null GSTM1 in responders followed by CYP 1A1 and GSTP1 -wild type (p = < 0.05). Whereas, homozygous GSTP1 and GSTT1 null genotype is significantly higher only among nilotinib non-responders.ConclusionHence, it can be concluded that wild type CYP1A1, GSTP1 and null GSTM1 may be frequently linked to favorable outcome in patients treated with nilotinib as depicted by sustained deep molecular response in most CML patients.

Long-term outcomes of patients with Chronic Myeloid Leukemia who commenced treatment with imatinib: a 20-year single-centre experience

We report on long-term outcomes of 267 patients (pts) with chronic myeloid leukemia (CML) treated with imatinib administered as initial therapy. The median follow-up time was 11.4 years. 38 (14.2%) pts attempted to discontinue imatinib therapy after achieving sustained deep molecular response (≥MR4), 15 of them achieved treatment-free remission (TFR). 144 pts (53.9%) have been switched to other TKI during the follow-up period. The estimated OS for 267 pts for 10, 15 and 18 years was 98.8%, 75.6% and 52.1%. According to prognostic scores (Sokal, Euro, ELTS), OS and PFS were significantly better in low-risk pts than in high-risk pts. According to ELTS, low-risk pts have a better chance of achieving MR4 than both intermediate (p = 0.03) and high-risk (p = 0.04) groups. It suggests that a specific ELTS-adapted treatment could help to optimize treatment results. In the study population, imatinib has demonstrated sustained efficacy and an acceptable rate of late toxic effects.

How I Manage Patients with Chronic Myeloid Leukemia (CML): Perspectives from Clinical Practice.

The management of chronic myeloid leukemia (CML) has remarkably changed in the last 20 years with the availability of tyrosine kinase inhibitors (TKI). Most patients with chronic phase CML now have a life expectancy like that of age matched controls. Understanding the practical aspects of choosing the appropriate TKI, monitoring response and side-effects are key to long term success. Currently, treatment cessation is also an option in patients achieving sustained deep molecular response. Novel agents are needed in patients with lack of response to TKI and in those with advanced disease.

Non-albuminuric chronic kidney disease in diabetes: A different approach?

Background & objectives: Both innovator and generic imatinib are approved for the treatment of Chronic Myeloid Leukaemia-Chronic phase (CML-CP). Currently, there are no studies on the feasibility of treatment-free remission (TFR) with generic imatinib. This study attempted to determine the feasibility and efficacy of TFR in patients on generic Imatinib. Methods: In this single-centre prospective Generic Imatinib-Free Trial-in-CML-CP study, twenty six patients on generic imatinib for ≥3 yr and in sustained deep molecular response (BCR ABLIS ≤0.01% for more than two years) were included. After treatment discontinuation, patients were monitored with complete blood count and BCR ABLIS by real-time quantitative PCR monthly for one year and three monthly thereafter. Generic imatinib was restarted at single documented loss of major molecular response (BCR ABLIS>0.1%). Results: At a median follow up of 33 months (interquartile range 18.7-35), 42.3 per cent patients (n=11) continued to be in TFR. Estimated TFR at one year was 44 per cent. All patients restarted on generic imatinib regained major molecular response. On multivariate analysis, attainment of molecularly undetectable leukaemia (>MR5) prior to TFR was predictive of TFR [P=0.022, HR 0.284 (0.096-0.837)]. Interpretation & conclusions: The study adds to the growing literature that generic imatinib is effective and can be safely discontinued in CML-CP patients who are in deep molecular remission.

Treatment-Free Remission (TFR) after Two Different Durations of Nilotinib Consolidation in Patients with Chronic Myeloid Leukemia (CML) Previously Treated with Imatinib: Enestpath Study Results

Treatment-Free Remission (TFR) after Two Different Durations of Nilotinib Consolidation in Patients with Chronic Myeloid Leukemia (CML) Previously Treated with Imatinib: Enestpath Study Results

A Phase 1b/2 Study of Navtemadlin (KRT-232), a Murine Double Minute 2 Inhibitor, Combined with a BCR-ABL Tyrosine Kinase Inhibitor in Patients with Relapsed/Refractory, TP53WT, Ph+ Chronic Myeloid Leukemia

A Phase 1b/2 Study of Navtemadlin (KRT-232), a Murine Double Minute 2 Inhibitor, Combined with a BCR-ABL Tyrosine Kinase Inhibitor in Patients with Relapsed/Refractory, TP53WT, Ph+ Chronic Myeloid Leukemia

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

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

Highly Sensitive Droplet Digital PCR to Identify CML Patients with a High Probability of Achieving Treatment-Free Remission

Introduction: Treatment Free Remission (TFR) is the ultimate goal of therapy for most CML patients. Despite adopting consensus eligibility criteria of a sustained deep molecular response and more than 4 years of TKI therapy, the relapse rate after TKI cessation is still around 50%. More sensitive detection of residual leukaemia has the potential to improve our capacity to predict TFR outcomes for individual patients.Aim: To correlate droplet digital PCR (ddPCR) assay results with TFR outcome, especially in the setting of undetectable levels measured by qRT-PCR.Method: ddPCR was performed on blood samples from 51 TFR-eligible CML patients at the time of TKI cessation. 5 µg RNA per sample was used in 8 wells/sample using the BioRad QXDx BCR-ABL %IS kit on QX200 ddPCR system which yielded BCR-ABL1% (IS) directly. All these patients achieved MR4.5 that was sustained for ≥ 2 years.Results: 100% of patient were in MR4.5 via qRT-PCR at the time of stopping. 61% of the 51 patients evaluated relapsed within 12 months. Median duration of TKI therapy for the whole group was 5.8 years (range 2.2- 14 years). 20 patients achieved TFR success with a median follow up of 24 months (TFR group; sustained BCR-ABL1 <0.1% (IS) after TKI discontinuation for ≥12 months), while 31 patients relapsed (Relapse group; BCR-ABL1 >0.1% (IS) after stopping; median time of relapse 3 months, range 1-10 months).A ROC curve analysis correlated TFR outcome with ddPCR results, with BCR-ABL1 level ≥0.003% via ddPCR at the time of stopping identified as an optimal cut-off. Kaplan-Meier analysis showed that 89% of the patients with ddPCR ≥0.003 relapsed after TKI cessation, whereas the ddPCR <0.003 demonstrated a significantly reduced relapse rate to 54% (p=0.01, Figure 1A). In addition, the TFR group (median BCR-ABL1 0.00065%) demonstrated approximately two-fold lower levels of BCR-ABL1transcript level compared to the relapse group (median 0.0012%). Interestingly, 7/31 (23%) of the relapsed group had undetectable BCR-ABL1 transcript even with the current highly sensitive method, while this undetectable level was only observed in 35% of the TFR group.We next assessed other known predictors of TFR success relative to ddPCR results in a Cox proportional hazard model. We have previously demonstrated that the BCR-ABL1 halving time after commencing therapy is highly predictive of TFR. At a univariate level, transcript type (e13a2 versus e14a2, p=0.01), BCR-ABL1 halving time (p>0.0001), and mRNA quantitation by ddPCR ≥ 0.003% (p=0.02) were all significantly associated with clinical outcome. Other variables including gender, age, ELTS score, Sokal score, MR4.5 duration and TKI duration were not associated with clinical outcome in this cohort (Figure 1B). In the multivariate analyses (Figure 1C), ddPCR remained an independent predictor after adjusting for ELTS, TKI duration and MR4.5 duration. Interestingly, ddPCR was not an independent predictor after adjusting for BCR-ABL1 transcript type or halving time.Conclusion: QXDx ddPCR assay is a promising tool for molecular residual disease monitoring in CML, especially when the BCR-ABL1 is undetectable by conventional method. The CML patients with levels of detectable BCR-ABL1 ≥0.003% measured by ddPCR have a significantly higher probability of relapse compared to patients with lower levels of the transcript. The ≥0.003% BCR-ABL1 level cut-off value could be a potential tool to aid decision-making when attempting TKI discontinuation in CML. However, even though a measurable level of BCR-ABL1 above 0.003% via ddPCR identified patients at high risk of relapse after a TFR attempt, it does not rule out the possibility of TFR; and a negative ddPCR result does not exclude the risk of molecular relapse. ddPCR may be most useful where other TFR predictive factors including BCR-ABL1 transcript type and halving time are not available.In-kind support was received from Bio-Rad for this study. [Display omitted] DisclosuresBranford: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cepheid: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes: Novartis: Honoraria, Research Funding; Incyte: Honoraria; BMS: Honoraria, Research Funding. Yeung: BMS: Honoraria, Research Funding; Amgen: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria.

Onset of Blast Crises in CML Patients in Treatment-Free Remission: Descriptive Analysis of 4 Cases

Aims: The onset of blast crisis (BC) in initially chronic phase (CP) CML patients that entered treatment-free remission (TFR) after TKI is an exceptional event, however, there is emerging evidence that this may occur in such patients (pts), although the pathogenesis remains unclear to date.Methods: Anonymous clinical case retrospective data collection from patients' datafiles, after written agreement of living patients, centralisation of available frozen nucleic acid collection from diagnosis and from blast crisis and reanalysis by Next-Generation Sequencing of samples (ASXL1, ASXL2, BCOR, CALR, CBL, CEBP alpha , CSF3R, DNMT3A, EP300, ETNK1, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2 JAK2, KIT, , KRAS,MPL, NPM1, NRAS, PHF6, PTPN11 , RAD2, RUNX1, SETBP1, SF3B1, SH2B3, SMC1A, SMC3, SRSF2, STAG1, STAG2, TET2, TP53, U2AF1, WT1 and ZRSR2 genes analysed) on Illumina platform. CNV analysis were performed using VisCAp or in-house pipelines and/or by Multiplex Ligation Dependant Probe Amplification (MLPA). ABL1 tyrosine kinase domain mutations were screened by NGS on cDNA or directly on DNA. BCR-ABL1 transcripts are expressed in % (IS) with at least 32,000 copies of ABL1 as control. All patients discontinued their TKI after 2 years of MR4.5 and a TKI was resumed in case of MMR loss.Results: Along 15-year experience of TFR in our country and ≥ ~800 patients experiencing a TKI cessation attempt, informations from 4 (~0.5%) TFR CML patients entering BC have been collected. All patients harboured Major BCR transcripts.The chronic phase characteristics are mentioned in Table 1.All these long-lasting CP CML pts were ELTS risk score low, and 1 was harbouring ACA at diagnosis. One pt was mutated for ASXL2 and 2 mutations for EP300, found again at BC. Three pts had IFN-a prior to imatinib for all. Three out of 4 lost their MMR after a first cessation attempt at 12, 10 and 3 months after cessation. Pt #1 experienced a 2 nd cessation attempt 52 months after re-initiation of TKIs and entered lymphoid BC 6 months after a second resumption of TKI for a 2 nd MMR loss.The BC characteristics are mentioned in Table 2.Three out of 4 BC were lymphoid, one had ACA different from those at CP diagnosis. Two pts explored had multiple mutations in Runx1, U2AF1, EP300 and ASXL2 genes, not present at CP diagnosis, in addition to multiple ABL1 mutations in 2 out of 4 pts (2 T315I, 3 P-Loop mutations). All pts underwent chemotherapy + various TKI leading to complete remission (CR) in all and 3 out of 4 pts could be allotransplanted in CR, one relapsed shortly after transplant, and a second one 34 months after transplant. Overall 3 pts are alive with 1 in controlled relapse.Conclusions: The onset of BC after TFR for sustained deep molecular response remains an exceptional event and is probably not induced by this therapeutic procedure. These 4 cases underline the need for a sustained long-lasting molecular follow-up of pts in TFR, although the majority of these BC seem sudden. [Display omitted] DisclosuresBauduer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.