Duration Of Deep Molecular Response Research Articles

Combination of dasatinib and venetoclax in newly diagnosed chronic phase chronic myeloid leukemia.

The dual inhibition of the BCR::ABL1 tyrosine kinase and BCL-2 could potentially deepen the response rates of chronic myeloid leukemia in chronic phase (CML-CP). This study evaluated the safety and efficacy of the combination of dasatinib and venetoclax. In this phase 2 trial, patients with CML-CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 was achieved. After 3 years of combination, patients were maintained on single-agent dasatinib. The primary end point was the rate of major molecular response (MMR) by 12 months of combination. Sixty-five patients were treated. Their median age was 46 years (range, 23-73). By 12 months of combination, the MMR, MR4, and MR4.5 rates were 86%, 53%, and 45%, respectively. After a median follow-up of 42 months, the 4-year event-free and overall survival rates were 96% and 100%, respectively. Outcomes with the combination were comparable to historical outcomes with single-agent dasatinib (cumulative 12-months MMR rate of 79% with both strategies). The incidence of grade 3-4 neutropenia was 22% with the combination and 11% with single-agent dasatinib (p<.001). Treatment with dasatinib and venetoclax was safe and effective in CML-CP. The cumulative response rates with the combination were similar to those with single-agent dasatinib. Further follow-up is needed to evaluate the rates of durable deep molecular response and treatment-free remission.

How to improve treatment-free remission eligibility in chronic myeloid leukaemia?

The achievement of treatment-free remission (TFR) has become a significant clinical end-point in the management of patients with chronic myeloid leukaemia (CML), providing an opportunity to discontinue therapy with tyrosine kinase inhibitors (TKIs) while maintaining deep molecular response (DMR). Early studies, such as the French STIM trial, have demonstrated that a portion of patients can maintain DMR after treatment cessation, with rates ranging from 40% to 50%, and most relapses occurring within the first 6 months. Key prognostic factors for successful TFR, including treatment duration, duration of DMR, risk scores, and transcript type, have been identified. Optimal patient selection for TFR remains a challenge, but recent research provides insights into potential strategies to increase TFR eligibility. Evidence suggests that early intervention switching to achieve optimal response, treatment combinations, proactive switch in the case of absence of DMR, dose-optimization and induction-maintenance approach can improve molecular responses and, consequently, enhance TFR eligibility. In this review, we report and discuss all the potential therapeutic strategies that may enhance eligibility for a first attempt at TFR, with a particular emphasis on potential future approaches.

The SNP rs460089 in the gene promoter of the drug transporter OCTN1 has prognostic value for treatment-free remission in chronic myeloid leukemia patients treated with imatinib

Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60–82%) compared to patients with GG (51%, 95% CI: 41–61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.

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

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

Treatment-Free Remission after Ponatinib Cessation in Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients. the Ponastop Observational Study

Introduction: Ponatinib has proven its efficacy as salvage therapy for patients intolerant, or resistant (and ABL1T315I+ mutation) to at least 2 tyrosine kinase inhibitors (TKI) in CP-CML. Despite the unfavourable profile of such patients, some durable deep molecular response (DMR, i. e. MR 4 and MR4.5) might be observed, and it is arguable to propose a treatment-free remission (TFR) strategy to these patients, despite the fact that this is not currently recommended. The aim of this study is to analyse the results of TFR in CP-CML patients that have received ponatinib as last line of therapy for any reason. Methods: This a retrospective multicentric European analysis of CP-CML patients undergoing ponatinib at any dose for prior TKI-intolerance or -resistance and obtaining at least 2 years of MR4.5, assessed on at least 4 successive samples, and undergoing a treatment-free remission (TFR) procedure and follow-up. All BCR::ABL1 assessments have been performed in ELN reference laboratories and expressed in % on the international scale (IS). Loss of major molecular response (MMR i. e. BCR::ABL1 transcript ≥0.1% IS) on one datapoint was sufficient to consider relapse. Clinical information were extracted from individual patients' files. All patients have given their written agreement in participating to this observational study. Results: Fifteen cases could be collected and analysed with 27% males, 73% females of a median age of 43 (24-79) years at CML diagnosis and of 56 (30-83) at ponatinib cessation. All patients were in CP at diagnosis and at ponatinib cessation. None of these patients were harbouring additional chromosomal abnormalities at diagnosis or beyond. Sokal scores were low in 50%, intermediate in 25% and high in 25% of patients, ELTS scores were low in 64% and intermediate in 36% of patients. None of these patients has undergone allogeneic stem cell transplant. Three patients were ABL1T315I mutated. The median time between CP-CML diagnosis and ponatinib initiation was 52 (1.5-145) months, the median initial dose of ponatinib was 45 mg QD for 12 patients, 30 mg QD for 2 patients and 15 mg QD for 1 patient. One patient had 4 previous lines of TKI prior to ponatinib, 4 patients 3 prior lines, 5 patients 2 prior lines, 4 patients 1 prior line and 1 patient was in ponatinib first-line (EPIC trial). Thirteen arterial events occurred on ponatinib in these 15 patients, all prior to ponatinib cessation. At cessation, the median dose of ponatinib was 30 mg QD for 1 patient, 15 mg QD for 7 patients, 7.5 mg QD for 2 patients, and ≤ 6.4 mg QD for 4 patients. Ten (67%) patients were resistant to prior TKI before ponatinib, 3 were intolerant, 1 intolerant and resistant and 1 was in first-line ponatinib. The median ponatinib treatment duration prior to cessation was 71 (21- 124) months and the time from ponatinib initiation to sustained DMR was 14 (2-112) months. The median follow-up after cessation was 11 (2-55) months. One patient died in TFR of severe SARS-CoV2 lung infection 23 months after cessation. The median survival without MMR loss after ponatinib cessation was 69.26% at 12-months, 24-months and 54-months. Time to MMR-loss KM curve is presented in Figure 1. The four patients loosing MMR after ponatinib cessation resumed low dose ponatinib (≤ 15 mg QD) for 2 and asciminib (80 mg BID) for 2, three patients regained MMR (one non evaluable with too short follow-up). Conclusions: TFR attempt represents a strategy that can be applied to ponatinib patients in the setting of heavily pretreated CP-CML in a similar way as of less advanced CP-CML patients, with high success rates and no disease progression. If those data are confirmed by further studies and longer follow-up, TFR strategies might have to be considered also in previously heavily pre-treated patients.

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.

Treatment-Free Remission in Ponatinib-Treated CML Patients: The Italy-Tfr Experience

Background: In recent years, treatment-free remission (TFR) has become a new therapeutic goal and is considered feasible even by international expert guidelines, at least in patients (pts) with a stable deep molecular response (DMR). From the EPIC study, we learned that many pts achieve a DMR very early, regardless of Sokal risk (Lipton, Lancet Oncol 2016). The Optic study showed that early dose reduction is associated with a containment of cardiovascular (CV) risk while maintaining therapeutic efficacy. In the cohort of pts initially treated with 45 mg QD, the number of events remained around 10% (Cortes, Blood 2021). Recommendations for treatment discontinuation suggest that it should be considered only after one line of treatment or after a second line if first-line TKI was switched for intolerance. Since 2016, there are case reports in the literature of imatinib-resistant pts, treated with ponatinib in second or following lines due to intolerance or resistance to previous TKIs, with or without ABL1 mutations, who reduced the daily dosage from 45 to 15 mg, still achieving a DMR and then discontinued ponatinib due to toxicity, obtaining a persistent TFR (Wisniowski, Blood 2016; Engel, J Oncol Pract 2016; Cohen, Leuk Lymphoma 2020). Methods: Within the context of the Italy-TFR retrospective and prospective study (NCT04769947) which is ongoing and actually includes 467 pts, we collected the data of 19 pts who attempted TFR after ponatinib treatment. Results: Median age was 44 years at diagnosis, 60 years at ponatinib discontinuation. 8 pts were male (42%); Sokal score was available for 14 pts: 5, 3 and 6 pts were low, intermediate and high risk, respectively. ELTS score was available for 11 pts: 6 pts, 4 and 1 were low, intermediate and high risk, respectively. 6 pts were treated with ponatinib in second line, 9 in third line, 3 in forth line. First-line therapy was available for 16 pts and was imatinib for 11 pts, nilotinib for 2 pts, dasatinib for 3 pts. Median duration of front-line treatment was 16 months (mos, IQR 11-34). Data on second line therapy was available for 11/12 pts: 5 pts were treated with nilotinib, 6 with dasatinib. Median duration of second-line treatment was 47 mos (IQR 19-58). Third line therapy was dasatinib for all 3 pts, with a duration of 1, 18 and 139 mos. Reason for starting ponatinib was intolerance for 8 pts, resistance for the others. For 7/11 resistant pts response at ponatinib start was CHR for one pt, MR1 for 3 pts, MR2 for 3 pts. 3 pts carried 1 ABL1 mutation at ponatinib start: 1 F359V, 1 M244V and 1 T315I; 1 pt carried 2 mutations: 1 Y253H and 1 E499E. Patients received ponatinib for a median of 47 mos (IQR 34-54). Starting dose was 45 mg for 6 pts, 30 mg for 8 pts and 15 mg for 5 pts. Response at 3 mos was available for 17 pts and was MR2 for 2 pts, MR3 for 9 pts and DMR for 6 pts. Median time to DMR was 18 mos (IQR 6-36). Ponatinib dose before treatment discontinuation was 15 mg for all but 4 pts: 1 was dose reduced from 45 mg to 30 mg, 1 stayed on 45 mg; 2 pts who had started with 15 mg dose reduced to 15 mg every other day. 11 pts discontinued in MR4, 7 pts in MR4.5 and 1 pt in MR5. Median duration of DMR before discontinuation was 25 mos (IQR 14-37). Reasons for discontinuation were: physician-patient shared choice for 9 pts, intolerance for 6 pts (among whom 1 had pancreatitis, 1 worsening of cardiac heart failure, 1 tachycardia, and 3 low-grade GI symptoms), need to start chemotherapy for a second neoplasia for 2 pts, pregnancy for 1 pt and auto-suspension for 1 pt. Only one pt had a CV adverse event (stroke) during treatment with ponatinib. 16/19 pts maintained TFR for a median time of 19 mos (IQR 8-32) and were still off treatment at the last follow-up. 3 pts had to resume treatment after 3, 4 and 9 mos. All 3 restarted treatment with ponatinib and reobtained DMR. All pts were alive at last follow-up, except for 2 pts who died for a gastric and a lung cancer. Conclusions: Our data confirmed the efficacy of ponatinib in second or later lines of treatment. All pts, including those treated for resistance, achieved optimal responses at 3 mos. We also showed that TFR may be feasible for some pts treated in second or subsequent lines, not only for intolerance. Follow-up time extension and collection of data from additional pts are desired to confirm our observations, and seem to be of utmost importance to better define the characteristics of pts who might benefit from ponatinib with the purpose of TFR attempt.

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.

Effect of BCR::ABL1 transcript type and droplet digital polymerase chain reaction on successful treatment-free remission in chronic myeloid leukemia patients who discontinued tyrosine kinase inhibitor.

Droplet digital polymerase chain reaction (ddPCR) is an exact method of measurement. We conducted this study to identify the prognostic factors for successful treatment-free remission in patients with chronic-phase chronic myeloid leukemia who discontinued tyrosine kinase inhibitors (TKIs). We also aimed to validate ddPCR for predicting molecular relapse. This is a prospective, multicenter study. We enrolled patients treated with TKIs for at least 3 years with a confirmed sustained deep molecular response (DMR) for at least 1 year. TKI was re-administered in patients who experienced the loss of major molecular response (MMR). A total of 66 patients from five institutions in South Korea were enrolled. During a median follow-up period of 16.5 months, 29/66 (43.9%) patients experienced molecular relapse; the probability of molecular relapse-free survival (RFS) at 6 or 12 months after TKI discontinuation was 65.6% or 57.8%, respectively, with most molecular relapses occurring within the first 7 months. All patients who lost MMR were re-treated with TKI, and all re-achieved MMR at a median of 2.8 months. E14a2 transcript type (p = 0.005) and longer DMR duration (⩾48 months) prior to TKI discontinuation (p = 0.002) were associated with prolonged molecular RFS and with sustained DMR. Patients with both e13a2 transcript type and detectable BCR::ABL1 (⩾MR5.0) by ddPCR at the time of TKI discontinuation showed shorter duration of molecular RFS (p = 0.015). Our data suggest that transcript type and BCR::ABL1 transcript levels on ddPCR should be taken into consideration when deciding whether to discontinue TKI therapy.

Long-Term Follow-up of Tyrosine Kinase Inhibitors Discontinuation in Chronic Myeloid Leukemia: A Single-Center Experience

Introduction: Ever since the availability of BCR-ABL1 tyrosine kinase inhibitors (TKIs) as treatment for chronic myeloid leukemia (CML), life expectancy of patients has dramatically improved, approaching that of the overall population. Several clinical trials have demonstrated the possibility of discontinuing TKI. However, the information on the safety of long-term TKI cessation is still limited. Methods: We carried out a descriptive, retrospective and single-center study, including 56 patients with CML who discontinued TKI treatment between January 2006 and July 2022. We defined strict molecular relapse as loss of MR4 (BCR-ABL1 International Scale (IS) ≤ 0,01% or undetectable BCR-ABL1 in samples with ≥10.000 transcripts), loose molecular relapse as loss of major molecular response (MMR) (BCR-ABL1 IS ≤ 0,1% in samples with ≥10.000 transcripts) and deep molecular response (DMR) as response greater than or equal to MR4. Progression-free survival (PFS) was estimated by the method of Kaplan-Meier and defined as the time from TKI discontinuation to the date of first event (loss of DMR or death). Results: We included 56 patients (table 1). Median age at time of stopping TKI treatment was 60,3 (50,7-75,8) years and 35 (62,5%) were male. 44 patients had received 1 line of TKI treatment, 7 two lines, 2 three lines and 3 four lines. The previous TKI treatment consisted of imatinib (n=34), nilotinib (n=6), dasatinib (n=34), two lines of imatinib because of pregnancy (n=1), imatinib dasatinib (n=3), imatinib nilotinib (n=1), dasatinib imatinib (n=1), dasatinib ponatinib (n=1), imatinib dasatinib nilotinib (n=1), nilotinib dasatinib nilotinib (n=1), imatinib dasatinib imatinib dasatinib (n=1), imatinib nilotinib dasatinib dasatinib+asciminib (n=1), imatinib nilotinib dasatinib nilotinib (n=1). Duration of imatinib treatment was 121,5 (100-172,8) months, dasatinib 74,4 (29-86,1), nilotinib 34,3 (19,1-45,6), ponatinib 49 and asciminib 20,7. The reasons for switching from first to second line were intolerance (n=7, 58,3%), resistance to any TKI (n=4, 33,3%) and pregnancy (n=1, 8,3%). From second to third line was intolerance (n=5, 100%). Duration of DMR before TKI discontinuation was 87,6 (49,2-116,4) months. The last molecular responses before TKI cessation were RM5 (n=18, 32,1%), RM4.5 (n=28, 50%), RM4 (n=9, 16%) y MMR (n=1, 1,8%). Reasons for TKI discontinuation were the presence of side effects (n=28, 50%), an attempt to achieve a treatment-free remission (TFR) in patients with a DMR (n=16, 28,6%), patient preference (n=10, 17,8%) and pregnancy (n=2, 3,6%). After TKI discontinuation, 34 (60,7%) patients have maintained DMR for a median of 4,22 (2,12-7,14) years, of which six more than 8 years being the maximum follow-up of 12,6 years. 5 patients had died while DMR due to CML-unrelated causes. The probability of PFS at 1 year and 12,6 years was 65,3% (95% CI: 58,6%-71,7%) and 34,8% (95% CI: 25%-44,1%) respectively (Figure 1). 22 (39,28%) patients had strict molecular relapse with a median of 3,9 (3,2-7,8) months, of which 12 (21,4%) were loose molecular relapses. Loss of DMR occurred most frequently in the first 6 months after TKI discontinuation (n=15, 68,1%). The last CMR loss was at 95 months. 18 patients restarted treatment, 2 died due to CML-unrelated causes, 1 maintained RMM without treatment due to intolerance and 1 stopped treatment due to personal preference. At the time of restarting treatment, the BCR-ABL1 IS was ≤10% (n=3), ≤1% (n=7), ≤0,1% (n=7) and ≤0,01% (n=1). After restarting treatment, 18 (100%) patients had MMR, of whom 16 (80%) had DMR. Median time to regaining DMR after resuming TKI therapy was 3 (0,9-3,05) months. A second attempt at TFR was made in 5 patients. The median duration of TKI therapy after restarting the treatment and the second discontinuation was 60,2 (40,2-63) months. 4 patients maintained CMR with a follow-up of 11 (7,2-24,4) months, and one patient died while DMR for reasons unrelated to CML. Adverse effects improved in most patients. TKI withdrawal syndrome was noticed in 12 (21,4%) patients. Conclusion: In our study, the PFS at 12,6 years was 34,8%. Including the patients who have had a second discontinuation of TKI, 39 (69,6%) patients remain in DMR off-treatment, with a median follow-up of 49,1 (26,7-85,7) months. 6 patients had a follow-up of more than 8 years without treatment, which is still ongoing. These data confirm the applicability and safety of TKI discontinuation. 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

Observational study of chronic myeloid leukemia Chinese patients who discontinued tyrosine kinase inhibitors in the real-world

Objective: This study aimed to observe whether the treatment-free remission (TFR) of second-generation tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML) is better than imatinib (IM) . Methods: The clinical data of 274 CML patients who discontinued treatment and with complete clinical data were retrospectively studied from June 2013 to March 2021. Using both univariate and multivariate Cox proportional hazards regression models, risk factors influencing TFR outcomes after drug withdrawal in CML patients were assessed. Results: A total of 274 patients were enrolled, 140 patients were women (51.1%) , with a median age of 48 (9-84) years at the time of TKI discontinuation. Prior to TKI discontinuation, 172 (62.8%) patients were treated with IM, and 102 (37.2%) had received second-generation TKI treatment, including 73 patients who had shifted from IM to a second-generation TKI and 29 patients who used second-generation TKI as the first-line treatment. The rationale for converting to a second-generation TKI are as follows: 37 patients aimed deep molecular response (DMR) to achieve TFR, seven patients changed due to IM intolerance, and 29 patients changed because of failure to achieve the optimal treatment response. The use of the last type of TKI included 96 patients (94.1%) with nilotinib, three patients (2.9%) with dasatinib, and two patients (2%) with flumatinib, including one patient who changed to IM due to second-generation TKI intolerance. No statistical differences were found in the median age at diagnosis and TKI discontinuation, sex, Sokal score, IFN treatment before TKI, median time of TKI treatment to achieve DMR, and the reasons for TKI discontinuation between the second TKI and IM (P>0.05) .The median cumulative treatment time of TKI (71.5 months vs 88 months, P<0.001) , the last TKI median treatment time (60 months vs 88 months, P<0.001) , and the median duration of DMR (58 months vs 66 months, P=0.002) were significantly shorter in the second-generation TKI compared with IM. In the median follow-up of 22 (6-118) months after TKI discontinuation, 88 patients (32.1%) had lost their MMR at a median of 6 (1-91) months; of the 53 patients (60.2%) who lost MMR within 6 months, the overall TFR rate was 67.9%, and the cumulative TFR rates at 12 and 24 months were 70.5% and 67.5%, respectively. Withdrawal syndrome occurred in 26 patients (9.5%) . For patients who restarted TKI treatment, 72 patients (83.7%) achieved DMR again at a median treatment of 4 (1 to 18) months. The univariate analysis showed that the TFR rate of patients treated with second-generation TKI was significantly higher than those who were treated with IM (77.5% vs 62.2%, P=0.041) . A further subgroup analysis found that the TFR rate of the second-generation TKI patients was significantly higher than those treated with IM (80.8% vs 62.2%, P=0.026) . No significant difference was found in the second-generation TKI used as the first line treatment compared with those who were treated with IM (69.0% vs 62.2%, P=0.599) . The multivariate analysis results showed that second-generation TKI treatment was an independent prognostic factor affecting TFR in patients who discontinued TKI (RR=1.827, 95%CI 1.015-3.288, P=0.044) . Conclusion: In the clinical setting, more CML patients rapidly achieved TFR using second-generation TKI than IM treatment.

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

Half: A Prospective Multi-Centre Phase II Clinical Trial Evaluating the Efficacy and Safety of Tyrosine Kinase Inhibitors' Discontinuation after Two-Step Dose Reduction in Patients with Chronic Myeloid Leukemia in Deep Molecular Remission

Background.Treatment-free remission (TFR) has become a new treatment goal for chronic myeloid leukemia (CML) patients. However, usually abrupt tyrosine kinase inhibitors (TKIs) therapy discontinuation has been successful only in about half of eligible patients and it can cause burdening TKI withdrawal syndrome (TWS) in about 30% of them. Moreover, any robust clinical or biological factor predictive for successful TFR has not been identified yet. On top of that, sustainable deep molecular response (DMR) as the main prerequisite for TKI discontinuation attempt is achieved only in 20-40% of patients. The majority of CML patients, therefore, need to be treated with the effective and well-tolerated drug for a long time or even life-long.Study design and methods.With the recognition of all these aspects, we designed a nationwide prospective investigator-initiated phase II clinical trial HALF (ClinicalTrials.gov NCT04147533) in order to evaluate efficacy and safety of TKI discontinuation after previous two-step dose reduction in patients with CML in DMR (Fig. 1). Step-wise TKI dose reduction, i.e. half of the standard during the first 6 months after study entry, and the same dose given alternatively (every other day) during the next 6 months, was derived from pharmacokinetics and experimental data as well as from clinical trials' results. We assume that the step-wise and eventually meaningful TKI dose reduction enables a higher rate of patients achieving successful TFR with less pronounce TWS, or even would represent a more reasonable and safer alternative to the complete and sudden TKI interruption. This unique nationwide academic project has been facilitated by hematological patients care centralization in the Czech Republic.A primary study objective is to evaluate the proportion of patients in major molecular response (MMR) at 6 and 12 months and in TFR at 18, 24, and 36 months after the study enrollment, respectively, and molecular recurrence-free survival at all mentioned time points as well. Main secondary and exploratory objectives are: to evaluate the proportion of patients loosing MMR and in whom MMR and MR4.0 would be re-achieved after TKI re-introduction, time to MMR and MR4.0 re-achievement, FFS, PFS, OS, TWS, and QoL assessment, predictive factors for successful TFR identification, quantification of BCR-ABL1 using digital droplet PCR at both the DNA and mRNA levels, immunological profiling, BCR-ABL1 kinetics mathematical modeling, assessment of TKI pharmacokinetics, clonal hematopoiesis and pharmaco-economics.Results.The study was launched in December 2019; however, due to the COVID-19 outbreak, patients' recruitment started on June 16, 2020. Here, characteristics of the first 74 patients included in the study until April 2021 are presented. There were 37 males and 37 females, with median age at the time of diagnosis of 53 years (range, 23-74) and at the time of the study entry of 67 years (range, 35-86). A median time of CML disease, TKI treatment, and DMR duration before the study initiation was as follows: 9.9 years (range, 4.4-22.5), 9.8 years (range, 4.2-20.2), and 7.3 years (range, 3.2-18.3), respectively. The ELTS score was low, intermediate, high and unknown in 62.2%, 21.6%, 13.5%, and 2.7% of patients, respectively. At the time of study entry, 58 patients (79.5%) were treated with imatinib, 10 (13.7%) with nilotinib, and 5 (6.8%) with dasatinib, respectively, whereas in 63 patients (86.3%) it was in the first line of therapy. With almost half of patients (48.6%), the TKI dose was already reduced at the time of study entry. With 10 (13.5%) patients, interferon-α treatment preceded TKI administration. At the time of this abstract preparation, on July 26, 2021, altogether 102 patients (from planned 150) have been enrolled in the study; 48 of them (47.1%) have already moved to the second de-escalation phase and 9 (8.8%) patients to the TFR phase. There were 2 cases of confirmed MMR loss (both in month 8 after the study entry) and no patient experienced symptoms resembling TWS.Conclusions.Despite the COVID-19 pandemic, the HALF study was successfully launched and initiated in the majority of centers, with 102 already included patients and continuing intensive enrolment. Based on our very preliminary results, the step-wise dose reduction seems to be an effective and safe approach. More included patients, longer follow-up and further analyses are needed in order to reach all set up objectives. [Display omitted] DisclosuresŽácková: Angelini: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Faber: Angelini: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Pfizer: Other: conference fees; TERUMO: Other: conference fees. Bělohlávková: Novartis: Consultancy; BMS/Celgene: Consultancy. Horňák: Angelini: Honoraria. Svobodník: Roche: Speakers Bureau; Janssen-Cilag: Speakers Bureau. Machová Poláková: Incyte: Consultancy; Angelini: Consultancy; Novartis: Research Funding. Mayer: Principia: Research Funding.

P50-3 Treatment-free remission in e19a2 BCR-ABL1 chronic myeloid leukemia

Chronic myeloid leukemia (CML) has become a chronic disease, for which the chronic phase is manageable with tyrosine kinase inhibitor (TKI) therapy. Several TKI discontinuation studies in patients with durable deep molecular response demonstrate that stopping TKI therapy is feasible, and this situation is called treatment-free remission (TFR). In present, The NCCN guidelines and the ESMO guidelines provide guidelines for TKI discontinuation. In these guidelines, quantifiable BCR-ABL1 transcript and monitoring using international scale (IS) are involved in the criteria of TKI discontinuation. Because IS can quantify only e13a2 or e14a2 transcripts, other transcript variants does not match the TFR criteria. Here we describe an e19a2-positive CML patient who maintain TFR. A 77-year old woman was diagnosed e19a2-positive CML, and achieved deep molecular response by nilotinib. Since 66 months of nilotinib treatment, e19a2 transcript has been undetected. Since 84 months of nilotinib treatment, she has refused subsequent medication for CML and therefore careful monitoring by QT-PCR has been done. By 40 months since nilotinib discontinuation, she has been well without any sign of withdrawal syndrome and e19a2 transcript has been undetected. In literature search, there is no report of the e19a2-positive CML who obtained TFR. As in the case we presented here, TFR may be achievable in patients with transcript variants other than e13a2 or e14a2. The problem to be solved is the standardization of transcript quantification. Both the ELN guidelines and the NCCN guidelines are created on the premise that they are monitored by the IS method which can only use for e13a2 or e14a2 transcript, meaning there is no treatment guidelines for other variants. Establishing standardized quantification of variant transcripts based on global clinical trials may contribute to prepare the treatment guideline including TFR as similar to e13a2 or e14a2 transcript.

“Duration of Deep Molecular Response” Has Most Impact on the Success of Cessation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia - Results from the EURO-SKI Trial

“Duration of Deep Molecular Response” Has Most Impact on the Success of Cessation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia - Results from the EURO-SKI Trial

Observational Study of CML Italian Patients Who Discontinued TKIs

Abstract Background: Different studies analysed the outcome of patients (pts) who discontinued tyrosine kinase inhibitors (TKIs) reporting a median treatment-free remission (TFR) rate of 55%. On these bases it is judged safe to discontinue treatment in experimental contexts. Aims: Aim of our study was to evaluate TFR in the setting of Italian pts . Material and Methods: We designed a retrospective observational study of Italian pts with chronic phase CML who discontinued TKI treatment in deep molecular response (DMR). All Hematological Centers who are part of the GIMEMA group were invited to participate to this retrospective study and 32 centers had cases and participated to the study. Results: We collected a total of 293 pts. Median age was 59 years; 59%, 30% and 11% of pts were low, intermediate and high Sokal score respectively. 72% of pts were on treatment with imatinib, 28.% with either nilotinib (n=58), dasatinib (n=23) or bosutinib (n=1) at the time of discontinuation. 55% of pts discontinued in first line, 40% in second line, 5% in third line. Median duration of treatment with the last TKI was 77 months (mos, IQR 54;111) median time to deep molecular response (DMR, i.e. undetectable transcript or MR4/MR4.5/MR5) with the last TKI was 46 mos (IQR 30;73), median duration of DMR was 46 mos (IQR 31;74) before stop. Duration of treatment with TKIs and duration of DMR were shorter with 2nd gen TKIs than with imatinib (p Conclusion: Although our study has the limitation of a retrospective study, our experience within the Italian population confirms that discontinuation of imatinib and 2nd gen TKIs is feasible and safe in the clinical practice. Disclosures Fava: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rege-Carmbrin: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Rosti: Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Castagnetti: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gugliotta: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gambacorti-Passerini: Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Abruzzese: Bristol Myers Squibb: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy. Orlandi: Incyte: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Pregno: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Crugnola: Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria. Bocchia: Celgene: Other: Travel grant; Novartis: Other: Travel grant; Roche: Other: Travel grant; Jansen: Other: Travel grant. Galimberti: Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau. Iurlo: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia: TEVA: Speakers Bureau. Cavazzini: Novartis: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Bristol-Meyers Squibb: Consultancy. Giai: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Musto: BMS: Honoraria; Celgene: Honoraria; Novartis: Honoraria; janssen: Honoraria. Specchia: BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Pane: Novartis: Honoraria, Speakers Bureau. Baccarani: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Saglio: Roche: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; BMS: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

Long-Term Outcome in Children and Adolescents with Chronic Myeloid Leukemia in Chronic Phase Treated with High-Dose Imatinib— the Italian Experience

The availability of imatinib (IM) and thereafter of second-generation tyrosine kinase inhibitors (TKI2) has extended therapeutic options for childhood chronic myeloid leukemia (CML) with a favorable influence on disease outcome and overall prognosis. The aim of this report was to evaluate the response to therapy and long-term outcome of children and adolescents with CML in chronic phase (CP) treated with high-dose imatinib (IM). CP-CML patients (pts) aged Between March 2001 and June 2015, 58 pts with a diagnosis of CP-CML (males/females 1.6; median age 114/12 years) were treated with IM at dose of 340 mg/m2/day in 14 Italian pediatric centers. Sixteen (27.5%) had an HLA-matched sibling. Thirty-eight pts (65.5%) received IM for a period >24 months. After 3 months of IM treatment, 83% and 56% of ptsshowed BCR-ABL1 IS ≤10% and ≤1%, respectively. BCR-ABL1 transcript levels ≤0.1% were found in 61% and 69% of pts at 12 and 18 months. At 24 months, 66% and 54% of pts showed BCR-ABL1 levels ≤0.1% and ≤0.01%, respectively. Overall, 91%, 85%, 56% and 39% of pts achieved CCyR, MR3, MR4, MR4.5 and MR5 after a median time of 6.1, 12.5, 16.4 and 19 months, respectively. BCR-ABL1 IS ≤10% and ≤1% after 3 months of treatment did not impact on the overall CCyR, MR3, MR4-MR4.5 and MR5. Treatment with IM was stopped in 29/58 pts (50%) after a median time of 16.7 months (range: 1.4-157) because of failure (58.5%), toxicity or intolerance (14%) and allogeneic hematopoietic stem cell transplant (HSCT) (27.5%). Eighteen pts (62%) received one or more TKI2, 3 pts (10%) α-interferon (IFN), 1 pt conventional chemotherapy (3.5%) and 16 pts (55%) underwent a HSCT (Table 1). Transplants were performed after a median of 12 months: 10 from an identical sibling, 5 from a matched unrelated donor and 1 from an umbilical cord blood. Three early transplanted pts had disease recurrence after 24, 36 and 83 months, respectively; they were rescued with IM ± conventional chemotherapy ± 2nd HSCT (2 pts) or dasatinib (1 pt). Among 29 pts who continued IM, 15 (52%) (1 in MR3, 6 in MR4-MR4.5 and 8 in MR5) started intermittent treatment (IM for 3 weeks a month); thereafter, 5 pts resumed continuous IM and 1 patient shifted to dasatinib because of response loss; 3 adolescents with long-lasting BCR-ABL1 IS In conclusion, this larger cohort of pts with a longer follow-up confirmed our previous results on the high response rates in children and adolescents treated with high-dose IM and the prognostic impact of the transcript levels after 3 months of treatment on the disease outcome. Unfortunately, failures occurred late during treatment with IM. Over time, the efficacy of IM and the availability of TKI2 also in childhood CML has limited the use of HSCT leading to avoid transplants even in children with an identical sibling. Both transplant and TKI did not prevent pregnancies. Although the stop of treatment is not recommended outside of clinical trials, IM or TKI2 can be safely discontinued in some children and adolescents with a durable deep molecular response. Disclosures Saglio: Ariad: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Foa: Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau.

An e13a2 Type of BCR-ABL Transcript Has a Significant Adverse Impact on the Achievement of a Sustained Deep Molecular Response and on the Maintenance of a Treatment Free Remission after Stopping Tyrosine Kinase Inhibitors

An e13a2 Type of BCR-ABL Transcript Has a Significant Adverse Impact on the Achievement of a Sustained Deep Molecular Response and on the Maintenance of a Treatment Free Remission after Stopping Tyrosine Kinase Inhibitors

Combination Therapies in Chronic Myeloid Leukemia for Potential Treatment-Free Remission: Focus on Leukemia Stem Cells and Immune Modulation.

Although tyrosine Kinase Inhibitors (TKI) has revolutionized the treatment of chronic myeloid leukemia (CML), patients are not cured with the current therapy modalities. Also, the more recent goal of CML treatment is to induce successful treatment-free remission (TFR) among patients achieving durable deep molecular response (DMR). Together, it is necessary to develop novel, curative treatment strategies. With advancements in understanding the biology of CML, such as dormant Leukemic Stem Cells (LSCs) and impaired immune modulation, a number of agents are now under investigation. This review updates such agents that target LSCs, and together with TKIs, have the potential to eradicate CML. Moreover, we describe the developing immunotherapy for controlling CML.