Kinetics of the Leukemic Clone in Patients with Chronic Myeloid Leukemia during Pregnancy

Abstract Background Observation without treatment in chronic myeloid leukemia (CML) is suggested only for patients (pts) with a durable and stable deep molecular response (DMR). However, CML women with various grade of molecular response usually stop tyrosine kinase inhibitors (TKIs) for conception/pregnancy and/or breastfeeding. The kinetics of the leukemic clone during these long interruptions needs to be understood in order to provide the optimal recommendations for the pts. Aim To analyze the loss and recovery of molecular response in CML pts with initial major molecular response (MMR) and deep molecular response (DMR) who had TKI interruptions during pregnancy. Patients and methods Pregnancy cases of women with BCR-ABL p210 transcript CML chronic phase and at least MMR before TKI interruption were included; cases with insufficient follow-up and previous bone marrow transplantation were excluded. Only cases with "ongoing pregnancy" or at term for pregnancy were evaluated as they had a valid off-treatment period. Data were obtained from observational studies of CML and pregnancy, like the CML pregnancy registries of Russian hematology society, and other institutional databases. Pregnancy cases were divided into 3 groups according to the molecular response before TKI interruption: 1) with DMR and "stop" criteria; 2) with DMR and no "stop" criteria; 3) with MMR only. DMR, MMR and molecular response 2 (MR2) were considered as BCR-ABL≤0,01%; BCR-ABL>0,01% and ≤0,1%; BCR-ABL>0,1% and ≤1% accordingly by international scale (IS). "Stop" criteria were considered as the main inclusion criteria of EURO-SKI multicenter "stop" trial: 1) treatment by TKIs for ≥3 years,2) stable DMR for ≥1 year before TKI cessation. Probability of MMR loss and recovery were evaluated by Cumulative incidence function (CIF) using Gray test for comparison. TKI restart without MMR loss and death were considered as competitors. The proportion of pts with MR2 loss during TKI interruption was additionally assessed. Results In total 227 pregnancies from 172 CML pts were evaluated and 87 cases were eligible for the analysis. Distribution by groups was as follows: 39, 26 and 22 cases in group 1, 2 and 3 accordingly. Median (Me) time without TKI therapy was 8 months (mo)(range 1-54) (table 1). In 72 (83%) cases TKIs were restarted after MMR loss (n=58) and without MMR loss (n=14). TKIs were restarted after and during pregnancy in 54 and 18 cases correspondingly. Imatinib and nilotinib were used at late pregnancy (2nd-3rd trimester) in 15 and 3 cases; no birth defects were observed. Seven pts got IFN during TKI interruption. TKIs were not restarted in 15 (17%) cases: 14 pts with DMR remained off-treatment after labour for a median of 29 mo (range 3-54) and in 1 pt with MMR loss pregnancy is ongoing. Cumulative incidence (CI) of MMR loss at 6 and 12 mo after TKI cessation was 57% and 66%, and CI of MMR recovery at 6 and 12 mo after TKI restart was 50% and 75% in the whole cohort. CI of MMR loss at 6 and 12 mo was 35%, 65%, 86% and 46%, 76%, 86% in group 1,2 and 3 accordingly. CI of MMR recovery at 6 and 12 mo was 75%, 55%, 23% and 100%, 73% and 55% in group 1,2 and 3, respectively. CI of MMR recovery in group 2 and 3 at 24 mo after TKI restart was 86% and 78%. Significant differences (p<0,05%) were found between all groups for MMR loss and MMR recovery except the MMR recovery rates between groups 2 and 3 (figure 1). In 45 (52%) cases MR2 was lost simultaneously with MMR loss or after it (table 1). In 4 (5%) cases a complete hematologic response (CHR) was lost after MR2 loss; however, a MMR was regained in 2 of 4 pts. Two more pts with MR2 and CHR loss died later from progression of CML: 6 mo and approximately 8 years after labour. Both of them were non-compliant to therapy and stopped treatment again by self-made decisions with no control follow-up. Conclusions CML pts with DMR and "stop" criteria have the best chance to keep MMR during pregnancy after TKI cessation and may remain without treatment after labour. MMR is lost in the majority of pts with MMR/DMR and no "stop" criteria. However, the loss of response is reversible and MMR can be recovered within 1-2 years after TKI resuming in spite of even MR2 loss. Our data confirm the option for planning pregnancy not only in CML pts with stable DMR but also in pts who have a MMR only or non-stable DMR followed up by a careful molecular monitoring during and after pregnancy. The use of TKI during at late pregnancy will be discussed. Disclosures Chelysheva: Novartis: Other: provided consultations and performed lectures; Bristol Myers Squibb: Other: provided consultations and performed lectures; Fusion Pharma: Other: provided consultations . Apperley:Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Abruzzese:Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy; Ariad: Consultancy. Kim:Pfizer: Research Funding; Novartis: Research Funding; Ilyang: Research Funding; BMS: Research Funding. Shukhov:Bristol Myers Squibb: Other: provided consultations and performed lectures ; Novartis: Other: provided consultations and performed lectures . Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations.

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Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽

10.1182/blood.v114.22.1128.1128 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1128-1128 ◽

Cited By ~ 2

Author(s):

Hanna Jean Khoury ◽

Michael J. Mauro ◽

Yousif Matloub ◽

Tai-Tsang Chen ◽

Erkut Bahceci ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Phase Iii ◽

Hematologic Toxicity ◽

Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

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Specific Drug Transporter Genotypes Are Significantly Associated with Increased Rates of Major and Complete Molecular Responses In Newly Diagnosed Chronic Myeloid Leukemia Patients Treated with Imatinib – A TOPS Correlative Substudy

Blood ◽

10.1182/blood.v116.21.670.670 ◽

2010 ◽

Vol 116 (21) ◽

pp. 670-670

Author(s):

Simona Soverini ◽

Sabrina Angelini ◽

Eleonora Turrini ◽

Matt Burnett ◽

Gloria Ravegnini ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Cumulative Incidence ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase Iii ◽

Molecular Response ◽

Newly Diagnosed ◽

First Line ◽

Favorable Alleles ◽

Summary Measures

Abstract Abstract 670 The availability of multiple options for chronic myeloid leukemia (CML) treatment is not paralleled by the availability of biological predictors of outcome allowing to identify patients (pts) who are more likely to benefit from dasatinib or nilotinib rather than imatinib (IM). Pharmacogenetics has proven a potential source of biomarkers given the known influence of polymorphisms in key genes encoding drug transporters and metabolizing enzymes on drug delivery – hence effectiveness. In CML, only two studies had so far explored this field, but both were conducted in heterogeneous populations including pts at different stages of disease, not all receiving IM first-line. We thus aimed to investigate a panel of 20 single nucleotide polymorphisms (SNPs) in ABCB1, ABCG2, SLC22A1, OATP1A2, OCTN1, CYP3A4 and CYP3A5 genes that can be hypothesized to influence IM transport and metabolism in 189 newly diagnosed CML pts enrolled in the TOPS phase III trial (Cortes et al, J Clin Oncol 2010). Pts selection was exclusively based on availability of written informed consent and sufficient amount of archived material. Median age was 46 years; male to female ratio was 103 to 86; 156 (83%) pts were Caucasian and 23 (12%) were Asian; low, intermediate and high Sokal risk pts were 84 (44.4%), 65 (34.4%) and 40 (21.2%), respectively. Baseline demographic/clinical features did not differ significantly from those of the overall population. Treatment outcomes (complete cytogenetic response [CCyR]; major molecular response [MMR] and complete molecular response [CMR]) were compared according to i) each candidate genotype ii) summary measures based on combinations of SNPs in the same gene and iii) summary measures based on combinations of SNPs in functionally related genes (uptake; efflux). CC genotype in OCTN1 had a favorable impact on the achievement of MMR at 12 months (MMR@12m; P = 0.03). With respect to the summary measures, combination of SNPs in the SLC22A1 gene was significantly correlated with MMR@12m (P = 0.03). When considering summary measures of uptake and efflux, the former was found to be associated with both MMR@12m and CMR@12m (P = 0.003 and P = 0.01, respectively). A separate analysis limited to Caucasian pts (n=156) yielded similar results (Table 1). In addition, the analysis in the Caucasian subgroup evidenced a significant association between the CC genotype in ABCB1 rs60023214 and MMR@12m (P = 0.005) (Table 1). Cumulative incidence plots based on the Kaplan-Meier method were also analyzed in the overall population and in Caucasians, with comparable results. Representative plots are shown in Figure 1. There was evidence for difference among MMR cumulative incidence curves for 2 single SNPs and 2 score measures. Presence of the major allele in OCTN1 (CC) and of the minor allele in CYP3A4 rs2740574 (GG) were associated with increased MMR rate (P = 0.028 and P = 0.042, respectively, in the overall population and P = 0.027 and P = 0.038, respectively, in Caucasians). Similarly, an increase in the number of favorable alleles in the SLC22A1 gene was associated with increased MMR rate (P = 0.030 and P = 0.043 in the overall population and in Caucasians, respectively). In addition, the combination of favorable alleles in the genes involved in IM uptake was associated with increased rates of both MMR and CMR (P = 0.004 and P = 0.015, respectively, in the overall population and P = 0.005 and P = 0.009, respectively, in Caucasians). Our results suggest that SNP genotyping might be helpful in selecting pts who are more likely to benefit from first-line use of more potent inhibitors. Further assessment of the SNPs here identified in larger series of pts is warranted. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Ariad: Honoraria. White:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Rosti:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Hatfield:Novartis: Employment. Martinelli:Novartis: Consultancy, Honoraria; BMS: Honoraria; Pfizer: Consultancy.

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Chronic Myeloid Leukemia Diagnosed during Pregnancy: Therapy, Outcomes and Follow-up

Blood ◽

10.1182/blood-2018-99-115983 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4255-4255 ◽

Cited By ~ 1

Author(s):

Ekaterina Chelysheva ◽

Elisabetta Abruzzese ◽

Delphine Rea ◽

Dong-Wook Kim ◽

Khamida Kazakbaeva ◽

...

Keyword(s):

Pregnancy Outcomes ◽

Myeloid Leukemia ◽

Research Funding ◽

Basic Research ◽

Late Pregnancy ◽

Molecular Response ◽

Advisory Committees ◽

Basic Research Grant ◽

Research Grant

Abstract Background Chronic myeloid leukemia (CML) diagnosed during pregnancy is a rare situation with no standard treatment schemes. If a pregnancy is prolonged weighting the risks/benefits of therapy or observation without therapy is a complicated task. If a pregnancy is terminated a possibility of a further childbirth has to be judged. The course of the disease, treatment options and possible outcomes need to be known in these patients (pts) in the era of tyrosine kinase inhibitors (TKIs). Aim To describe pregnancy outcomes, therapy and follow-up in women with CML diagnosed during pregnancy in the era of TKIs Methods We made a search in the databases of pregnancy cases in CML pts after 2003 year, since the first TKI imatinib became available. The data were obtained from observational studies: CML pregnancy registries of Russian hematology society and ELN. Clinical and demographic characteristics of pts, therapy, monitoring, pregnancy outcomes and follow-up were analyzed. Results. We found that 48 of 199 women with CML and pregnancy were diagnosed as having CML during pregnancy in years 2006-2018. Median (Me) age at CML diagnosis was 26 years (range 19-39). All pts had a chronic phase of CML. Sokal score was low in 34(71%), intermediate in 9(19%) high in 4(8%) and not known in 1(2%) pt. CML was diagnosed during 1st, 2ndand 3rd trimester of pregnancy in 26(54%), 11(23%) and 11(23%) females, respectively. Elective abortion was done in 14 (29%) pts, 1(2%) pt had a miscarriage. All 15 pts started TKI therapy shortly after delivery. Me observation time after labour was 52 months (range 4-139). Imatinib (IM) and nilotinib (NIL) were used as 1st line therapy in 14 and 1 pt accordingly. Five pts were switched from IM to a second line TKI due to resistance in 3 pts and to physician choice in 2 pts. Deep molecular response (DMR or BCR-ABL≤0,01% IS) and major molecular response (MMR or BCR-ABL≤0,1% IS) was achieved in 6 and 5 pts. No molecular response 2 (MR2 or BCR-ABL≤1%) was reported in 4 pts with the follow-up of 24-184 months. One pt died due to CML progression in BC (resistant to IM, T315I mutation, relapsed after allogenic bone marrow transplant (BMT), pre ponatinib availability). Pregnancy was carried out in 33(71%) pts: in 11 of 26 pts with CML diagnosed at 1st trimester and in all 22 pts diagnosed at 2nd-3rd trimester. Pregnancy ended in labour in 32 pts while in 1 pt pregnancy was ongoing pregnancy (week 26th) at the time of evaluation. No therapy for whole pregnancy was in 14 pts: 1, 5 and 8 of them were diagnosed in 1st, 2nd and 3rd trimester accordingly. Therapy during pregnancy was started in 19 pts: 10, 6 and 3 pts with CML diagnosed in 1st, 2nd and 3rd trimester accordingly. Five pts got interferon (IFN) in 1st trimester and 3 of 5 were switched to IM in 2nd-3rd trimester. Four pts got hydroxyurea (HU) for 5-7 days in 1st-2nd trimester prior to any other therapy. Fourteen pts with no therapy in 1st trimester started therapy at late pregnancy: IM since 2nd-3rd trimester in 10 pts, HU in 3rd trimester in 1 pt. A total of 13 pts got IM with Me time of IM start at 18 weeks (range 16-35). Me time of observation after delivery was 52 months (range 4-139). Me time of delay in TKI administration after diagnosis was 7 weeks (range 1-51) and in total 12(36%) of 33 pts got IFN or HU before TKI. TKIs used as 1st line were as follows: IM, dasatinib and NIL in 30, 1 and 1 pts accordingly. Nine pts were further switched from IM to TKI2 as 2nd line due to resistance/suboptimal response. DMR and MMR was achieved in 11 and 17 pts accordingly, MR2 in 5 pts, no MR2 in 1 pt with short follow-up (4 months), 4 pts were too early to evaluate. Two pts were resistant to 2 lines of TKIs and died from disease progression; one of them had a BMT failure and 1 pt was non-compliant. Thirty three children were born (one twins): 17 boys and 16 girls, no births defects were observed. Seven newborns had a low birth weight (<2500g): 6 of them were exposed to IM at late pregnancy and 3 were born preterm at week 35-37. Follow-up of the children was uneventful. Eleven pts later had 13 pregnancies which ended in childbirth within Me 5 years (1-9 years) Conclusion CML may be diagnosed at any pregnancy stage and pregnancy termination/prolongation should be judged individually. A normal childbirth may take place including cases with use of IM at late pregnancy. It is reasonable to adjust therapy options to pregnancy trimester and to avoid potential teratogenic drugs at 1st trimester. A careful follow-up and timely monitoring of these cases is needed. Disclosures Chelysheva: Fusion Pharma: Other: provided consultations ; Bristol Myers Squibb: Other: provided consultations and performed lectures; Novartis: Other: provided consultations and performed lectures. Abruzzese:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Kim:BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Ilyang: Research Funding. Chabaeva:Russian Foundation for Basic Research grant 18-015-00399 A: Research Funding. Kulikov:Russian Foundation for Basic Research grant 18-015-00399 A: Research Funding. Turkina:Novartis: Other: provided consultations; Bristol Myers Squibb: Other: provided consultations; Phizer: Other: provided consultations; Fusion Pharma: Other: provided consultations.

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Comparative Effectiveness of Generic Imatinib and Brand-Name Imatinib for the Treatment of Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.2778.2778 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2778-2778 ◽

Cited By ~ 3

Author(s):

Adi J Klil-Drori ◽

Laurent Azoulay ◽

Hui Yin ◽

Michel-Olivier Gratton ◽

Michaël Harnois ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Cumulative Incidence ◽

Myeloid Leukemia ◽

Case Series ◽

The Self ◽

Molecular Response ◽

Brand Name ◽

Major Molecular Response ◽

First Line

Abstract Background: Generic versions of imatinib (GEN) have been approved for use in Canada for chronic myeloid leukemia, chronic phase (CML-CP) on the basis of bioequivalence studies and were reimbursed in Québec starting from October 2013. Molecular responses with GEN have not yet been examined in detail. This study assesses the risk of diminished molecular response in switchers from brand-name imatinib (BN) to GEN and compares the effectiveness of initiating first-line GEN and first-line BN. Methods: Prospective individual patient data were available from nine hospitals participating in the Québec CML registry. To allow equipoise between GEN and BN, we focused on stable BN users at the time of GEN market entry, of which some were subsequently switched to GEN. We further selected only those who had a 1-log rise in international reporting scale (IS) BCR-ABL1 transcript level and conducted a self-controlled case series study (SCSS).1 Using SCSS, each patient contributed follow-up for BN use, and for GEN use (if a switch occurred). The analysis used pooled BN and GEN person-time and compared the odds ratio (OR) of 1-log rise during GEN and BN treatment using conditional Poisson regression. A second analysis used a cohort of initiators of BN and GEN from 2013 and onwards. Kaplan Meier (KM) analyses were used to estimate the cumulative incidence of early molecular response (EMR) corresponding to < 10% IS. Cox proportional hazards models were used to estimate age-adjusted hazard ratio (HR) with 95% confidence intervals (CI) for EMR with GEN use, when compared with BN use. Results: We identified 184 patients treated with BN, 38 who were switched from BN to GEN, and 5 who used GEN only. For the SCSS analysis we included 23 patients, of which 17 had 1-log rise during BN use and 6 during GEN use. All patients had achieved major molecular response (MMR) prior to cohort entry (Table). Mean follow-up was 1.45±0.43 years. Overall, the use of GEN was associated with an increased incidence of 1- log rise (OR: 3.34, 95% CI: 0.33-33.68), although not reaching statistical significance. Ten of 23 rises in BCR-ABL1 levels were subsequently confirmed (7 in BN and 3 in GEN). Eleven patients lost MMR (IS>0.1%), 9 during BN use and 2 during GEN use. The cohort of first-line imatinib included 11 patients, 4 GEN and 7 BN. GEN users were slightly older (61 vs 53, GEN vs BN), and Sokal scores were comparable (low, 2 vs 4; intermediate, 2 vs 3). There was no clear separation of the EMR curves (Figure). However, the adjusted HR of EMR with GEN was 0.38 (95% CI: 0.07-2.15), compared with BN. Conclusions: While these analyses are preliminary, our results call for an initiative on a larger scale to examine the clinical effectiveness of generic imatinib for CML-CP. 1. Whitaker HJ, Farrington CP, Spiessens B, Musonda P. Tutorial in biostatistics: the self-controlled case series method. Stat Med. 2006;25(10):1768-1797. Table 1. Baseline characteristics of the self-controlled case series cohort (n=23) Characteristic Value Mean age, years (SD) 62.87 (15.4) Female sex (n, %) 9 (39.1) Mean number of concomitant medications (SD) 1.07 (2.2) Mean years of brand-name imatinib use (SD) 6.85 (2.8) Number major molecular response (%) 23 (100.0) Figure 1. Cumulative incidence of EMR (<10% IS) following the initiation of generic or brand-name imatinib. Figure 1. Cumulative incidence of EMR (<10% IS) following the initiation of generic or brand-name imatinib. Disclosures Chamakhi: Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Delage:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Laneuville:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Mollica:Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Olney:Cellgene: Honoraria; Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy. Busque:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Assouline:Pfizer: Consultancy; BMS: Consultancy; Novartis: Consultancy.

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Second-Generation Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response: A Systematic Review and a Meta-Analysis

Computational and Mathematical Methods in Medicine ◽

10.1155/2021/3110622 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Qiongnan Di ◽

Huiyang Deng ◽

Yingxin Zhao ◽

Bo-ya Li ◽

Ling Qin

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

Meta Analysis ◽

Chronic Phase ◽

Molecular Response ◽

Weighted Mean ◽

Deep Molecular Response ◽

Tki Discontinuation

The treatment with 2nd-generation tyrosine kinase inhibitors (2G-TKIs), namely, dasatinib and nilotinib, has been reported to have faster and deeper responses in newly diagnosed chronic phase-chronic myeloid leukemia (CP-CML) patients as compared with imatinab. A number of studies on the discontinuation of 2G-TKIs have been conducted and recently published. A meta-analysis was conducted in this study to assess the rate of treatment-free remission (TFR) rate as well as the long-term safety of 2G-TKI discontinuation in CML patients with stable deep molecular response (DMR). 517 patients were recruited in 5 single-armed, prospective cohort studies. The overall weighted mean TFR rate at the follow-up of 12 months reached 57% (95% CI 51-64%; I 2 = 56.4 %). The weighted mean TFR rate at the 24-month follow-up was 53% (95% CI 47-60%; I 2 = 47.1 %). The loss of TFR was primarily concentrated in the first 12 months. 96.5% of patients, having restarted TKI therapy after a molecular relapse, achieved major molecular response (MMR) rapidly. There were four deaths at the two-year follow-up. As suggested from the results of the final study, 2G-TKI discontinuation in CML patients with stable DMR was reported to be feasible. Relapsed patients were retreated with 2G-TKI, and over 95% of patients could reach MMR. Almost no deaths occurred due to adverse events in two years after discontinuation, and more than half of the patients could maintain a TFR.

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Duration of Major Molecular Response and Discontinuation in Deep Molecular Response (MR4.5) Were Associated with Longer Treatment-Free Survival after Imatinib Discontinuation - Results from Two Prospective Brazilian Trials

Blood ◽

10.1182/blood-2019-125368 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1655-1655

Author(s):

Katia B Pagnano ◽

Fernanda S Seguro ◽

Eliana C Miranda ◽

Ana Beatriz Pascoal Lopes ◽

Andre Abdo ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Cox Regression ◽

Chronic Phase ◽

Molecular Response ◽

Free Survival ◽

Deep Molecular Response ◽

Treatment Free Remission

Several trials have demonstrated the feasibility of discontinuation of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients (pts) with deep molecular response. Aims: to report the results of two Brazilian imatinib (IM) discontinuation trials and to evaluate factors impacting in treatment-free remission (TFR) and treatment-free survival (TFS) after IM discontinuation. Methods:Between September 2016 and January 2019, 60 CML pts were included in two ongoing phase II, single arm, prospective Brazilian discontinuation trials: Pilot Study of Discontinuation in Patients With Chronic Myeloid Leukemia With Deep Molecular Response - Evaluation of Pioglitazone in Treatment-free Remission (TFR) (EDI-PIO UNICAMP)(NCT02852486)and Imatinib Discontinuation in Patients With Chronic Myeloid Leukemia Chronic Phase With Sustained MR4log(USP) (NCT03239886). Inclusion criteria: age >18 years, chronic phase, minimum of 3 years of IM therapy, deep molecular response for ≥ 2 years (confirmed by 4 tests in the last 2 years, defined as MR4.0 in USP trial and MR4.5 in EDI-PIO). Patients participating in EDI-PIO trial used pioglitazone 30 mg/day plus IM for 3 months before IM discontinuation (n=30). After discontinuation, pts were monitored by quantitative RQ-PCR monthly in the first year, every 2 months in the second year and every 3 months in the third year. Criteria for IM re-initiation: loss of MMR (in one test), loss of cytogenetic response, loss of hematologic response, disease progression or confirmed loss of MR4.0 (this criteria used only in EDI-PIO trial). TFR was calculated from the date of discontinuation until first event (loss of MMR; IM reintroduction; death any cause or last follow-up); TFS was calculated from the date of IM discontinuation until reintroduction or last follow-up (censoring deaths not related to CML). Adverse events after IM discontinuation were reported according to CTCAE. Results:Data cut-off for analysis was February 2019. In the 1stanalysis 48 pts who discontinued IM in MR4.5 were analyzed. Patient's characteristics from EDIPIO (n=30) and USP (n=18) trials were: 57% vs. 67% male, median age of 55 (29-77) and 56 (33-95) years (29-95) at discontinuation; 16% and 33% had used previously Interferon; median duration of IM treatment of 10 (3-16) vs. 10 (5-15) years; median duration of MMR 95 (30-149) vs. 93 (57-130) months; MR4.0 was 90 (26-135) vs. 89 (30-123) months; and MR4.5 was 76 (23-135) vs. 75 (30-102) months; none variable had statistical difference.One patient died in MMR due to cardiac failure. TFR was 61% (95% CI 47-75) at 20 months. Sixteen (33%) out 48 re-initiated IM (2 with confirmed loss of MR4.0 and 14 with loss of MMR) in a median time of 20 (1-26) months. All relapsed pts recovered MMR after IM reintroduction, in a median time of 2 months (0-4). There was no transformation to advanced phases. No serious adverse events were reported during pioglitazone treatment. In the Cox regression the duration of MMR was associated with a longer TFR HR: 0.96 (beta-) (CI 95%:0.94-0.99, P= 0.006). Gender, age at diagnosis, age at discontinuation, treatment with pioglitazone, Sokal and EUTOS scores, BCR-ABL transcripts type, duration of IM therapy, duration of MR4.0 and MR4.5 and previous use of Interferon did not affect TFR.In the second analysis all 60 pts were included. TFS was 56% and was higher in pts who discontinued IM in sustained MR4.5 vs. MR4.0 (63% vs. 33%, P=0.04)(Figure). The independent factors for TFR in the multivariate analysis by Cox-regression were the duration of MMR [HR: 0.97 (beta-), 95%CI: 0.95-0.98, P=0.001] and intermediate/high risk Sokal [HR 3.14 95%CI: 1.08-9.11, P= 0.035]. Twenty-four out of 60 pts (40%) re-initiated IM (2 with confirmed loss of MR4.0 and 22 with loss of MMR).Adverse events occurred in 38 (63%) pts, 30% attributed to withdrawal syndrome. Some pts presented more than one event. Grade 1-2: arthralgia or muscular pain (17), hyperglycemia (4), hypertriglyceridemia (2), polycythemia (2), hypertension (3), and others (11). Four pts had grade 3-4 event: arthralgia (1), death for cardiac failure (1), abortion and hypertriglyceridemia (1). Conclusions:both trials demonstrated the feasibility and safety of IM discontinuation in pts in sustained deep molecular response. The duration of MMR was associated with a higher TFR and TFS rate. Imatinib discontinuation was more successful in pts in stable MR4.5. Figure Disclosures Pagnano: Pint Pharma: Consultancy; Abbvie: Consultancy; Sandoz: Consultancy. Delamain:Novartis: Honoraria.

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Randomized, Open-Label, Multicenter, Phase 2 Study of Asciminib (ABL001) As an Add-on to Imatinib Versus Continued Imatinib Versus Switch to Nilotinib in Patients with Chronic Myeloid Leukemia in Chronic Phase Who Have Not Achieved a Deep Molecular Response with Frontline Imatinib

Blood ◽

10.1182/blood-2019-124702 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5910-5910

Author(s):

Giuseppe Saglio ◽

Timothy P. Hughes ◽

Jan Geissler ◽

Shruti Kapoor ◽

Anne-Sophie Longin ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Molecular Response ◽

Phase 2 ◽

Atp Binding Site ◽

Phase 2 Study ◽

Deep Molecular Response ◽

Ongoing Phase

Background: In patients with chronic myeloid leukemia in chronic phase (CML-CP), the efficacy of ATP-competitive tyrosine kinase inhibitors (TKIs) has resulted in treatment-free remission (TFR) as a primary treatment goal for those with a sustained deep molecular response (DMR). However, most patients treated with imatinib fail to achieve a sustained DMR, meaning that they cannot benefit from TFR. Asciminib is a potent and specific inhibitor of BCR-ABL1. Unlike BCR-ABL1 TKIs that target the ATP binding site, asciminib binds to the myristate pocket of ABL1. Preclinical data showed that the combination of asciminib with ATP-competitive TKIs may provide more potent BCR-ABL1 inhibition and prevent emergence of resistance mutations (Wylie et al. Nature. 2017;543:733-737). In an ongoing phase 1 study (NCT02081378), asciminib demonstrated clinical activity and was well tolerated as a single agent (Hughes et al. Blood. 2016;128 [abstract 625]). In the same study, asciminib in combination with imatinib showed promising preliminary efficacy and a good safety profile in patients resistant/intolerant of ≥2 prior TKIs (Cortes et al. HemaSphere. 2019;3(S1) [abstract S388]). These findings informed the dose of asciminib to be further evaluated in combination with imatinib. An ongoing phase 3 study (NCT03106779) is evaluating asciminib vs bosutinib in patients previously treated with ≥2 ATP-binding site TKIs (Mauro et al. J Clin Oncol. 2019;37 [abstract TPS7070]). Here, we describe the ASCiminib add-on 4-arm study evaluating MOlecular REsponse (ASC4MORE) in patients. This is a phase 2 study evaluating the efficacy of adding asciminib to ongoing imatinib therapy in patients with CML-CP who have not achieved DMR with long-term frontline imatinib (CABL001E2201; NCT03578367). Methods: Study participants are aged ≥18 years, have CML-CP, and have been treated with frontline imatinib for ≥12 months. Study entry requires patients to be receiving imatinib 400 mg once daily (QD) at randomization, have BCR-ABL1 transcript levels in the range of ≤1% to >0.01% on the International Scale (IS), no prior achievement of MR4 (BCR-ABL1IS ≤0.01%) confirmed by two consecutive tests, and no prior treatment failure. Overall, ~80 patients will be randomized 1:1:1:1 to one of four arms (Figure): either asciminib 40 mg QD or 60 mg QD added to imatinib 400 mg QD; continued treatment with imatinib 400 mg QD; or switch to nilotinib 300 mg twice daily. Study treatment will continue until treatment resistance or intolerance, or up to 96 weeks after the last randomized patient has begun treatment. The primary objective of this study is to assess whether asciminib add-on to imatinib is more effective than imatinib continuation; the primary endpoint is the rate of MR4.5 (BCR-ABL1IS ≤0.0032%) at 48 weeks. Secondary objectives include: to estimate the efficacy of switch to nilotinib; to estimate the difference in efficacy between asciminib add-on to imatinib and switch to nilotinib; and to characterize the safety of asciminib add-on to imatinib. Exploratory objectives include TFR eligibility at the end of the study and patient-reported outcomes. Patients in the imatinib continuation arm who have not achieved MR4.5 at 48 weeks may cross over to receive add-on asciminib. This study is ongoing, with 23 patients randomized as of 22 July 2019. Disclosures Saglio: BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Jansen: Consultancy; Celgene: Consultancy. Hughes:Novartis, Bristol-Myers Squibb, Celgene: Research Funding; Novartis, Bristol-Myers Squibb: Consultancy, Other: Travel. Geissler:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy; Amgen: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Biomarin: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; UCB: Consultancy, Speakers Bureau; Servier: Consultancy. Kapoor:Novartis: Employment. Longin:Novartis: Employment. Mukherjee:Novartis: Employment. Cortes:Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Biopath Holdings: Consultancy, Honoraria; Sun Pharma: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.

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Results of following up patients with chronic myeloid leukemia and a deep molecular response without tyrosine kinase inhibitor therapy

Terapevticheskii arkhiv ◽

10.17116/terarkh2017891286-96 ◽

2017 ◽

Vol 89 (12) ◽

pp. 86-96 ◽

Cited By ~ 2

Author(s):

A G Turkina ◽

E Yu Chelysheva ◽

V A Shuvaev ◽

G A Gusarova ◽

A V Bykova ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Molecular Response ◽

Therapy Discontinuation ◽

Deep Molecular Response ◽

Tki Discontinuation

Aim. To assess the results of following up patients with chronic myeloid leukemia (CML) and a deep molecular response (MR) without tyrosine kinase inhibitor (TKI) therapy. Subjects and methods. The reasons for TKI discontinuation in 70 patients with CML and a deep MR of more than 1 year’s duration were adverse events, pregnancy, and patients’ decision. Information was collected retrospectively and prospectively in 2008-2016. Results. The median follow-up after TKI therapy discontinuation was 23 months (2 to 100 months). At 6, 12 and 24 months after TKI therapy discontinuation, the cumulative incidence of major MR (MMR) loss was 28, 41 and 48%, respectively; the survival rates without TKI therapy were 69, 50, and 39%, respectively. MMR loss was noted in 28 (88%) patients at 12 months; it was not seen without TKI therapy at 2-year follow-up. Deaths due to CML progression were absent. The Sokal risk group was a reliable factor influencing MMR loss (p ≤ 0.05). The cumulative recovery rate for deep MR after resumption of TKI use was 73 and 100% at 12 and 24 months, respectively, with a median follow-up of 24 months (1 to 116 months). Deep MR recovered at a later time when the therapy was resumed more than 30 days after MMR loss. Conclusion. Safe follow-up is possible in about 50% of the patients with CML and stable deep MRs without TKI therapy. The introduction of this approach into clinical practice requires regular molecular genetic monitoring and organizational activities. Biological factors in maintaining remission after TKI discontinuation need to be separately studied.

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Discontinuation of Nilotinib in Patients with Chronic Myeloid Leukemia Who Have Maintained Deep Molecular Responses for at Least 2 Years: A Multicenter Phase 2 Stop Nilotinib (Nilst) Trial

Blood ◽

10.1182/blood.v128.22.790.790 ◽

2016 ◽

Vol 128 (22) ◽

pp. 790-790 ◽

Cited By ~ 19

Author(s):

Norimitsu Kadowaki ◽

Tatsuya Kawaguchi ◽

Junya Kuroda ◽

Hirohisa Nakamae ◽

Itaru Matsumura ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Treatment Discontinuation ◽

Molecular Response ◽

Phase 2 ◽

Multicenter Phase ◽

Kaplan Meier ◽

Deep Molecular Response ◽

Treatment Free Remission

Abstract Background Sustained treatment-free remission (TFR) has been reported in 40-60% of patients with chronic myeloid leukemia-chronic phase (CML-CP) after discontinuation of imatinib or dasatinib following at least 1-2 years of deep molecular response (MR). We investigated safety and efficacy of discontinuing nilotinib treatment after 2 years of sustained MR4.5 (BCR-ABL1IS ≤ 0.0032%) on nilotinib in patient for whom MR4.5 was achieved by prior treatment with imatinib or nilotinib. Methods The Stop Nilotinib (NILSt) trial was a single-arm multicenter phase 2 study in Japan. CML-CP patients who obtained MR4.5 by treatment with imatinib or nilotinib were enrolled, and were further treated with nilotinib for 2 years. The patients who maintained MR4.5 during those 2 years were eligible for discontinuation of nilotinib. After treatment discontinuation, maintenance of MR4.5 was monitored by quantitative RT-PCR every month during the 1st year and every 2 months during the 2nd year. Nilotinib was reintroduced in patients who lost MR4.5. The primary endpoint was the proportion of patients who maintained MR4.5 at 1 year after the discontinuation. This study is registered, number UMIN000007141. Results 112 patients were enrolled between April 11, 2012 and November 30, 2012, and were treated with nilotinib for 2 years. 90 of those patients maintained MR4.5 during the entire 2-year period and were eligible to discontinue treatment, among which 87 patients actually discontinued nilotinib to intend a treatment-free remission period. Median follow-up after the discontinuation was 13.4 months (range 4.8-20.1). At 1 year, 53 patients (58.9%, 90% CI 49.7-67.7) maintained MR4.5, whereas 34 patients experienced loss of MR4.5 mostly within 6 months after the discontinuation (Figure 1). Thirty-two of those 34 patients (94.1%) regained MR4.5 2.2 months (median, 95% CI 1.5-2.6) after reintroduction of nilotinib. The following parameters did not significantly predict the probability of MR4.5 at 1 year after the discontinuation: age, sex, Sokal, Hasford, EUTOS scores, history of IFN-a therapy, total duration of imatinib or nilotinib therapy, time to MR4.5, or trough concentrations of nilotinib in sera. Notably, the percentages of patients maintaining MR4.5 for one year without treatment did not improve significantly with longer duration of prior MR4.5 on treatment; even some patients with a duration of prior deep MR on treatment exceeding 10 years experienced loss of MR4.5 after treatment discontinuation (Table 1). The rates of all grade (grade 3/4 in parentheses) cardiovascular events were 5.5% (2.7%), fluid retention were 14.1% (0%), and musculoskeletal pain were 9.7% (1.8%) during the 2-year treatment periods. Conclusion Nilotinib can be discontinued without relapse in more than half of the patients who maintained MR4.5 for at least 2 years. However, relapse occurred after the discontinuation following even more than 10 years of sustained deep MR in the rest of the patients. This suggests that the period of deep MR after which nilotinib can be discontinued without relapse is considerably long, if any, in a substantial proportion of patients. Biomarkers to detect such patients are awaited. Furthermore, additional strategies may be required to safely discontinue nilotinib as early as possible in such patients, in order to avoid serious adverse events caused by prolonged administration. Figure 1. Kaplan-Meier estimates of TFR after discontinuation of nilotinib Figure 1. Kaplan-Meier estimates of TFR after discontinuation of nilotinib Table 1. Rates of MR4.5 maintenance at 1 year after discontinuation of nilotinib in relation to the duration of deep molecular response before the discontinuation Table 1. Rates of MR4.5 maintenance at 1 year after discontinuation of nilotinib in relation to the duration of deep molecular response before the discontinuation Disclosures Kawaguchi: Novartis: Honoraria. Kuroda:Janssen: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding. Matsumura:Bristol-Myers Squibb Company: Honoraria; Novartis Pharma K.K: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria; Pfizer Japan Inc.: Honoraria. Kanakura:Bristol Myers: Research Funding; Alexionpharma: Research Funding; Nippon Shinyaku: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Chugai Pharmaceutical: Research Funding; Shionogi: Research Funding; Kyowa Hakko Kirin: Research Funding; Fujimotoseiyaku: Research Funding; Toyama Chemical: Research Funding.

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Pioglitazone Did Not Affect PPAR-Γ, STAT5, HIF2α and CITED2 Gene Expression in Chronic Myeloid Leukemia Patients with Deep Molecular Response

Blood ◽

10.1182/blood-2019-128265 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1637-1637 ◽

Cited By ~ 1

Author(s):

Ana Beatriz Pascoal Lopes ◽

Eliana C Miranda ◽

Valquíria Mariane Oliveira Póvoa ◽

Bruna Rocha Vergílio ◽

Graziele Cristina Pavan Furlin ◽

...

Keyword(s):

Gene Expression ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Gene Expression Analysis ◽

Chronic Phase ◽

Molecular Response ◽

Ppar Γ ◽

Deep Molecular Response ◽

Treatment Free Remission

Preliminary reports demonstrated that pioglitazone, an antidiabetic drug that is agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ) was able to reduce expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of chronic myeloid leukemia (CML) leukemia stem cells (LSCs). Leaving quiescence would turn the LSCs more sensitive to imatinib (IM) and cause an erosion of the LSCs. This was demonstrated in vitro and in vivo in CML patients that achieved complete molecular response after pioglitazone use. This was the rational for the design of EDI-PIO trial (Pilot Study of Imatinib Discontinuation in Patients with Chronic Myeloid Leukemia with Deep Molecular Response - Evaluation of Pioglitazone in Treatment-Free Remission) (NCT02852486). In this trial, pioglitazone was given in association with IM, with the aim to pull out the LSCs from the quiescence and sensitizing them to IM effect, increasing treatment-free remission (TFR) rates after treatment interruption. Aims: to evaluate PPAR-γ, STAT5, HIF2α and CITED2 gene expression before and after pioglitazone use in CML patients with criteria for IM discontinuation Patients and methods: EDI-PIO is a prospective, phase II trial. Inclusion criteria: CML in chronic phase, treated with IM for at least 3 years, with stable deep molecular response (MR4.5) for at least 2 years. Patients received pioglitazone 30 mg/day, orally, for 3 months before IM discontinuation. BCR-ABL levels were measured by real-time quantitative PCR monthly in the first year after discontinuation, every two months in the second year, and then every 3 months during the subsequent follow-up. Imatinib was reinitiated at molecular relapse (loss of major molecular response or confirmed loss of MR4.0). Total RNA was extracted from peripheral blood leukocytes, pre and post pioglitazone, and at 3 and 6 months after IM discontinuation. After cDNA synthesis, an aliquot was used for gene expression analysis by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), using specific primers for PPAR-γ, STAT5, HIF2α and CITED2. The relative gene expression was calculated using the equation, 2-ΔΔCT. GAPDH was used as control gene. Statistical analysis was performed using ANOVA. Treatment-free remission (TFR) was calculated from IM discontinuation until molecular relapse, reintroduction of IM by any cause, progression to advanced phases or death to any cause. Results: The study is closed for enrollment. Between June 2016 and January 2019, 32 chronic phase CML patients were recruited, of which 30 patients were included in gene expression analysis. Median age was 55 years at trial initiation; 56.7% were men, 50% low risk Sokal and the median time of IM treatment was 117 months (41-191). The median follow-up time was 20 months. TFR was 60% at 24 months. Eleven patients relapsed and IM was reintroduced, but none presented hematologic relapse or progression to advanced phases. There was no significant difference in STAT5, PPAR-γ, HIF2α and CITED2 expression pre and post pioglitazone, at 3 and 6 months after IM discontinuation. No difference was found in the comparison of the relapsed vs. non-relapsed group. Conclusions: pioglitazone did not affect STAT5, PPAR-γ, HIF2α and CITED2 gene expression in this group of pts with deep molecular response. The ACTIM trial demonstrated a reduction in STAT5 expression in bone marrow cells 6 months after pioglitazone exposure, but pioglitazone was given to pts with MMR, without MR4.0. There was no difference in gene expression in the groups with or without molecular relapse. TFR rates remains similar to those reported in other discontinuation trials. Disclosures Delamain: Novartis: Honoraria. Pagnano:Sandoz: Consultancy; Pint Pharma: Consultancy; Abbvie: Consultancy.

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