scholarly journals Programme for Harmonization to the International Scale in Latin America for BCR-ABL1 quantification in CML patients: findings and recommendations

2020 ◽  
Vol 58 (12) ◽  
pp. 2025-2035
Author(s):  
María Sol Ruiz ◽  
María Belén Sánchez ◽  
Yuly Masiel Vera Contreras ◽  
Evangelina Agrielo ◽  
Marta Alonso ◽  
...  
Keyword(s):  
Latin America ◽  
Myeloid Leukemia ◽  
World Health ◽  
Molecular Response ◽  
Limit Of Quantification ◽  
International Scale ◽  
Deep Molecular Response ◽  
Health Organization ◽  
First Time

AbstractObjectivesThe quantitation of BCR-ABL1 mRNA is mandatory for chronic myeloid leukemia (CML) patients, and RT-qPCR is the most extensively used method in testing laboratories worldwide. Nevertheless, substantial variation in RT-qPCR results makes inter-laboratory comparability hard. To facilitate inter-laboratory comparative assessment, an international scale (IS) for BCR-ABL1 was proposed.MethodsThe laboratory-specific conversion factor (CF) to the IS can be derived from the World Health Organization (WHO) genetic reference panel; however, this material is limited to the manufacturers to produce and calibrate secondary reference reagents. Therefore, we developed secondary reference calibrators, as lyophilized cellular material, aligned to the IS. Our purpose was both to re-evaluate the CF in 18 previously harmonized laboratories and to propagate the IS to new laboratories.ResultsOur field trial including 30 laboratories across Latin America showed that, after correction of raw BCR-ABL1/ABL1 ratios using CF, the relative mean bias was significantly reduced. We also performed a follow-up of participating laboratories by annually revalidating the process; our results support the need for continuous revalidation of CFs. All participating laboratories also received a calibrator to determine the limit of quantification (LOQ); 90% of them could reproducibly detect BCR-ABL1, indicating that these laboratories can report a consistent deep molecular response. In addition, aiming to investigate the variability of BCR-ABL1 measurements across different RNA inputs, we calculated PCR efficiency for each individual assay by using different amounts of RNA.ConclusionsIn conclusion, for the first time in Latin America, we have successfully organized a harmonization platform for BCR-ABL1 measurement that could be of immediate clinical benefit for monitoring the molecular response of patients in low-resource regions.

scholarly journals Efficacy and Safety of Generic Imatinib Compared to Glivec in Chronic Phase - Chronic Myeloid Leukemia-Single Center Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4162-4162 ◽  
Author(s):  
Seema Shrinivas Bhatwadekar ◽  
Shubhangi Vishwas Deshpande ◽  
Arpan Mehta ◽  
Parth Shah
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
International Scale ◽  
Deep Molecular Response ◽  
Generic Groups ◽  
Starting Date ◽  
Sokal Score

Introduction: Glivec, Imatinib (IM), first tyrosine kinase inhibitor (TKI) has proven its efficacy and safety in Chronic Myeloid Leukemia - Chronic Phase (CML CP) in a large number of trials. In developing country like India Generic Imatinib formulations have been used recently as a more cost effective treatment, data on efficacy and safety of these drugs is sparse. Aim: To analyse and compare safety profile, the overall survival (OS) and progression-free survival (PFS) data of CML-CP patients receiving Glivec/Generic IM as first line therapy Method: A single centre retrospective analysis done on CML-CP patients who initiated treatment with either Glivec or Generic IM between July 2012 and July 2019 at Hemato-oncology Care Centre (HOCC) Vadodara India. Total 109 newly diagnosed CML-CP received IM as 400mg daily dose, dose was adjusted if significant cytopenia observed or in paediatric patients. Response assessment was made as per NCCN CML Version 1 2019 guidelines.Molecular monitoring of patients was done through BCR-ABL1 RQPCR, reported on international scale. Major Molecular Response (MMR) was considered when the ratio on international scale was less than 0.1% level or ≥ 3-log reduction in BCR-ABL1 mRNA from the standardized baseline, while Deep Molecular Response-MR4 was considered when the ratio on international scale was less than 0.01%.OS was measured from starting date of IM until to the date of death from any cause while on therapy or last seen.PFS was measured from starting date of IM to transformation to AP or BC or deaths while on therapy. Survival curves were calculated by the Kaplan-Meier method and compared with the log-rank test. Cox regression with Backward Wald Method, Chi-square test and t-test is applied using SPSS software version 21.0. A p-value <0.05 is considered to be statistically significant. Results: A Total 109 patients were analysed, received Glivec (47)43% or Generic IM (62)56%. The mean (SD) age was 42.2 years (13.3 years) in Glivec and 47.5 years (14.9 years) in the Generic IM group (P=0.06). There was male preponderance in both groups (Glivec 55%, Generic IM 62 %). Sokal score stratification in Glivec and Generic groups, was respectively: low risk 43%/40%; intermediate risk 36%/48% and high risk 21%/11% (P=0.08). The median follow‐up period was 36 months (range, 9-84). MMR was 61% and 38% in Glivec and Generic IM respectively(p=0.02), MMR was achieved in 40%,04%,11%,06% of Glivec and 29%,2%,5%,2% of Generic IM group patients, at 1st,2nd,3rd,4th year of treatment respectively(P=0.15).Deep Molecular Response-MR4 was significantly higher 40% in Glivec vs 23% in Generic IM group (P=0.01). Nearly 35% of patients were lost to follow up, 28% and 40% in Glivec and Generic IM group respectively(p=0.27). Reasons for drop out were - cost constraints, noncompliance, lack of understanding, lack of transport. Dose limiting cytopenia was observed in initial 3 months of treatment in 12% and 23 % in Glivec and Generic IM group respectively(P=0.28).The most common non haematological side effects in Glivec and Generic groups were skin hyperpigmentation 19%,17%, abdominal discomfort 16 %,11% ,Facial Puffiness 9%,5%, respectively(P =0.73). In each group 4% patients progressed to AP, managed with second generation TKI in Generic IM group and with increasing dose of Glivec to 600mg daily in Glivec group. Total 5% patients progressed to BC and died, 3% in Glivec vs 2% in Generic IM group. The risk factors for progression to AP or BC were high Sokal score, poor molecular response and dose limiting cytopenia. OS and PFS at 36 months were similar in Glivec and Generic IM (93.6% vs. 96.8% P=0.834) and (89.4% vs. 91.9%, P=0.839) respectively. Conclusion: Both the groups have shown similar OS and PFS at 36 months of median follow up, there was also no difference in the safety profile, meeting Generic IM unmet needs in developing country. However in view of higher MMR and Deep molecular response-MR4 in Glivec group, need long term follow up to determine its impact on outcome especially in reference to treatment free remission. Figure Disclosures No relevant conflicts of interest to declare.

Molecular Response of CML Patients to INFα Based Treatment or to STI Based Therapy.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4872-4872
Author(s):  
Debora Luzi ◽  
Rosanna Capozzi ◽  
Annamaria Rauco ◽  
Roberta Pace ◽  
Emilio Donti ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Response Duration ◽  
Cytogenetic Response ◽  
The Other ◽  
Entire Group ◽  
Molecular Response ◽  
Rt Pcr ◽  
Molecular Remission ◽  
First Time

Abstract Introduction: Continous improving results have been obtained during last two decades in the control of Ph’positive chronic myeloid leukemia(CML). However the final goal of molecular remission remains difficult to obtain even in the STI age. Aims : Evaluation of the rate of molecular response to IFNα,IFNα based treatment,to STI or to STI-INFα combination was analized in 100 consecutive Ph+ CML patients observed in a single Institution over a period of 20 years. Patients, Methods and Results All patients were treated at the time of diagnosis (87) or late (13) during the course of their disease. Distribution according to treatment was: INFα,63pts (late or early:13,50);INFα-ARA-C combination,20pts;STI,14 pts;STI-INFα association, 3 pts. Two pts, both initially assigned to INFα-ARA-C combination, were crossed-over to STI, one because relapsing off-therapy after a long lasting continous (25 mths) molecular remission and the other in cytogenetic response because intolerant to the initial treatment. In addition, other 3 pts patients, with persistent complete cytogenetic, but not molecular remission to INFα or INFα-ARA-C combination were subsequentially trated with the STI-IFNα association. At present,99/100 pts are evaluable. The median times of follow-up for the entire group and form the different treatment subgroups are: late IFNα 154 months(42–263); early IFNα, 71 months(1–197); IFNα-ARA-C, 61 months(5–203); STI- IFNα,78 mths(11–47), STI,31 mths(3–41). A complete kariotypic remission(CKR) was observed in 15/63 IFNα treated pts, in 10/20 IFNα-ARA-C pts group, in 10/13 cases of STI group and in 3 /3 pts who received STI-IFNα. A molecular response(RT-nested PCR, JQ Guo, Leukemia: 2002,15,2447–53) was observed in 4/15,2/10,5/10 and in 2/3 CKR pts initially trated with the different modalities listed above. Response was confirmed from 2 to 7 consecutive or not consecutive times in the 2/4 cases responsive to INFα, in the 2 cases responsive to INFα-ARA-C combination,4/5cases responsive to STI and in 2/3 cases responsive to STI-IFNα association. The 2nd and the 3rd molecular remission to STI were obtained in the patient molecularly and cytogenetically relapsed off-therapy and, for the first time from the diagnosis, in the other patient in CKR to IFNα-ARA-C combination and crossed to STI treatment. Furthermore, all 3 cases, in CKR, but not molecular response to other treatments at the time of cross-over to STI-IFNα combination, achieved a persistent (in 2 to 3 tests over a period ranging from 6+ to 12+ mths) molecular remission. The first interval between the start of the treatment and the first molecular response varied from 12 to 52, from 3 to 22, from 11 to 24, from 5 to 11 mths in the groups initially treated with IFNα, IFNα-ARA-C, STI or STI-IFNα respectively. The 2 pts, crossed-over to STI alone, both, obtained a response after 29 mths of therapy. In addition in the 3 pts crossed-over to STI-IFNα therapy, the molecular response was obtained after 14,23 and 25 mths from the start of last treatment. Conclusion It is not possible to achieve any conclusion regarding the treatment effect on molecular response duration because of the different length of follow-up of various groups of patients. However in responsive patients to IFN alone or combined to ARA-C or STI, consecutive negative RT-PCR tests were observed more frequently than in patients receving STI alone.

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

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.

scholarly journals 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 ◽  
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.

scholarly journals Therapy-related myelodysplastic syndrome after successful treatment of acute promyelocytic leukemia: case report and literature review

2017 ◽  
Vol 25 (2) ◽  
Author(s):  
Mihaela Cîrstea ◽  
Adriana Coliță ◽  
Bogdan Ionescu ◽  
Alexandra Ghiaur ◽  
Didona Vasilescu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Promyelocytic Leukemia ◽  
World Health ◽  
Term Therapy ◽  
Molecular Response ◽  
Acute Myeloid

AbstractIn the 2016 revision of the World Health Organization classification the term therapy-related myeloid neoplasia (t-MN) defines a subgroup of acute myeloid leukemia (AML) comprising patients who develop myelodysplastic syndrome (MDS-t) or acute myeloid leukemia (AML-t) after treatment with cytotoxic and/or radiation therapy for various malignancies or autoimmune disorders. We report the case of a 36 year old patient with t-MN (t-MDS) after achieving complete remission (CR) of a PML-RARA positive acute promyelocytic leukemia (APL) at 32 months after diagnosis. Initially classified as low risk APL and treated according to the AIDA protocol - induction and 3 consolidation cycles - the patient achieved a complete molecular response in September 2013 and started maintenance therapy. On follow-up PML-RARA transcript remained negative. In January 2016 leukopenia and thrombocytopenia developed and a peripheral blood smear revealed hypogranular and agranular neutrophils. Immunophenotyping in the bone marrow aspirate identified undifferentiated blast cells that did not express cytoplasmic myeloperoxidase. The cytogenetic study showed normal karyotype. The molecular biology tests not identified PMLRARA transcript. A diagnosis of t-MDS (AREB-2 - WHO 2008) was established. Treatment of AML was started with 2 “3+7” regimens and 1 MEC cycle. Two months from diagnosis, while in CR, an allogeneic HSCT from an unrelated HLA compatible donor was performed after myeloablative regimen. An unfavorable clinical evolution was followed by death on day 9 after transplantation. The occurrence of t-MNs during CR of APL represents a particular problem in terms of follow-up and differential diagnosis of relapse and constitutes a dramatic complication for a disease with a favorable prognosis.This work was supported by the grants PN 41-087 /PN2-099 from the Romanian Ministry of Research and Technology

scholarly journals Comparison of BCR-ABL1 quantification in peripheral blood and bone marrow using an International Scale-standardized assay for assessment of deep molecular response in chronic myeloid leukemia

2020 ◽  
Vol 58 (8) ◽  
pp. 1214-1222
Author(s):  
Georg Greiner ◽  
Franz Ratzinger ◽  
Michael Gurbisz ◽  
Nadine Witzeneder ◽  
Hossein Taghizadeh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Quantitative Polymerase Chain Reaction ◽  
Molecular Response ◽  
International Scale

AbstractBackgroundMonitoring of molecular response (MR) using quantitative polymerase chain reaction (PCR) for BCR-ABL1 is a pivotal tool for guiding tyrosine kinase inhibitor therapy and the long-term follow-up of patients with chronic myeloid leukemia (CML). Results of MR monitoring are standardized according to the International Scale (IS), and specific time-dependent molecular milestones for definition of optimal response and treatment failure have been included in treatment recommendations. The common practice to use peripheral blood (PB) instead of bone marrow (BM) aspirate to monitor the MR monitoring in CML has been questioned. Some studies described differences between BCR-ABL1 levels in paired PB and BM specimens.MethodsWe examined 631 paired PB and BM samples from 283 CML patients in a retrospective single-center study using an IS normalized quantitative reverse transcription (qRT)-PCR assay for quantification of BCR-ABL1IS.ResultsA good overall concordance of BCR-ABL1IS results was found, a systematic tendency towards higher BCR-ABL1IS levels in PB was observed in samples of CML patients in a major MR. This difference was most pronounced in patients treated with imatinib for at least 1 year. Importantly, the difference resulted in a significantly lower rate of deep MR when BCR-ABL1IS was assessed in the PB compared to BM aspirates.ConclusionsIn summary, our data suggest that the classification of deep MR in patients with CML is more stringent in PB than in BM. Our study supports the current practice to primarily use PB for long-term molecular follow-up monitoring in CML.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4254-4254 ◽  
Author(s):  
Ekaterina Chelysheva ◽  
Jane Apperley ◽  
Elisabetta Abruzzese ◽  
Dong-Wook Kim ◽  
Konstantin Kotlyarchuk ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cumulative Incidence ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Late Pregnancy ◽  
Molecular Response ◽  
Deep Molecular Response ◽  
Leukemic Clone ◽  
Kinetics Of

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.

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

2017 ◽  
Vol 89 (12) ◽  
pp. 86-96 ◽  
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.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1637-1637 ◽  
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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