ENESTop 192-week results: Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after stopping second-line (2L) nilotinib (NIL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7005-7005
Author(s):  
Timothy P. Hughes ◽  
Carla Boquimpani ◽  
Naoto Takahashi ◽  
Noam Benyamini ◽  
Nelma Cristina D. Clementino ◽  
...  
Keyword(s):  
Musculoskeletal Pain ◽  
Chronic Phase ◽  
Molecular Response ◽  
Free Survival ◽  
Study Results ◽  
Deep Molecular Response ◽  
Treatment Free Remission ◽  
Clinical Trial Information

7005 Background: In the ENESTop study (NCT01698905) of TFR in pts with CML-CP who achieved a sustained deep molecular response (MR) with 2L NIL, 57.9% remained in TFR 48 wks after stopping NIL (primary endpoint). Analyses at 144 wks showed durability of TFR. Data from longer follow-up (192 wks) evaluating the maintenance of TFR are reported. Methods: Pts treated with ≥2 y NIL after > 4 wks imatinib (≥3 y total) and achieving MR4.5 ( BCR-ABL1IS ≤0.0032%) on NIL were eligible. After a 1 y consolidation, pts with no confirmed loss of MR4.5 could attempt TFR. NIL was resumed upon loss of major MR ( BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 ( BCR-ABL1IS ≤0.01%). At the data cut-off (Sep 24 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 126 pts entering TFR, 56 were ongoing, 59 had resumed NIL, and 11 had discontinued. TFR rate at 192 wks was 46.0% (58/126; 95% CI, 37.1–55.1%); all but 1 of the 58 pts were in MR4.5. Only 1/61 pts in TFR at 144 wks lost response by 192 wks (confirmed loss of MR4); another 2 pts discontinued due to serious AE (polycythemia vera) and pt/guardian decision, respectively. Of 59 pts who resumed NIL, 56 (94.9%) and 55 (93.2%) regained MR4 and MR4.5, respectively. 40/56 pts (71.4%) who regained MR4 had stable MR4 at 96 wks (12 discontinued < 96 wks, and 4 remained on study with < 96 wks, after regaining MR4); 37/55 pts (67.3%) who regained MR4.5 had stable MR4.5 at 96 wks (12 discontinued < 96 wks, and 6 remained on study with < 96 wks, after regaining MR4.5). There were no disease progressions, deaths due to CML, or new deaths since the 144-wk analysis. The 192 wk treatment-free survival rate was 50.3% (95% CI, 41.2–58.7%). Of 62 pts who remained in TFR for > 144 wks, 11.3%, 53.2%, 21.0%, 14.5% and 3.2% had musculoskeletal pain AEs during consolidation and each subsequent 48 wk period of TFR. Among 59 pts who resumed NIL, most common AEs were hypertension (20.3%) and arthralgia (13.6%); the majority of AEs were grade 1/2. Conclusions: Results demonstrate long-term durability and safety of TFR following 2L NIL, with no disease progressions or CML-related deaths, and musculoskeletal pain AEs were transient. Clinical trial information: NCT01698905.

Treatment-free remission (TFR) following frontline (1L) nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 192-week data from the ENESTfreedom study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7013-7013
Author(s):  
Francis J. Giles ◽  
Tamas Masszi ◽  
María Teresa Gómez Casares ◽  
Andrzej Hellmann ◽  
Jesper Stentoft ◽  
...  
Keyword(s):  
Musculoskeletal Pain ◽  
Chronic Phase ◽  
Molecular Response ◽  
Free Survival ◽  
Study Results ◽  
Stopping Treatment ◽  
Treatment Free Remission ◽  
Event Rates

7013 Background: In ENESTfreedom (NCT01784068), which evaluated TFR following 1L NIL in CML-CP pts, 51.6% remained in TFR 48 wks after stopping treatment (primary endpoint) and durability of TFR was demonstrated at 144 wks. Data from longer follow-up (192 wks) evaluating maintenance of TFR are reported. Methods: Pts with MR4.5 ( BCR-ABL1IS ≤0.0032%) and ≥2y of 1L NIL entered a 1y consolidation; pts with sustained deep molecular response (MR) were eligible for TFR. NIL was resumed after loss of major MR (MMR; BCR-ABL1IS ≤0.1%). At the latest data cut-off (Sep 17 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 190 pts entering TFR, 87 were ongoing, 91 had resumed NIL, and 12 had permanently discontinued. The TFR rate at 192 wks was 44.2% (84/190, 95% CI: 37.0–51.6%). Of 89 pts with successful TFR at 144 wks, 5 were not assessable for TFR at 192 wks as 2 had discontinued by 192 wks due to pt/physician decision, and 3 with MR4.5 previously did not have 192 wk PCR data. Of 91 pts who resumed NIL, 90 (98.9%) regained MMR and 84 (92.3%) regained MR4.5. 75/90 and 73/84 pts, respectively, had stable MMR and MR4.5 at 48 wks later. There were no cases of disease progression or new deaths. 10 deaths were reported in the 144-wk analysis, none due to CML. The 192-wk treatment-free survival rate was 48.7% (95% CI 41.4–55.6%). Of 89 pts remaining in TFR for > 144 wks (including 87 pts for > 192 wks), all-grade AE rates during consolidation and each subsequent 48 wk period of TFR were 84.3%, 77.5%, 70.8%, 48.3%, and 52.8%, respectively. All-grade musculoskeletal pain AE rates were 15.7%, 40.4%, 9.0%, 3.4% and 3.4%, respectively; cardiovascular event rates were low across these periods. Among pts who resumed NIL, most common AEs were nasopharyngitis (18.7%) and pruritus, fatigue, and increased lipase (14.3% each); the majority of AEs were grade 1/2. Conclusions: Results continue to support the long-term durability and safety of TFR at 192 wks after stopping 1L NIL; overall AE rates declined during the TFR phase and musculoskeletal pain AEs were transient. Pts should continue to be regularly monitored during TFR. Clinical trial information: NCT01784068.

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.

Seven-Year Follow-up Data on Sequential Prospective Trials of Imatinib 400mg Vs 800mg Daily Schedule for Front-Line Treatment of Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3438-3438
Author(s):  
Naveen Pemmaraju ◽  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Srdan Verstovsek ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Research Funding ◽  
Chronic Phase ◽  
Annual Rate ◽  
Molecular Response ◽  
Free Survival ◽  
Cumulative Rate ◽  
Prospective Trials

Abstract Abstract 3438 Background: The standard of care for most patients (pts) with CML has been imatinib mesylate at a dose of 400mg by mouth daily. Earlier studies have suggested that there may be a benefit to pts to start treatment at a higher dose as this may result in faster and more durable responses to imatinib. It is not yet known whether long-term event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) will be impacted by the higher dosing schedule. Objectives: To determine the long term responses and clinical benefit of imatinib 800mg daily versus 400mg daily dosing when used as upfront treatment strategy in CML. Methods: We conducted sequential prospective trials using imatinib 400mg or 800mg daily as initial therapy for patients with previously untreated chronic phase CML. Results: A total of 281 pts were included in these trials: 208 treated with 800mg and 73 with 400mg. The median follow-up for each group was 79 months (range: 3–107) and 110 months (range: 2–116). The overall, cumulative rate of complete cytogenetic response (CCyR) was 91% and 87%, respectively (p=0.49) for those treated with high- and standard-dose, and the cumulative rate of major molecular response (MMR) was 87% and 78%, respectively (p=0.06). Rates of CCyR at 12 months were 90% and 66%, respectively (p < 0.001), and MMR at 18 months 82% and 68%, respectively (p=0.04). A significantly better EFS (definition per IRIS criteria) was observed for the 800 mg group compared to that in the 400mg group (log-rank test, p=0.049; estimated 7-year EFS 86% vs 76% by Kaplan-Meier method). No significant differences were seen for survival free from transformation to accelerated and blast phase (p = 0.46) and overall survival (p = 0.27). For OS, thus far 19 pts in the 800mg group have died (2 probable CML-related, 3 unknown causes, 14 non CML related) compared to 13 pts (10 probable CML-related, 3 non CML-related) in the 400mg group. The table below shows the annual rate of events and transformation for each dose group. Treatment discontinuation for toxicity occurred in 16 (8%) pts treated with 800mg and 6 (8%) pts treated with 400mg. Conclusions: At 7-year follow up, pts treated with 800mg demonstrated a significantly better EFS (by IRIS criteria) compared to those treated with 400mg. There is a trend for a lower annual rate of events and transformation with the higher dose, particualry in the earlier years, but no difference in OS. These results suggest a modest benefit for patients treated with higher dose imatinib. Disclosures: Off Label Use: imatinib at dose of 800mg po daily for CML. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Verstovsek:Incyte Corporation: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; BMS: Honoraria, Research Funding; Novarits: Honoraria, Research Funding.

scholarly journals Final Study Results of Newly Diagnosed Chronic Myeloid Leukemia Chronic Phase (CML-CP) Patients Receiving Radotinib 300 Mg BID or Imatinib: Rerise 48 Months Follow-up

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1733-1733
Author(s):  
Young Rok Do ◽  
Jae-Yong Kwak ◽  
Hawk Kim ◽  
Jeong-A Kim ◽  
Hyeoung-Joon Kim ◽  
...  
Keyword(s):  
Research Funding ◽  
Safety Data ◽  
Chronic Phase ◽  
Standards Of Care ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Study Results

Abstract Background: In RERISE phase 3 study, radotinib demonstrated significantly higher and faster rates of major molecular response (MMR) than imatinib in patients with newly diagnosed CML-CP. By 36 months follow up, MMR (BCR-ABL1IS ≤ 0.1%) and MR4.5 (BCR-ABL1IS ≤ 0.0032%) in radotinib 300 mg twice daily (bid) were higher than imatinib group. Also, early molecular response (EMR) at 3 months could predict better long term outcomes in both radotinib and imatinib groups. Here, authors updated 48 months long-term benefits and risks of 300mg bid and imatinib 400mg qd from RERISE phase 3 study (NCT01511289). Methods: RERISE study was randomized trial of radotinib 300 mg bid (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81) in patients with newly diagnosed CML-CP. We evaluated long-term MMR and MR4.5, overall survival (OS), and progression-free survival (PFS) including safety data by 48 months. Results: At the study completion, 53% of patients with radotinib and 44% of patients with imatinib treated were remained. MMR and MR4.5 continued to be higher in patients receiving radotinib 300 mg bid compared with imatinib 400mg qd (Table). Especially, MMR rate by 48 months was significantly higher for radotinib compared to imatinib (76% vs 56%; P=0.0070, Figure). Also, early molecular response (EMR) at 3 months were observed in 86% of patients in the radotinib 300 mg bid group and 68% in the imatinib group (P = 0.0179). More patients treated with radotinib 300mg bid who had EMR at 3 months achieved MMR and MR4.5 by 48 months: 84% and 53% in the radotinib 300 mg bid group and 71% and 44% in the imatinib group, respectively. 48 months estimated OS and PFS rate were not significantly different in two groups (99% vs 94%; P=0.3224, 97% vs 94%; P=0.4328). Treatment failure was lower in radotinib group compared with imatinib group (Table). The safety profiles were consistent with those previously reported and most of adverse events (AEs) developed within 12 months. No new or unexpected safety events were reported in both arms by 48 months and no serious CVE related with radotinib reported. Conclusions: With a minimum 48 months follow-up, radotinib continued to demonstrate higher rates of MMR and MR4.5 than imatinib in newly diagnosed CML-CP. Also, these responses with radotinib were earlier and deeper compared with imatinib. Up to 48 months, no new and serious safety events related with radotinib reported. These results demonstrate that radotinib may have higher possibility of treatment- free remission (TFR) on frontline therapy as well as it can be one of the standards of care in newly diagnosed CML-CP. Figure. Figure. Disclosures Bunworasate: IL-YANG: Research Funding. Comia:IL-YANG: Research Funding. Mun:IL-YANG: Research Funding. Caguioa:IL-YANG: Research Funding. Kim:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Ilyang: Research Funding.

Frontline Treatment With Imatinib Mesylate in Chronic Myeloid Leukemia Patients in Early Chronic Phase: a Very Long-Term Analysis by the GIMEMA CML Working Party

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 258-258 ◽  
Author(s):  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Massimo Breccia ◽  
Giorgina Specchia ◽  
Tamara Intermesoli ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Chronic Phase ◽  
Working Party ◽  
Molecular Response ◽  
Advisory Committees ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival

Abstract Background The chronic myeloid leukemia (CML) therapeutic scenario has been enriched by the approval of second generation TKIs as frontline treatment of early chronic phase (ECP) patients, but imatinib mesylate (IM) still represents the standard for many patients. The long term outcome is extremely important to assess the treatment efficacy and to decide on the allocation of resources. The phase 3 trials comparing second generation TKIs versus standard-dose IM have not still demonstrated a clear improvement in terms of progression-free survival and overall survival. In the IRIS trial, at 8 year, 55% of patients were still on IM and the overall survival (OS) was 85%. Other published reports have shorter follow-up. Aims and Methods To assess the very long-term outcome of CML patients treated frontline with IM, we analyzed 559 patients enrolled within 3 multicentric prospective studies conducted by the GIMEMA CML Working Party (NCT00514488, NCT00510926, observational trial CML023). Definitions: major molecular response (MMR), BCR-ABLIS ratio <0.1%; deep molecular response (MR4.0), detectable disease ≤ 0.01% BCR-ABLIS or undetectable disease with ≥10,000 ABL transcripts; progression, transformation to accelerated or blastic phase; failure, according to 2013 ELN criteria; event, treatment discontinuation for any reason or lost to follow-up. Information on survival and progression were regularly collected. All deaths, at any time and for any reason, were included. All the analysis have been made according to the intention-to-treat principle. Results Baseline demographics characteristics: median age: 52 years (extremes 18-84 years); male sex: 60%; high Sokal, high Euro and high EUTOS scores: 22%, 7% and 7%, respectively; clonal chromosomal abnormalities (CCA) in Ph+ cells: 4% (not evaluable in 32% of patients for insufficient number of metaphases); e13a2 BCR-ABL transcript: 36%. Median follow-up: 76 (7-99) months. The cumulative incidence of complete cytogenetic response (CCyR), MMR and MR4 was 88%, 85% and 61%, respectively. The median time to CCyR, MMR and MR4 was 6, 7 and 42 months, respectively. Patients with high Sokal, high Euro and high EUTOS scores had significantly lower overall estimated probability of CCyR and MMR with respect to low and intermediate risk patients. A high Sokal score also predicted a significantly inferior probability of MR4; patients with high Euro and high EUTOS score had lower overall estimated probability of MR4, but the difference were not statistically significant. The reasons for IM discontinuation were: lack of efficacy (19%), toxicity or death (9%), withdrawal of informed consent (3%); 4% of patients were lost to follow-up. The 8-year event-free survival (EFS), failure-free survival (FFS), progression-free survival (PFS) and OS were 55% (95% CI: 51-60%), 66% (95% CI: 61-70%), 84% (95% CI: 78-89%) and 85% (95% CI: 79-90%), respectively. A high Sokal and a high Euro scores were able to identify patients with significantly lower probability of EFS, FFS, PFS and OS with respect to the other patients. High EUTOS score patients had significantly poorer EFS and FFS, but PFS and OS differences were not significant. Age, performance status and e13a2 transcript resulted independent prognostic factors on PFS and OS. Conclusions Until now, the available data on the very long-term outcome of newly diagnosed chronic phase CML patients treated frontline with imatinib are limited to a company sponsored study (IRIS study). The GIMEMA CML Working Party provided an unbiased overview of the long-term imatinib therapeutic effects in a multicentric nationwide experience. These results should be taken into consideration to make treatment decision concerning the choice of the first line TKI, particularly in low risk patients. Acknowledgments University of Bologna, BolognaAIL, COFIN, Fondazione Carisbo. Disclosures: Castagnetti: Novartis Farma: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gugliotta:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Abruzzese:BMS, Novartis: Consultancy. Soverini:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; ARIAD: Consultancy. Cavo:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Second TKI Discontinuation in CML Patients That Failed First Discontinuation and Subsequently Regained Deep Molecular Response after TKI Re-Challenge

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 788-788 ◽  
Author(s):  
Thomas Pagliardini ◽  
Franck E. Nicolini ◽  
Stephane Giraudier ◽  
Philippe Rousselot ◽  
Gabriel Etienne ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Chronic Phase ◽  
Disease Free Survival ◽  
Molecular Response ◽  
Advisory Committees ◽  
Term Survival ◽  
Deep Molecular Response ◽  
Tki Discontinuation

Abstract Background: Tyrosine kinase inhibitors (TKIs) are able to induce, in some chronic myeloid leukemia (CML) patients, long-term undetectable molecular disease (UMD). Several studies have now demonstrated that TKIs could be safely discontinued in those patients previously treated with imatinib (STIM, TWISTER, EUROSKI) and more recently with nilotinib and dasatinib (STOP 2G-TKI). All these studies show a Treatment-Free Remission (TFR) rate reaching ~50%. However, a major issue needs to be resolved for the ~50% of patients that fail such TFR strategies. Methods: We have previously reported the possibility of a second imatinib discontinuation in 16 patients who obtained a second UMD state according to the STIM criteria (RE-STIM observational study, Legros et al. Blood 2012). Here, we report a larger cohort of patients who attempt twice TKI-discontinuations with enlarged inclusion criteria: Adults CML patients without prior allogeneic transplantation or progression to advanced phase CML undergoing a 2nd attempt of TKI discontinuation for sustained deep molecular response after a 1st failure. All patients were followed in CML reference centers and according to the EUTOS-ELN accreditation criteria for BCR-ABL assessments with minimal numbers of 32,000 ABL copies/sample. Results: At the time of analysis (1st July 2016), 67 patients (median age: 51 years (range: 25-80 years)) were included. At CML diagnosis, 64 patients were in chronic phase (CP) and 3 patients in accelerated phase (AP). The Sokal risk and the EUTOS long-term survival scores (ELTS) were respectively low in 47% and 68%, intermediate in 36% and 16%, high in 11% and 2% and unknown in 6% and 14% of patients. All patients were treated initially with imatinib and 16% of patients switch to nilotinib (6/11) or to dasatinib (5/11) for intolerance/resistance reasons prior to the 1st TKI discontinuation. The median time on TKI prior to the 1st discontinuation was 63 months (range: 30-146) and the median duration of 1st CMR was 35 months (range: 20-85). The 1st molecular relapse occurred with a median of 2.5 months (range: 0-22) and the second UMD after TKI re-challenge was obtained with a median of 4.4 months (0-40). The reason of the TKI re-challenge was loss of UMD in 43%, loss of MMR in 55% and unknown in 1%. The TKI re-challenge (imatinib 73%, nilotinib 16%, dasatinib 11%) was then administered during a median of 31 months (range: 9-72 months) before the 2nd attempt of discontinuation. At 2nd TKI cessation, 85% of patients were in UMD, 3% in MR4.5, 6 % in MR4, 3% in MMR and 3% unknown. Thirty out of sixty-eight (44%) patients remained treatment-free after a median follow-up of 21.5 months (1-106), see figure. Similarly to 1st attempts, the majority of loss of MMR occurred during the first 6-12 months in this 2nd attempt cohort. Gender, age, disease phase, prognosis scores, prior interferon exposure, initial TKI type, and duration of UMD were not found to have any impact on the outcome after the 2nd attempt in a multivariate analysis. In contrast, a longer time to obtain the first UMD before the 1st attempt was associated with a significantly lower molecular disease-free survival rate after the 2nd discontinuation (p = 0.048). All patients are alive at last follow-up except one who died from an unrelated CML reason (heart attack under imatinib). Conclusion: TKIs could safely and successfully be discontinued a second time in CML pts despite a 1st failure. Figure. Figure. Disclosures Nicolini: BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:BMS: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Guerci-Bresler:Pfizer: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ARIAD: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria.

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.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

scholarly journals Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2521
Author(s):  
Gabriel Etienne ◽  
Stéphanie Dulucq ◽  
Fréderic Bauduer ◽  
Didier Adiko ◽  
François Lifermann ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
De Novo ◽  
Chronic Phase ◽  
Risk Scores ◽  
Prolonged Treatment ◽  
Molecular Response ◽  
First Line ◽  
Treatment Free Remission ◽  
Tki Discontinuation

Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

Long Term Follow up of Patients with CML in Chronic Phase Treated with First-Line Imatinib Suggests That Earlier Achievement of a Major Molecular Response Leads to Greater Stability of Response.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2113-2113 ◽  
Author(s):  
Susan Branford ◽  
Rebecca Lawrence ◽  
Andrew Grigg ◽  
John Francis Seymour ◽  
Anthony Schwarer ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Low Risk ◽  
Initial Slope ◽  
Molecular Response ◽  
Average Dose ◽  
Major Molecular Response ◽  
First Line ◽  
Significant Difference

Abstract A major molecular response (MMR) by 12 or 18 months (m) of standard dose imatinib for patients (pts) with newly diagnosed chronic phase CML is associated with a low risk of progression to accelerated phase or blast crisis. Phase II/III trials suggest that MMR may be achieved earlier with higher doses of imatinib. We determined whether the timing of MMR affects the long term stability of response with regard to the acquisition of BCR-ABL mutations and/or loss of MMR (collectively defined as an “event”) for pts with up to 8 years of follow up since commencing first-line imatinib. All pts treated with 400 to 600mg of first-line imatinib who were monitored regularly at our institution for BCR-ABL levels by real-time quantitative PCR and mutation analysis by direct sequencing were evaluated: 181 pts were followed for a median of 45m (range (r) 3–96m). The event rate was compared for pts dependent on the time to MMR (≤0.1% IS (international scale)) in 6m intervals to 18m of imatinib. The events for pts with undetectable BCR-ABL (complete molecular response, CMR) were also determined. Strict sensitivity criteria were used for CMR: undetectable BCR-ABL where the sensitivity of analysis indicated BCR-ABL was &lt;0.003% IS, (equivalent to at least 4.5 log below the standardized baseline) which was confirmed on a subsequent analysis. Loss of MMR was defined as a confirmed &gt;2 fold rise from nadir to a level &gt;0.1% IS in pts who maintained imatinib dose. 144/181 pts (80%) achieved MMR at a median of 12m (r 3–53m). Consistent with other studies, maintaining a higher dose of imatinib in the first 6m of therapy was associated with a significantly higher frequency of pts achieving MMR by 6m. 118 pts received an average dose of &lt;600mg in the first 6m and 18/118 (15%) achieved MMR by 6m, whereas 63 pts received an average dose of 600mg in the first 6m and 23/63 (37%) achieved MMR by 6m, P=0.002. Mutations were detected in 14/181 pts (8%) at a median of 9m (r 3–42m). An event occurred in 8 pts with MMR at a median of 36m (r12–57m) after commencing imatinib, including one patient who had achieved CMR. Mutations were found in 4 pts and 3/4 lost MMR. The remaining 4 lost MMR without a mutation. The one patient with a mutation who did not lose MMR had a 3-fold rise in BCR-ABL at the time of mutation detection and responded to a higher imatinib dose. The other pts with mutations had therapeutic intervention upon cytogenetic relapse (2) or loss of MMR (1). The 4 pts with loss of MMR and no mutation had accelerated phase (1), cytogenetic relapse (2) and one maintained CCR with 3m of follow up. The median fold rise in BCR-ABL upon loss of MMR was 26 (r 4–220). The probability of an event if MMR was achieved by a) 6m was 0% (n=41 evaluable pts), b) &gt;6 to 12m was 12% (n=40) and c) 12 to 18m was 19% (n=33). The median follow up since MMR was achieved was not significantly different for the groups: 49m (r 3–87m), 38m (r 6–87m), 40m (r 9–78m), respectively, P=0.5. The risk of an event for pts with MMR achieved by 6m was significantly lower than in pts with MMR achieved by &gt;6 to 18m, P=0.04. CMR occurred in 55 pts who were followed for a median of 24m (r 3–55m) after its attainment. Only 1 event occurred in these 55 pts, which was at 6m after CMR was achieved and 57m after commencing imatinib. This patient had maintained MMR for 45m but loss of a major cytogenetic response occurred 6m after loss of MMR. There was a significant difference in the probability of CMR by 60m of imatinib dependent on the time to MMR, P&lt;0.0001 (Figure). All pts failed to achieve CMR by 60m if not in MMR at 18m whereas the actuarial rate of CMR at 60m was 93% in those with MMR by 6m. The initial slope of BCR-ABL decline correlated strongly with the decline over the longer term. The mean time to CMR after attainment of MMR was significantly faster for pts with MMR by 6m compared to those with MMR at &gt;6 to 12m and &gt;12 to 18m: 24m vs 37m vs 42m, respectively, P=0.001. This suggests the rate of BCR-ABL reduction below the level of MMR was faster in pts with MMR by 6m, which may be clinically beneficial as none of these pts had a subsequent event. Based on these findings we propose that inducing earlier molecular responses with higher dose imatinib or more potent kinase inhibitors may lead to more durable and deeper responses. It remains possible however, that early molecular response reflects a more biologically favourable disease rather than being the direct cause of more durable response. Finally, CMR was associated with an extremely low risk of events, making it an appropriate next target of therapy after MMR is achieved. Figure Figure

Sign in / Sign up

Export Citation Format

Share Document