High Level of Successful TKI Discontinuation in Chronic Myeloid Leukemia (CML) Patients: Preliminary Results of AST-Argentina Stop Trial

Introduction: Treatment-free remission (TFR) is an emerging treatment goal for chronic myeloid leukemia (CML) patients in deep molecular response (DMR). Current evidence shows that 40%-60% of patients relapse while in TFR; and nearly all regain response once tyrosine kinase inhibitors (TKIs) treatment are reinitiated. However a robust predictor of prolonged TFR has not been reported yet. Considering real-life setting, 2 key factors may affect TFR outcome if not properly done: Access to serial molecular monitoring at optimal timepoints and quality laboratory terms as accuracy, sensitivity and rapid results. This motivated the creation of the AST study in our region to guarantee adequate molecular monitoring for TFR in Argentina and characterize new prognostic biomarkers helpful to identify more accurately patients who will be able to sustain TFR. We aimed to assess the proportion of patients with sustained major molecular response (MMR) after TKIs discontinuation and define precise conditions for stopping treatment. Methods: This prospective, multicentre Argentina Stop Trial (AST) trial is recruiting chronic phase CML patients under TKI treatment for at least ≥ 4 years, in DMR (≥MR4.0) sustained for ≥ 2 years in standardized laboratory, confirmed typical BCR-ABL1 transcripts b3a2 and/or b2a2 and aged > 18 years. Molecular tests are centralized in 2 harmonized laboratories and performed monthly for the first 6 months, every 2 months until the first year, and every 3 months during the second year. If patients lost MMR, TKI was restarted immediately. Molecular relapse Free Survival was estimated by Kaplan-Meier method. Difference between survival variables was evaluated through log-rank test. Multivariate analysis was performed through Cox proportional hazards model. The cutoffs of the numerical variables were considered according to the log-rank test. Results: Between February 2019 and July 2020, we evaluated 50 CML patients of whom 46 were enrolled from 7 centers in Argentina and 4 were screening failures. Recruitment was interrupted due to COVID-19 pandemic. Patient median age was 57.5 years (range 24-85). Before discontinuation, TKI treatment was as follows: Imatinib 37/46 (80%), Nilotinib 5/46 (11%) and Dasatinib 4/46 (9%), 2G-TKI as 1st line, 11% of the patients received non-branded treatment. Sokal risk score showed to be low in 22 patients (48%), intermediate in 14 (30%) and high in 10 (22%). Median follow-up was 10 months (range 4-17) and the estimated molecular relapse-free survival was 80.2% (95%CI 69-93) at 6 months Fig 1. Longer DMR durations before discontinuation were associated with increased probability of maintaining response at 6 and 12 months: 83.2% for patients who had >54 months in DMR vs 70% with <54 months and 72% vs 23.3% respectively (p=0.0453) Fig 2. Cox multivariate analysis was performed including different variables as age at diagnosis, time in DMR, time in TKI previous to discontinuation and Sokal risk. The only significant variable associated to improved prognosis was time in DMR (HR 2.8 95%CI 1.002-8.07 p=0.0495). Our cohort had a long time on TKI treatment previous to discontinuation, median 10.5 years (4.16-17.5) probably considering it a favorable factor for the high TFR rates described at 6 months. Among the 46 patients included, 15 (33%) lost MMR, all restarted treatment with the same TKI used before discontinuation, 12/15 (80%) regained MMR with a median time of 3 months (range1-8) and 9/15(60%) obtained MR 4.0 with a median time of 3 months (range1-5). Conclusion: This is the first multicenter study of TKI discontinuation in CML patients in Argentina showing that TKI can be safely discontinued in those who achieve and maintain a DMR before discontinuation. We observed high rates of molecular relapse free survival, although longer follow-up is needed. We must continue with this approach for patients participating in TFR trials or TFR programs in order to decrease the risk of relapse and make this goal a fact in our region. This discontinuation study will allow in a near future significant saving of economic resources and might improve patients quality of life specially in those who are currently experiencing treatment adverse events. Disclosures Pavlovsky: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Pfizer: Speakers Bureau; Pint Pharma: Speakers Bureau. Varela:Novartis: Consultancy, Speakers Bureau. Pavlovsky:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Varifarma: Speakers Bureau. Moiraghi:BMS: Speakers Bureau; Novartis: Speakers Bureau.

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Updated 18-Month Results from Dasfree: A Study Evaluating Dasatinib Discontinuation in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Deep Molecular Response (DMR)

Blood ◽

10.1182/blood-2018-99-116563 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4253-4253 ◽

Cited By ~ 5

Author(s):

Neil P. Shah ◽

Jose Valentín García Gutiérrez ◽

Antonio Jiménez-Velasco ◽

Sarah Larson ◽

Susanne Saussele ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitor ◽

Safety Data ◽

Chronic Phase ◽

Molecular Response ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival

Abstract Introduction: Tyrosine kinase inhibitor (TKI) discontinuation is being investigated in pts with CML-CP with sustained DMR (defined here as MR4.5 or BCR-ABL1 ≤ 0.0032% on the International Scale [IS]), with the goal of treatment-free remission (TFR). Successful TFR has been reported previously for pts enrolled in DASFREE (CA180-406/NCT01850004), which showed that 48% of CML-CP pts with DMR for ≥ 1 year were able to stop dasatinib and maintain major molecular response (MMR) 12 months after discontinuation. Here we present updated results from pts followed for a minimum of 18 months, in order to understand the durability of TFR beyond 12 months. Methods: DASFREE is a phase 2, open-label, single-arm study in adult pts with CML-CP on dasatinib for ≥ 2 years as 1st-line or subsequent therapy. Eligible pts had dasatinib-induced DMR (MR4.5) confirmed at a local lab for ≥ 1 year prior to enrollment, with a 1-log reduction in BCR-ABL1 from baseline within 3-6.5 months of starting dasatinib. MR4.5 was confirmed at a central lab twice within 3 months prior to dasatinib discontinuation (screening phase). BCR-ABL1 was monitored centrally after discontinuation every month in the 1st year, then every 3 months. Pts resumed dasatinib at their previous dose if MMR was lost. The primary endpoint is the rate of MMR 12 months after dasatinib discontinuation. Secondary endpoints include BCR-ABL1 kinetics, molecular relapse-free survival (MRFS; no loss of MMR), relapse-free survival (RFS; no loss of MMR, complete cytogenetic response, or complete hematologic response, or progression to accelerated/blast phase [AP/BP] CML), rate of transformation to AP/BP, progression-free survival, and overall survival. Exploratory analyses include frequency of adverse events (AEs) after discontinuation and during dasatinib treatment, and MMR after reinitiating dasatinib. Results: In total, 84 pts enrolled between February 2014 and June 2016 discontinued dasatinib; all had ≥ 18 months of follow-up after discontinuation at the time of this analysis. Pt characteristics were previously reported (the majority [64%] had low Sokal scores; no pt had prior interferon; 37 pts were on 1st-line dasatinib, 47 on subsequent lines of dasatinib). At 18 months after discontinuation, the RFS rate was 48% (95% CI 37-58) in all pts (Figure), 54% (95% CI 38, 70) in 1st-line pts, and 42% (95% CI 28, 57) in pts who received subsequent-line therapy. With longer follow-up, 1 additional pt lost MMR at 18 months following discontinuation. Of the 45 pts who lost MMR and restarted treatment, 44 regained MMR (1 pt discontinued after only 1 molecular assessment) in a median of 2 months (range 1-4) and 42 regained MR4.5 in a median of 3 months (range 2-18). Analyses of baseline pt characteristics revealed that for the 40 pts who did not lose MMR after discontinuation, 15 (37.5%) were able to maintain MR4.5. Additionally, the median time in prior MR4.5 was 28 months (range 13-116) for all pts, and was similar for 1st-line pts who maintained (27 months [range 13-56]) or lost MMR (27 months [range 15-68]) at 12 months. With longer follow-up, AEs (any cause) identified were consistent with previous reports and were found to be similar on and off treatment: 8 (10%) pts off treatment and 8 (18%) pts on treatment experienced grade 3/4 AEs of any cause after restarting dasatinib (4.4% were drug related). No transformation events or deaths occurred. Of the 13 reported withdrawal events occurring in 8 (9.5%) pts, 10 were resolved (5 off treatment, 5 resolved after restarting treatment due to loss of MMR) after a median of 5 months (range 1-12) after onset. One pt discontinued after restarting dasatinib due to malignancy unrelated to treatment. In addition to efficacy and safety data, multivariate analyses evaluating prognostic factors for MMR will be presented. Conclusions: Additional follow-up of pts enrolled in DASFREE revealed that TFR remained durable at 18 months after discontinuing dasatinib. AEs reported here were consistent with the known safety profile of dasatinib, and withdrawal was well tolerated. Collectively, this trial, the largest dasatinib discontinuation trial to date, continues to support the feasibility and practicality of TFR in pts with CML-CP in DMR treated with dasatinib in the 1st line and beyond. Figure. Figure. Disclosures Shah: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. García Gutiérrez:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Larson:Bristol-Myers Squibb: Consultancy; Takeda: Speakers Bureau. Saussele:Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Rea:Incyte: Honoraria; Bristol-Myers Squibb: 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; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Gómez-Casares:Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Pane:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy. Nicolini:Incyte: Consultancy, Honoraria, Speakers Bureau; Sun Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding. Sy:Bristol-Myers Squibb: Employment. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Lipton:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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In Pursuit of Surrogate Markers for Treatment-Free Remission in Patients with Chronic Myeloid Leukemia from Argentina Stop Trial

Blood ◽

10.1182/blood-2020-141067 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-24

Author(s):

Maria Belen Sanchez ◽

Beatriz Moiraghi ◽

Ana Ines Varela ◽

Estrella Levy ◽

Masiel Vera ◽

...

Keyword(s):

Nk Cells ◽

Board Of Directors ◽

Rank Test ◽

Molecular Response ◽

Advisory Committees ◽

Log Rank Test ◽

Stop Trial ◽

Significant Difference ◽

Treatment Free Remission ◽

Tki Treatment

INTRODUCTION: Long-term survival of patients with chronic myeloid leukemia (CML) has significantly improved since the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs). Several considerations about the side effects, risks and cost associated with the lifetime treatment, have led patients and physicians to explore the possibility of TKI discontinuation after achievement of a sustained deep molecular response (DMR), so-called treatment-free remission (TFR). Several clinical trials show that approximately half of patients who achieve a sustained DMR during TKI treatment maintain molecular remission after suspension of TKIs. There is currently no biomarker that reliably predicts TFR in CML, mainly due to different study designs that have generated inconsistent data. Thus, further investigations are needed to identify factors that consistently favor achievement of TFR. With the aim of developing a biomarker for TFR prediction we analyzed the phenotype of Natural Killer (NK) cells and their relation to successful TKI cessation. METHODS: This analysis was conducted as a substudy of the Argentina Stop Trial. Altogether, 50 consecutive chronic phase CML patients who participated in the clinical trial were recruited from 7 Argentinian centers. Peripheral blood samples were collected before stopping TKI treatment, at month 3, 12 and at any time when MR3.0 was lost. Freshly isolated mononuclear cells from 46 patients were immunophenotyped by staining with CD3, CD16, CD25, CD56, CD57, CD158, NKp30, NKp44, NKp46, NKG2A, NKG2C, NKG2D and PD-1 antibodies and NK cells subpopulations were analyzed by flow cytometry (BD FACS Canto™II). Molecular recurrence-free survival was estimated by the Kaplan-Meier method and compared within groups by the log-rank test. The cutoffs of the numerical variables were optimized according to the log-rank test. Quantitative variables were dichotomized according to receiver operating characteristics (ROC) curves in order to describe sensibility and specificity. Multivariate analysis was performed through Cox proportional hazards model. Main results are provided with hazard ratio (HR) at 6 months and 95% confidence intervals (95% CI). RESULTS: At the time of discontinuation the median proportion of NK cells (CD3-CD56+) among lymphocytes was significantly increased in patients compared with controls (15% vs 9%, P = 0.0016). A significant difference between molecular relapsed vs no-relapsed patients was observed when optimal cutoff (0.43) for CD56bright low and high was determined (at 6 months 74% vs 100% respectively, log rank test, p=0.023). At this time of follow up, no significant difference was observed for CD56dim NK cells. Phenotypic markers for adaptive-like NK cells were analyzed, however, no significant differences were observed between the non-relapsing and relapsing groups. Nevertheless, molecular non-relapsing patients had significantly higher frequencies of PD-1+ NK cells as compared with molecular relapsing patients (at 6 months 85% vs 64%, Log Rank test, P=0.009). Based on the ROC and Youden Index analysis, at 6 months the 1.2 cutoff shows an 80% specificity and 50% sensitivity. Moreover, after multivariable Cox proportional analysis, including age, time of treatment, deep molecular response time, Sokal risk, NK cells and PD-1+ NK cells, the last subpopulation was identified as an independent prognostic factor for molecular-relapse-free survival (Hazard ratio = 3.63; 95% CI 1.3 - 10.1; P=0.014). CONCLUSIONS: The clinical impact of NK cells in patients who have discontinued TKIs is controversial. The effects of TKIs against immune cells, including NK cell subsets, could depend on the type of TKIs; this aspect is particularly relevant in Argentinian treated patients real world, since many different copies of TKIs are routinely used in the clinical setting. Our study is the first, to our knowledge, to report a significant increase in PD-1 expression in NK cells at TKI cessation in patients who do not relapse. Accordingly to recent reports, PD-1 expression is more abundant on NK cells with an activated and more responsive phenotype and does not mark NK cells with an exhausted phenotype. To fully understand how PD-1 on NK cells modulates immune responses we are planning to carry out functional studies. In the future, we are also planning a comprehensive study of immune suppressors, including regulatory T cells and myeloid-derived suppressor cells. Disclosures Moiraghi: Novartis: Speakers Bureau; BMS: Speakers Bureau. Varela:Novartis: Consultancy, Speakers Bureau. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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FINAL Analysis of a PAN European STOP Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI Study

Blood ◽

10.1182/blood-2021-148369 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 633-633

Author(s):

Francois-Xavier Mahon ◽

Johan Richter ◽

Andreas Hochhaus ◽

Panayiotis Panayiotidis ◽

Antonio Medina de Almeida ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Final Analysis ◽

Molecular Response ◽

Molecular Test ◽

Advisory Committees ◽

Free Survival ◽

Tki Treatment

Abstract Background: With the dramatic success of tyrosine kinase inhibitors (TKI) to treat Chronic myeloid leukemia (CML), the life expectancy of CML patients is now close to that of the general population. In addition, treatment cessation is now a realistic goal for some CML patients. This was shown by several clinical trials such as the STIM study leading to the concept of TFR (treatment free remission). Around 40-60% of patients with stable DMR [deep molecular response, corresponding to <0.01% BCR-ABL (IS)] can stop the TKI successfully, e.g. in accordance with recommendations from the European LeukemiaNet. In the interim analysis of the first 200 patients of the EURO-SKI (European Stop TKI) trial, 62% were in major molecular response (MMR: <0.1% BCR-ABL1 IS) at 6 months. DMR duration before TKI stop was most predictive for maintenance of MMR. Here we present the final analysis of the EURO-SKI trial after 3 years of follow-up. Aims: The main objectives of The EURO-SKI trial were the evaluation of molecular recurrence-free survival (MRecFS) after Stopping TKI in a large Pan-european cohort of CML patients and definition of prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims are the evaluation of harmonized methods of molecular monitoring. Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed DMR for at least one year (confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. DMR confirmation was performed in standardized laboratories. Primary endpoint was maintenance of MMR after stopping TKI. According to protocol, a 36 months follow-up was planned. The null hypotheses were that MMR maintenance at 6 and 36 months was less or equal than 40% and less or equal than 35%, respectively. Results: Between May 2012 and December 2014, 868 patients were pre-registered by 61 centers from 11 countries. 140 pts were excluded (consent withdrawal n=1, protocol violation n=38, not eligible n=74, DMR not confirmed n=11, atypical/unknown transcript n=15, missing data n=1) resulting in 728 eligible patents. Of these, 46.8% were female. Median age at diagnosis was 52 years (range, 11 to 85 years). Median duration of TKI treatment was 7.5 years (range, 3.0-14.1 years) and median duration of MR4 before TKI cessation was 4.7 years (range, 1.0-13.3 years). Nine patients died without MMR loss (none CML related), 15 patients restarted TKI without MMR loss. At 6 months, 713 patients were available (without molecular test at 6 months: n=6, TKI restart without relapse: n=9). Since 434 patients (61%) [95% CI: 57-64] remained without relapse during the first 6 months, the null hypothesis was rejected (p<0.0001). At 36 months, 678 patients could be analyzed (TKI restart without relapse: n=17, no molecular test at 36 months: n=33). With 309 patients in MMR, corresponding to 46% [95% CI: 42-49], the null hypothesis of 35% or less was rejected (p<0.0001). MRecFS at 36 months resulted in 48% (CI: 44-52%) and molecular recurrence- and treatment-free survival (MRecTFS) in 46% (CI: 43-50%) (Fig 1). No blast crisis occurred. Regarding prognostic factors, we confirmed that TKI treatment duration and DMR duration were still the most important factors to predict MMR loss at 6 months. For the late recurrence, i.e., between 6 and 36 months (57 patients), TKI treatment duration before stop was the only relevant variable in a preliminary univariate logistic analysis. Summary/Conclusion: With this final analysis of the largest TFR trial, we confirm the MRecFS and MRecTFS rates at 6 months previously obtained from the interim analysis. However, late molecular recurrence (15% between 6 and 36 months) occurred and the underlying mechanisms need to be discussed. Nevertheless, 46% of the patients, were still in MRecTFS at 3 years. Figure 1 Figure 1. Disclosures Hochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Hjorth-Hansen: AOP: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Mustjoki: Novartis: Research Funding; BMS: Research Funding; Janpix: Research Funding; Pfizer: Research Funding. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

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ENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP)

Blood ◽

10.1182/blood.v116.21.207.207 ◽

2010 ◽

Vol 116 (21) ◽

pp. 207-207 ◽

Cited By ~ 18

Author(s):

Timothy P. Hughes ◽

Andreas Hochhaus ◽

Giuseppe Saglio ◽

Dong-Wook Kim ◽

Saengsuree Jootar ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clonal Evolution ◽

Molecular Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Free Survival ◽

Superior Efficacy ◽

Rate Of Progression

Abstract Abstract 207 Background: Results from the phase 3, international, randomized ENESTnd trial have demonstrated the superior efficacy of nilotinib over imatinib with significantly higher rates of major molecular response (MMR), complete cytogenetic response (CCyR), and with significantly lower rates of progression to AP/BC on treatment. Here, we present data with a median follow-up of 18 months. Methods: 846 CML-CP patients were randomized to nilotinib 300 mg twice daily (bid) (n=282), nilotinib 400 mg bid (n=281), and imatinib 400 mg once daily (n=283). Primary endpoint was MMR (≤ 0.1% BCR-ABLIS) rate “at” 12 months, as previously presented. Key secondary endpoint was durable MMR at 24 months. Other endpoints assessed at 24 months include progression to AP/BC (with and without clonal evolution), event-free survival, progression-free survival, and overall survival (OS). Results: With a median follow-up of 18 months, the overall best MMR rate was superior for nilotinib 300 mg bid (66%, P < .0001) and nilotinib 400 mg bid (62%, P < .0001) compared with imatinib (40%). Superior rates of MMR were observed in both nilotinib arms compared with the imatinib arm across all Sokal risk groups (Table). The overall best rate of BCR-ABLIS ≤ 0.0032% (equivalent to complete molecular response, CMR) was superior for nilotinib 300 mg bid (21%, P < .0001) and nilotinib 400 mg bid (17%, P < .0001) compared with imatinib (6%). The overall best CCyR rate was superior for nilotinib 300 mg bid (85%, P < .001) and nilotinib 400 mg bid (82%, P=.017) compared with imatinib (74%). The superior efficacy of nilotinib was further demonstrated using the 2009 European LeukemiaNet (ELN) 12-month milestone in which fewer patients had suboptimal response or treatment failure on nilotinib 300 mg bid (2%, 3%) and nilotinib 400 mg bid (2%, 2%) vs imatinib (11%, 8%). Rates of progression to AP/BC on treatment were significantly lower for nilotinib 300 mg bid (0.7%, P=.006) and nilotinib 400 mg bid (0.4%, P=.003) compared with imatinib (4.2%). The rate of progression on treatment was also significantly lower for nilotinib when including clonal evolution as a criteria for progression (Table). There were fewer CML-related deaths on nilotinib 300 mg bid (n=2), and 400 mg bid (n=1) vs imatinib (n=8). Estimated OS rate (including data from follow-up after discontinuation) at 18 months was higher for nilotinib 300 mg bid (98.5%, P=.28) and nilotinib 400 mg bid (99.3%, P=.03) vs imatinib (96.9%). Both drugs were well-tolerated. Discontinuations due to adverse events or laboratory abnormalities were lowest for nilotinib 300 mg bid (7%) compared with nilotinib 400 mg bid (12%) and imatinib (9%). With longer follow up there has been minimal change in the occurrence of AEs. Minimum 24-month follow-up data for all patients will be presented. Conclusions: With longer follow-up, nilotinib was associated with a significantly lower rate of progression to AP/BC on treatment and lower rates of suboptimal response or treatment failure vs imatinib. Nilotinib resulted in fewer CML-related deaths and a higher OS rate vs imatinib. Nilotinib induced superior rates of MMR, CMR, and CCyR vs imatinib in patients with newly diagnosed CML-CP. Taken together, these data support nilotinib as a new standard of care for patients with newly diagnosed CML. Disclosures: Hughes: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol-Meyers Squibb: Honoraria, Research Funding; Ariad: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. le Coutre:Novartis: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Reiffers:Novartis: Research Funding. Pasquini:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Clark:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Honoraria, Research Funding. Gallagher:Novartis Pharma AG: Employment, Equity Ownership. Hoenekopp:Novartis Pharma AG: Employment. Haque:Novartis: Employment. Larson:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Pfizer: Research Funding.

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Analysis of Transfusion Dependency Development and Disease Evolution in Patients with MDS with 5q- and without Transfusion Needs at Diagnosis

Blood ◽

10.1182/blood.v128.22.3180.3180 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3180-3180

Author(s):

Felix Lopez-Cadenas ◽

Blanca Xicoy ◽

Silvia Rojas P ◽

Kaivers Jennifer ◽

Ulrich Germing ◽

...

Keyword(s):

Multivariate Analysis ◽

Board Of Directors ◽

Research Funding ◽

Statistical Significance ◽

Univariate Analysis ◽

Rank Test ◽

Advisory Committees ◽

Disease Evolution ◽

Free Survival

Abstract Introduction: Myelodysplastic syndrome with del5q (MDSdel5q) is the only cytogenetically defined MDS category recognized by WHO in 2001, 2008 and 2016 and is defined as a MDS with deletion on the long arm of chromosome 5 and less than 5% of blast cells in bone marrow. It is known that for patients with MDSdel5q and transfusion dependence (TD), Len (LEN) is the first choice of treatment. However, data regarding factors that may impact on the development of TD or disease evolution in patients diagnosed without TD are scanty. In our study a retrospective multicenter analysis on patients with low-int 1 MDSdel5q without TD at diagnosis has been performed in order to answer these questions. Patients and methods: We performed a multicenter collaborative research from the Spanish (RESMD) and German MDS registries. Data from 153 low risk MDSdel5q without TD at diagnosis were retrospectively analyzed. Statistical analysis: Data were summarized using median, range, and percentage. The event of TD was defined as the development of TD according to the IWG criteria (2006) and/or the beginning of a treatment which could modify disease course (LEN or ESA). Transfusion or treatment free survival (TFS), overall survival (OS) and leukemia free survival (LFS) were measured from diagnosis to TD or treatment, the first occurred (or to last follow up if none), last follow up or death from any cause and evolution to AML, respectively. TFS, OS and LFS were analyzed using the Kaplan Ð Meier method. The Log-rank test was used to compare variables and their impact on survival for univariate analysis.Multivariate analysis was performed using Cox's proportional hazards regression model. For comparison of Kaplan Meier curves the long rank test was used, with statistical significance with p<0.05. Statistical analysis was performed using SPSS 20.0. Results: Main clinical and biological characteristics were summarizing in table 1. From the total of 153 patients, finally 121 were evaluable. During the study 56 patients (46.2%) became in TD and 47 (38.8%) did not develop TD but received a modified disease course treatment. In this sense, most of the patients developed relevant anemia regarding those data (103 out of 121 patients, 85%). Median time to TD or treatment (TFS) was 20 months (1-132) from diagnosis. Secondary MDS (p=0.02), thrombocytosis (>350 109/L) (p=0.007), and neutropenia (<1.5 x 109/L) (p=0.02) were associated with poorer TFS. Thrombocytosis and neutropenia retained statistical significance in the multivariate analysis (Table 2). Among the TD patients (N=56), 42 (75%) received treatment: 28 LEN, 7 ESA and 7 other treatments. Among patients that did not develop TD (N=65), 47 (72.3%) received treatment before TD development: 16 LEN, 28 ESA and 3 other treatments. In order to know the evolution of these patients, survival analysis was performed. Median follow up was 58.9 months among alive patients and 57% of them were alive at the time of the last follow up. Estimated OS at 2 and 5 years was 94% and 64%. Regarding Univariate analysis, platelet <100 x 109/L (p=0.03), patients older than 71 years (p=0.001), and progression into AML (p=0.02) were associated with poorer OS. On the contrary, patients who had received treatment showed better OS (p<0.0001). This benefit is more evident among patients receiving LEN, median OS for patients receiving LEN, ESA/other treatments and not treated group was 137 months (CI 95%: 59,4 -215,5), 99,3 months (CI 95%: 46,6 -152) and 57,9 months (CI 95%: 38,2 -77,6), respectively, p<0.0001 (Figure 1). In the multivariate analysis, patients older than 71 years and LEN treatment retained the statistical significant impact on OS (Table 2). Twenty-eight patients (23%) progressed into AML, median time to AML was 35 months (5-122). When univariate analysis was performed, variables with adverse impact on LFS were platelets <100 x 109/L(p=0.019), neutropenia < 0.8 x 109/L (p=0.026), an additional cytogenetic abnormality (p=0.013) while treatment with LEN had a favorable impact (p=0.035). In the multivariate analysis only the presence of additional cytogenetic abnormalities retained statistical significance (Table 2). CONCLUSIONS: Most of the patients with low risk del(5q) MDS and no TD at diagnosis developed symptomatic anemia very early after diagnosis (20 months). Carefully monitoring should be stablished in order to detect this time point. Outcome of this subset of patients could improve after target therapy. Figure 1 Figure 1. Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees. Díez Campelo:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees.

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Single UM171 Expanded Cord Blood Permits Transplantation of Better HLA Matched Cords with Excellent Gvhd Relapse Free Survival

Blood ◽

10.1182/blood-2018-99-110188 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4658-4658 ◽

Cited By ~ 2

Author(s):

Sandra Cohen ◽

Jean Roy ◽

Silvy Lachance ◽

Anne Marinier ◽

Jean-Sébastien Delisle ◽

...

Keyword(s):

Board Of Directors ◽

Culture System ◽

Research Funding ◽

Chronic Gvhd ◽

Relapse Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Cell Dose ◽

Equity Ownership

Abstract Cord blood (CB) transplants have fallen into disfavor in large part due to low cell dose leading to prolonged hospitalizations and high transplant related mortality (TRM). UM171, a novel and potent agonist of hematopoietic stem cell (HSC) self-renewal could solve this major limitation, allowing for CB's important qualities of lower risk of chronic GVHD and relapse to prevail. In addition, UM171 could permit transplantation of smaller, better HLA matched cords, associated with lower TRM. Hence, we initiated a clinical trial to test the safety and efficacy of UM171 expanded CB (eCB). Our goal was to design a clinically viable eCB transplant with a TRM as low or lower than other HSC sources all the while maintaining CB's low relapse rate. Patients (pts) received a myeloablative conditioning regimen. On day (D)-7 of transplant, CB was thawed and CD34+ selected. The CD34- lymphocyte containing fraction was cryopreserved and infused on D+1. The CD34+ component was placed in a closed culture system with UM171 and media was injected once a day until D0, when cells were washed and infused. This fed-batch culture system allowed for small culture volumes, saving cost and labor. Between 7/16-6/18, 21 adult pts (median age 44 years) were transplanted with an eCB. Median final culture volume and net viable CD34 fold expansion were 670 mL and 35, respectively. Median 1st day of 100 and 500 neutrophils were D+10 and D+18, respectively. Achieving 100 neutrophils was 5 days faster than seen with our pts receiving peripheral blood (PB) or marrow (BM) and appeared cell dose independent, suggesting that clinically meaningful expansion of an early repopulating myeloid progenitor is at saturation even with smaller CBs. In contrast, attaining 500 neutrophils was accelerated but dependent on cell dose. More importantly, pts appeared to derive clinical benefit beyond neutrophil engraftment (defined as 500 neutrophils). Pts' median last day of fever prior to 500 neutrophils was D+8, much earlier than engraftment and 4 days earlier than seen with our PB-BM pts. We offer 2 hypotheses as explanation: i) 100 neutrophils, which are attained early, provide significant defense against infection, ii) the graft contains a significant proportion of dendritic cell precursors (30-40%) which offer mucosal protection during severe neutropenia. Duration of hospitalization was shorter by 12 days and longer by 2 days compared to our non eCB and PB-BM transplants, respectively. In addition, because cell dose requirements were lower, 12/21 pts received a better HLA matched CB, thus >80% of patients were transplanted with a ≥6/8 HLA matched eCB. As a result of lower minimal cell dose criteria, we can now use ∼half the CBs in the banks instead of only 5% for a 70 kg patient. Platelet engraftment occurred at a median of 42 days. With a median follow up of 14 months, there has been no CMV disease, no PTLD, 2 adenovirus cystitis, 2 (10%) grade 3-4 acute GVHD, no moderate/severe chronic GVHD and 1 TRM (5%) despite a median comorbidity index of 2 (0-5). Full donor chimerism was achieved in all cell subsets. Immune recovery was faster than seen in our unrelated donor transplants who routinely receive ATG prophylaxis with 196, 300 and 413 CD4+/µL at 3, 6 and 12 months, respectively. Interestingly, transcriptome analysis of UM171-eCB cells shows an enhanced lymphoid progenitor-associated gene signature when compared to DMSO exposed cells. Animals transplanted with UM171-eCB cells showed a 20 to 35-fold increase in thymic cellularity at 8 weeks post-transplant. Despite some very high risk pts in our trial, only 3 relapsed. Overall, progression free, and GVHD/relapse free survival (GRFS) are excellent at 95, 77 and 67%, respectively, at 12 months. A 7 day UM171 single eCB protocol is feasible and provides clinical benefits beyond faster engraftment with fewer infectious complications, better HLA matching and very low TRM, all the while saving production and hospitalization costs. Nevertheless, longer follow up will be required to better assess relapse howbeit encouraging preliminary results. Furthermore, patients' quality of life is paramount and best evaluated by GRFS which is excellent thanks to a very low rate of significant chronic GVHD all the while maintaining a low risk of relapse. In conclusion, this 1st trial documents the potency of UM171 and positions UM171-eCB as a promising HSC source which could compete with the current standard of care. Figure. Figure. Disclosures Cohen: ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Lachance:ExCellThera: Patents & Royalties: Royalities from sales of UM171. Roy:Hopital Maisonneuve Rosemont: Patents & Royalties: Author on patent; Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent. Busque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy. Kiss:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees, Research Funding. Caudrelier:ExCellThera: Employment. Zandstra:ExCellThera: Equity Ownership. Sauvageau:ExCellThera: Employment, Equity Ownership.

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Administration of BPX-501 Cells Following Aβ T and B-Cell-Depleted HLA Haploidentical HSCT (haplo-HSCT) in Children with Acute Leukemias

Blood ◽

10.1182/blood-2018-99-119481 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 307-307 ◽

Cited By ~ 2

Author(s):

Franco Locatelli ◽

Annalisa Ruggeri ◽

Pietro Merli ◽

Swati Naik ◽

Rajni Agarwal ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Pediatric Patients ◽

Unrelated Donor ◽

Relapse Free Survival ◽

Advisory Committees ◽

Steroid Resistant ◽

Free Survival ◽

Equity Ownership

Abstract Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established treatment for children with Acute Leukemia (AL). For patients lacking a compatible matched related or unrelated donor, HLA-haploidentical HSCT (haplo-HSCT) from a relative represents a viable alternative. Promising results were reported with a novel method of selective depletion of αβ T and B cells (Locatelli, Blood 2017). This approach is associated with limitations such as suboptimal adaptive immune reconstitution, increased risk of infection and disease relapse. BPX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of BPX-501 following transplant. The polyclonal nature of the BPX-501 provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid which induces dimerization and activation of iC9, inducing apoptosis of BPX-501. Aims To evaluate the safety and efficacy of BPX-501 administered after a αβ T and B-cell depleted haplo-HSCT in pediatric patients with AL in morphological complete remission (CR). The objective was to determine whether BPX-501 infusion can increase relapse-free survival (RFS) and overall survival (OS) through an enhanced graft-versus-leukemic (GvL) effect, while maintaining a low risk of GvHD. Methods This multicenter US (NCT03301168) and EU (NCT02065869), prospective trial utilizes αβ-T and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified with iC9 safety switch (BPX-501) in patients with malignant or non-malignant disorders. A subset of patients had acute high-risk leukemias (AML and ALL). BPX-501 was planned to be infused on day14±4 after the allograft. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy could receive ≥1 dose of rimiducid to activate iC9. The efficacy-evaluable population (EEP) was defined as any patient with AL who received HSCT, BPX-501 infusion, and at least one follow-up assessment. Results At clinical cut-off (June 30, 2018), 100 patients (EU: 75, US: 25) with AL met the EEP definition. Median follow-up was 14.7 mos (1 - 40.6 mos). Key baseline characteristics are shown in Table 1. The median time for neutrophil and platelet engraftment was 16 (15 - 17) and 12 (11 - 12) days, respectively. Four patients (4.1% [95% CI: 0 - 8%]) experienced primary graft failure. Of 96 evaluable patients, 21 patients developed Grade I-IV aGvHD (21.7% [95% CI: 13.5 - 29.8%]). Five patients developed Grade III-IV aGvHD (3.1% [95% CI: 0 - 6.5%]). Of 82 evaluable patients, 12 patients developed cGvHD (18.1% [95% CI: 8.2 - 22%]), with only three cases being moderate-severe. Rimiducid was administered to 10 patients with steroid-resistant acute GvHD. Best overall clinical response of CR or PR post-rimiducid administration was seen in 8 patients (80%). Among responding patients, 7 patients (87.5%) had a CR. Six patients died after transplantation (6.6% [95% CI: 1.4 - 11.7%]). Relapse Free Survival (RFS) was 82.2% (95% CI: 74.5 - 89.7%). Overall Survival (OS) was 90.1% (95% CI: 83.9 - 96.3%). Efficacy outcomes (TRM, RFS and OS) in AL subsets (AML and ALL) are shown in Table 2. CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 270 days, respectively. IgA and IgM levels achieved normal values by 180 days. The percentage of circulating and median absolute BPX-501 cells at Day 100 were 9.96% ± 11.6% (0 - 54.9%) and 85.58 ± 165.57 cells/ul (0 - 1001 cells/ml), respectively. Conclusion The adoptive transfer of BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a novel and highly effective transplantation strategy for pediatric patients with AL. Compared to data from children receiving only αβ T and B-cell depleted haplo-HSCT or matched unrelated donor HSCT (https://bloodcell.transplant.hrsa.gov/research/transplant_data/us_tx_data/survival_data/survival.aspx), this novel approach resulted in a comparable risk of transplant-related mortality and a lower risk of recurrence. Rimiducid was also an effective treatment for patients who developed steroid-resistant GvHD. Disclosures Locatelli: bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Qasim:Orchard: Equity Ownership; Autolus: Equity Ownership; Servier: Research Funding; Bellicum: Research Funding. Nemecek:Novartis Pharmaceuticals Corporation: Other: advisory boards.

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Real World Efficacy Evaluation of Branded and Copy Imatinib in Chronic Myeloid Leukemia: A Retrospective Multicentric Study from Argentina

Blood ◽

10.1182/blood-2020-137792 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Ana Ines Varela ◽

Georgina Bendek ◽

Carolina Pavlovsky ◽

Maria Josefina Freitas ◽

Veronica Ventriglia ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Molecular Response ◽

Advisory Committees ◽

Free Survival ◽

Safety And Efficacy ◽

Kaplan Meier ◽

Sokal Score

Background: Data on the safety and efficacy of copy drugs is usually unavailable. Imatinib mesylate is used to treat chronic myeloid leukemia (CML) patients in Argentina since 2002. During the last decade more than ten different imatinib copies are marketed by the different health-care systems in the country, usually for cost issues. In spite of the undoubted benefit of this tyrosine-kinase inhibitor indication in CML, there is no solid evidence that supports copy drug equivalent outcomes for this patient population. Aim: To compare the clinical presentation, treatment response and outcome of a chronic phase (CP) CML patient cohort treated with branded and copy imatinib in the real-life setting. Methods: Multicentric, retrospective trial based on data obtained from medical charts of adult CP CML patients treated with imatinib in 9 centers in Argentina from 2002 to 2020.We analyzed demographic characteristics and clinical characteristics described for branded and copy imatinib treated cohorts. Frequency of complete cytogenetic response (CCyR) at 12 months, Major molecular response or better(≥MMR) at 12, 18 and 24 months and overall MR4.0, MR4.5 and deep molecular response (MR4.0 +MR4.5 IS) were analyzed. Event was defined as failure, progression or CML related death. Kaplan Meier comparison of event free, progression free and overall survival. Statistics: IBM SPSS version 1. Results: A total of 568 CP CML adult patients (pt) treated with imatinib were included. Mean age at diagnosis: 45.7 years (range 18 - 85). Male 55.6% (316/568). Sokal Score was recorded in 471 pt: 57% (269/471) low, 26% (122/471) intermediate and 17% (80/471) high-risk. Median follow-up 107 months (RIQ: 36-149). Branded imatinib treatment 330 (58%) and imatinib copies 238 (42%). For branded and copy imatinib cohorts mean age 46,1 (18-85) and 45.3(18-80), male 53% (175/330) and 59% (141/238), median follow up 102 (RIQ 101-130) and 61 (RIQ 62-146) respectively. Sokal score low 58% (164/284) and 56% (105/187), intermediate 27% (77/284) and 24% (45/187) and high 15% (43/284) and19% (37/187). Frequency of CCyR at 12 months 71% (67/94) and 69% (41/59), ≥MMR at 12 months 57% (79/138) and 43% (39/89), ≥MMR 18m 66 % (61/92) and 71% (43/60), ≥MMR 24m 65% (96/147) and 79% (58/73). Overall MR4, MR 4.5 and Deep MR with branded imatinib 62.4% (186/298), 42% (118/276) and 63% (189/300), compared to 45(97/214), 24% (50/207) and 46% (99/215) with copies. Difference in evaluation throughout the treatment periods with loss of data did not allow response rate statistical comparison in predetermined timepoints. Kaplan Meier Event free survival median 229 months vs 75 months p 0.001, Progression free survival mean 318 months vs 208 pt 0.034 and Overall Survival mean 275 months vs 206 months for branded and copy imatinib respectively. Discussion: Several case reports have shown poor outcomes in patients treated with imatinib copy drugs, including loss of responses previously attained with branded imatinib. This study reports data from a large cohort of CP CML patients treated in daily practice during a long period of time. Treatment results at determined timepoints is comparable. Although management and treatment decisions were performed in different time periods, results show different outcomes in EFS and PFS between patients treated with branded vs copy imatinib. Overall survival in both cohorts is comparable. As studies assesing the safety and efficacy of the copy drugs compared with branded imatinib will hardly be performed this evidence calls for careful attention and strict follow up measures when managing CML patients with copy imatinib. Figure Disclosures Varela: Novartis: Consultancy, Speakers Bureau. Pavlovsky:Pint Pharma: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Freitas:Pfizer: Consultancy, Other: Advisory Board. Pavlovsky:Varifarma: Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau. Moiraghi:Novartis: Speakers Bureau; BMS: Speakers Bureau.

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Deep Molecular Response in Imatinib First-Line 418 Newly Diagnosed CP CML Patients.

Blood ◽

10.1182/blood-2018-99-113044 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3014-3014

Author(s):

Franck Emmanuel Nicolini ◽

Vincent Alcazer ◽

Pascale Cony-Makhoul ◽

Stephanie Dulucq ◽

Sandrine Hayette ◽

...

Keyword(s):

Board Of Directors ◽

Univariate Analysis ◽

Molecular Response ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Free Survival ◽

Deep Molecular Response ◽

Chi2 Test

Abstract Introduction Deep molecular response (DMR) are now highly desirable goals in the treatment of CP-CML, especially in the front-line setting, because it can lead to a definitive treatment-free remission (TFR). However, such a goal is difficult to attain and does not concern the majority of patients (pts), but currently the precise number of pts able to access to TFR is unknown. Aims We aim to determine the number or newly diagnosed CP-CML pts reaching DMR, stable DMR, and access to TFR, on Imatinib (IM, Glivec®) first-line. Methods We retrospectively analyzed in an observational study, a cohort of newly diagnosed CP-CML pts treated with IM first-line 400 mg daily alone in our 3 reference centers between 2000→2018. All pts were followed according to the ELN recommendations 2006, 2010 and 2013. Clinical data were extracted from medical files, and responses (hematologic, cytogenetic, molecular) were analysed according to standard methods. Molecular results were standardised according to the ELN/Eutos programs since 2003, and were all expressed as BCR-ABLIS in %. DMR have been defined according to the ELN (NCP. Cross et al., Leukemia 2015). Stability of DMR has been defined as a stable if ≥2 years at least on 4 datapoints. TFR has been proposed to pts presenting the only current recommended criteria: MR4.5 ≥2 years at least on 4 datapoints [(Rea et al., Cancer 2018)], in the 3 centers involved, within clinical trials, pioneered in our country, or now as a clinical routine recommendation. Loss of MMR was the trigger for TKI resumption after IM cessation for TFR. Overall survival (OS), progression-free survival (PFS), failure-free survival (FFS, defined as progression to advanced phases death, loss of CHR, CCyR, or MMR, discontinuation of IM for toxicity, primary cytogenetic resistance) were analysed since IM initiation in intention-to-treat. Results Four hundred and eighteen pts have been included in this study, with a median age of 60.7 (48-70) years at diagnosis, with 57% males and 43% females. Sokal score (n=401) was low in 32%, intermediate in 51% and high in 17%. ACA were present at diagnosis in 5.5% of the pts (NA in 1.44%). Major BCR transcripts were found in 98% of pts, and atypical transcripts in 1.9%. CHR was reached in a median of 1 (0.85 to 1.64) month of IM, <10% BCR-ABL transcript (IS) level at 3 months was found in 81% of the pts, and only 9.5% of pts were in MMR at 3 months. The median follow-up after IM initiation is 77.4 (0.9-231.5) months, 125 (30%) pts have switched to TKI2 for IM resistance or intolerance. Overall, 252 (60%) pts reached MR4, 127 (30%) stable MR4, 170 (41%) MR4.5, and 82 (20%) stable MR4.5. The median time on TKI necessary for obtaining stable MR4.5 is 15.6 (5.9-28) months. The cumulative incidence of MR4.5 at 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months were 12.5%, 23.4%, 31.6%, 36.72%, 43.55%, 48.7%, 48.3%, 52.98%, 54.03%, 59.18% respectively (Figure 1A.). The cumulative incidence of stable MR4.5 at 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 months were 5.76%, 11.5%, 17.83%, 21.82%, 26.35%, 28.13%, 28.13%, 29.13%, 29.13%, 29.13% respectively (See figure 1B.). Seventeen (13%) and 10 (12%) pts have switched IM→TKI2 before obtaining a stable MR4 and a stable MR4.5 respectively. Overall, 41 (10%) pts have reached the TFR criteria and stopped their TKI and 23 (56%) never lost their MMR after cessation, with a median follow-up of 41.7 (9.4-121.8) months. In an univariate analysis, only gender (female vs male, 39% vs 61% for no MR4.5 and 53.66% vs 46.34% for stable MR4.5, p=0.028, Pearson's CHI2 test), and MMR at 3 months (yes vs no, 3.74% vs 96.26% for no MR4.5 and 17.46% vs 82.54% for stable MR4.5, p<0.001, Pearson's CHI2 test) were identified variables impacting on stable MR4.5. A multivariate analysis could not be performed on so few discriminant factors identified in the univariate analysis. Conclusions Only 42 out 418 (10%) of the newly diagnosed CP-CML pts on IM first-line in our study reach the TFR criteria we recommended, and only 22 over 418 pts (5%)will finally definitively stop any TKI durably within the limits of this retrospective observational study. Urgent strategies in order to increase the access to definitive TFR are needed. Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Incyte Biosciences: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; Incyte: Other: Travels for attending to Congress; Novartis: Consultancy, Other: Writing support, Travels for attending to Congress. Dulucq:BMS: Consultancy; Incyte: Consultancy. Hayette:Incyte: Consultancy. Mahon:BMS: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Incyte: Speakers Bureau. Etienne:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau.

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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 ◽

10.1182/blood.v122.21.258.258 ◽

2013 ◽

Vol 122 (21) ◽

pp. 258-258 ◽

Cited By ~ 2

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.

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