scholarly journals 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 ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4253-4253 ◽  
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.

Excellent Outcomes at 3 Years with Nilotinib 800 Mg Daily In Early Chronic Phase, Ph+ Chronic Myeloid Leukemia (CML): Results of a Phase 2 GIMEMA CML WP Clinical Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 359-359 ◽  
Author(s):  
Gianantonio Rosti ◽  
Fausto Castagnetti ◽  
Gabriele Gugliotta ◽  
Massimo Breccia ◽  
Luciano Levato ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Phase 2 ◽  
Advisory Committees ◽  
Free Survival ◽  
Daily Dose ◽  
Cumulative Rate

Abstract Abstract 359 Background: Nilotinib is a potent and selective inhibitor of BCR-ABL. In the phase 3 ENESTnd trial, nilotinib demonstrated superior efficacy to imatinib with higher and faster molecular responses. With a median follow-up of 18.5 months (ASCO/EHA 2010), the rates of progression to accelerated or blast phase (AP/BC) were 0.7% and 0.4% with nilotinib 300 mg and 400 mg BID, respectively, and significantly lower in comparison to imatinib (4.2% P = .006 and .003, respectively). Based on the results of the ENESTnd trial, nilotinib has been approved (FDA) for the frontline treatment of Ph+ CML. With imatinib 400 mg (IRIS trial), the rate of any event and the rate of progression to AP/BC were higher during the first 3 years on treatment (15.6% and 6.1%, respectively). Consequently, a confirmation of the durability of nilotinib responses at 3 years is extremely important. Aims: To evaluate responses (either cytogenetic and molecular) and to investigate outcomes of patients treated for 3-years with nilotinib 400 mg BID as frontline therapy. Outcomes evaluated include Overall Survival (OS), Progression-Free Survival (PFS), Failure-Free Survival (FFS) and Event-Free Survival (EFS). Method: A multicentre phase 2 trial (nilotinib 400 mg BID) was conducted by the GIMEMA CML Working Party (ClinicalTrials.gov.NCT00481052). The median follow-up is currently 30 months (3 years by November 2010). Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio < 0,1% IS; Complete Molecular Response (CMR): undetectable transcript levels and nested PCR negative; failures: no CHR at 3 months, no CgR at 6 months, no PCgR at 1 year, no CCgR at 18 months, loss CHR or CCgR, progression and death (according to the revised European LeukemiaNet recommendations); events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-to-treat principle. Result: 73 patients have been enrolled; median age 51 years (range 18–83); 45% low, 41% intermediate and 14% high Sokal risk. The cumulative CCgR rate (primary endpoint) at 12 months was 100%. CCgR at each milestone: 78% at 3 months, 96% at 6, 12 and 18 months, 92% at 24 months. The cumulative rate of MMR was 96%, while the rates of MMR at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. The cumulative rate of CMR was 41%, while the rates of CMR at 12 and 24 months were 7% and 12%, respectively. None of the patients who achieved a MMR progressed to AP/BC. Only one patient progressed at 6 months to AP/BC: a 63 years old female with a high Sokal risk disease in CCgR at 3 months, who developed a T315I mutation. During the first 12 months, the mean daily dose was 600–800 mg, 400–599 mg, and less than 400 mg in 74%, 18% and 8% of patients, respectively. The nilotinib last daily dose was as follows: 800 mg in 48 (71%) patients, 400 mg in 19 (28%) patients and 200 mg in 1 (1%) patient. Adverse events (AEs) were mostly grade 1 or 2 and manageable with appropriate dose adaptations. Two patients (3%) showed a prolongation of the QTcF above 450 msec (none above 50 msec). Four events lead to permanent discontinuation of nilotinib: 3 patients discontinued after 9, 15 and 27 months on treatment for recurrent episodes of amylase and/or lipase increase (no pancreatitis) and 1 patient after 25 months due to atrial fibrillation, unrelated to study drug. Three of them are currently on imatinib second-line and 1 on dasatinib third-line. Overall, 5 events have been recorded so far (1 progression to AB/BC and 4 permanent discontinuation of nilotinib due to AEs). At 30 months the OS, PFS and FFS are 99% and the EFS is 92%. Conclusion: The rate of failures was very low during the first 3 years. Responses remain stable. The very high rates of responses achieved during the first 12 months on treatment are being translated into optimal outcome for most of the patients. Acknowledgments: European LeukemiaNet, COFIN, Bologna University, BolognAIL Disclosures: Rosti: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau. Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Gugliotta:Novartis: Honoraria. Saglio:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Martinelli:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; pfizer: Consultancy. Baccarani:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding.

Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1125-1125 ◽  
Author(s):  
Michael P Osborn ◽  
Susan Branford ◽  
Deborah L White ◽  
John F Seymour ◽  
Ruth Columbus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Event Rates

Abstract Abstract 1125 Poster Board I-147 The Australasian Leukaemia and Lymphoma Group conducted a trial (TIDEL I) in 103 patients with newly diagnosed chronic phase CML, using imatinib 600 mg/day with dose escalation to 800 mg/day for suboptimal response. This was defined as failure to achieve (1) complete haematological response (CHR) at 3 months, (2) major cytogenetic response (MCR) at 6 months, (3) complete cytogenetic response (CCR) or molecular equivalent at 9 months, or (4) less than 0.01% (IS) BCR-ABL by RQ-PCR at 12 months. Here we report the outcomes with all surviving patients having been treated for at least 60 months. We aimed to determine whether the patient outcome at 60 months was predicted by the molecular response within the first 18 months of imatinib therapy. The outcomes for patients maintaining a dose of imatinib of ≥600 mg/day in the first 12 months was compared to those who were on a reduced dose for at least part of this time. Event-free survival (EFS) was defined as death from any cause, accelerated phase/blast crisis (AP/BC), and loss of CHR, MCR or CCR. The 103 patients included 66 males and 37 females with a median (±SD) age of 49 (±14) years. All patients had an ECOG performance status of 0-2 at enrolment. The 5-year EFS was 71%, transformation (AP/BC) free survival (TFS) was 95%, and overall survival was 87%. Of the 14 patients who died, 3 died in blast crisis, 2 from transplant-related complications, 8 from CML-unrelated causes, and the cause of death of 1 patient was unavailable. The annual rates of progression to AP/BC over 5 years were 3%, 1%, 0%, 1%, and 0%, while annual event rates were 13%, 8%, 8%, 1%, and 4%. CCR was achieved by 89% of patients by 60 months, while 72% achieved a major molecular response (MMR) by this time. In the first 12 months of treatment, 55% of patients maintained an imatinib dose of ≥600 mg/day (mean ±SD dose = 604 ±10 mg/day), while 45% were on <600 mg/day for at least part of this time (mean ±SD dose = 511 ±100 mg/day). EFS at 60 months was significantly higher in patients taking ≥600 mg/day compared with those who had been dose-reduced to <600 mg/day (89% vs 56%, P<0.001). Annual event rates for the ≥600 mg/day group were 6%, 2%, 2%, 0%, and 2%, while annual event rates for those on <600 mg/day were 14%, 16%, 16%, 8%, and 4%. By 60 months, 96% of patients who had been on ≥600 mg/day within the first 12 months had achieved CCR, while only 80% of those who had been on <600 mg/day had achieved this milestone (P<0.001). Log rank analysis of the achievement of MMR was also significant (P=0.03). Overall survival and TFS after 12 months were both similar between the dosing groups. There was no difference between the dosing groups' median age (50 vs 48 years, P=0.36) or Sokal score (1.04 vs 0.94, P=0.33) that may otherwise account for these results. The outcome was also determined for all patients dependent on the BCR-ABL levels at various assessment timepoints. Patients with a BCR-ABL level of <10% (IS) at 6 months (n=92) had an EFS of 78% at 60 months, while all of those with a level >10% (IS) (n=8) had an event (P<0.001). Patients with a level of ≤1% (IS) at 12 months (equivalent to CCR) (n=81) had an EFS of 75% compared with 25% (n=13) for those with levels >1% (IS) (P<0.001). At 18 months, a level ≤0.1% (IS) (n=58) conferred an EFS of 88%, while those who had failed to attain this depth of response (n=30) had an EFS of 60%. There was a significant difference in EFS between those who had achieved an MMR at 18 months and those who had achieved a CCR, but no MMR (88% vs 67%, P=0.03). In conclusion, our data suggest that patients maintaining a dose of ≥600mg in the first 12 months of imatinib therapy are more likely to achieve CCR and MMR, and superior EFS compared to those with a lower dose. This study also confirms that achieving an MMR by 18 months is associated with improved EFS. This emphasises the value of achieving a molecular response early in the treatment course, as well as adding weight to the evidence supporting the role of molecular monitoring in CML. Disclosures Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis and Britol-Myers Squibb: Research Funding. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Catalano:Roche: Honoraria, Research Funding, Travel grants. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

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

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 207-207 ◽  
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.

Pegylated Interferon-Alpha 2a in Combination with Nilotinib As First-Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (Nilopeg trial). Four-Year Follow-up Results

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1578-1578 ◽  
Author(s):  
Franck E. Nicolini ◽  
Gabriel Etienne ◽  
Viviane Dubruille ◽  
Lydia Roy ◽  
Françoise Huguet ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Phase ◽  
Pegylated Interferon ◽  
Molecular Response ◽  
Advisory Committees ◽  
Molecular Responses ◽  
Log Reduction

Abstract Background & aims In the Nilopeg trial (EudraCT 2010-019786-28), we have previously demonstrated that the combination of nilotinib (Tasigna® Novartis), a second generation inihibitor (TKI2), combined to pegylated interferon-alpha 2a (Peg-IFN, Pegasys®, Roche) in de novo chronic phase chronic myeloid leukemia (CP-CML) patients is able to induce high rates of molecular responses with an acceptable additional toxicity (F. E. Nicolini et al. Lancet Haematology 2015) within 24 months of follow-up. We report here the ≥4-year follow-up of such patients for toxicity and efficacy. Methods In a phase 2 study, newly diagnosed CP-CML patients were assigned to a priming strategy by Peg-IFN (± HU) for a month at 90 mg/wk, prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 micro.g/wk for ≥ 1 year, maximum 2 years. After 2 years nilotinib was continued alone. The primary endpoint was the rate of confirmed molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in % for 2 years and then performed in each center [all expressed in % on the international scale (IS)]. All data presented here are in intention-to-treat. Events were defined as death, progression to AP or BC, failure on nilotinib or nilotinib treatment discontinuation for any cause excluding treatment-free remission (TFR). Results Fourty-two patients were enrolled in this trial (one withdrawn its consent prior to treatment initiation), and the median follow-up is now 50.7 (47.8-52.8) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. The median age at treatment initiation was 53 (23-85) years, 2 patients had a masked Philadelphia chromosome, 3 a variant form, and 1 additional chromosomal abnormalities, all patients had "major" BCR-ABL1 transcripts. The rates of Complete Cytogenetic Responses (CCyR) at "6", and "12" months of combination (i. e. at 5 and 11 months of TKI2) were 71%, and 100% respectively. Eighty seven percent of patients had a BCR-ABLIS ≤10% at M3 (i. e. after 2 months TKI). The rates of molecular responses respectively at 12, 24, 36 and 48 months were 76%, 78%, 83%, 73% for MMR, 51%, 58.5%, 66%, 58.5% for 4 log reduction (MR4), 17%, 34%, 34%, 44% for 4.5 log reduction (MR4.5), 12%, 32%, 29%, 41.5% for ≥5 log reduction (MR5), shown as cumulative incidence curves for MR4.5 in figure 1. The median doses of Peg-IFN delivered to the patients during the first year were 45 (0-45) micro.g/wk, and for nilotinib 600 (300-600) mg daily. Interestingly, logistic regression analysis adjusted on MR4.5 responses showed a significant relationship with the mean doses of Peg-IFN delivered to the patients at 12 months (p=0.003, OR = 1.09 [1.03-1.16]), 24 months (p=0.005, OR = 1.08 [1.02-1.14]) and 48 months (p=0.024, OR = 1.09 [1.01-1.17], but not with the mean doses of nilotinib [p=0.84, OR = 0.99 [0.99-1.01], p=0.087, OR = 1 [0.99-1.01], and p=0.88, OR = 1 [0.99-1.01] respectively. Eight patients (19.5%) were in TFR for a median of 6.8 (0.5-9.5) months after 2-year consecutive MR4.5, and none lost MMR yet at last follow-up. One patient died of progression (unmutated myeloid blast crisis at M6, who relapsed after unrelated allogeneic stem cell transplantation). There was no additional grade 3-4 hematologic or biochemical toxicities occurring after 24 months. At last follow-up 10 patients switched for another TKI (2 for dasatinib, 5 for imatinib, and 3 for imatinib followed by dasatinib), for unsufficient cytogenetic or molecular response (2 patients) or for toxicity (7 patients). Overall, 4 patients presented some cardio-vascular events 3 coronary stenoses, one brain stroke). Conclusion Despite additional initial toxicities Peg-IFN priming strategy, followed by the combination of nilotinib and Peg-IFN during the first year induces very high rates of durable deep molecular responses (MR4 and MR4.5) at later time-points, offering TFR for number of patients. To date, no emerging severe adverse events occurred. However, to confirm these promising results, a randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is absolutely warranted and in progress. Figure 1. Cumulative incidence of MR4.5 Figure 1. Cumulative incidence of MR4.5 Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Huguet:Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; PFIZER: Consultancy, Speakers Bureau. Legros:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Rea:Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Amé:BMS: Speakers Bureau; Novartis: Speakers Bureau. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis: Speakers Bureau; BMS: Speakers Bureau. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Mahon:ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria.

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

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4658-4658 ◽  
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.

Nilotinib Versus Imatinib in Patients (pts) with Newly Diagnosed Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENESTnd 36-Month (mo) Follow-up

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 452-452 ◽  
Author(s):  
Giuseppe Saglio ◽  
Philipp D. LeCoutre ◽  
Ricardo Pasquini ◽  
Saengsuree Jootar ◽  
Hirohisa Nakamae ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Safety Data ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Abstract 452FN2 Background: In ENESTnd, pts treated with nilotinib demonstrated higher and faster rates of major molecular response (MMR, ≤ 0.1% BCR-ABLIS), deeper molecular response (MR4, ≤ 0.01%IS and MR4.5, ≤ 0.0032%IS), and complete cytogenetic responses (CCyR) along with significantly lower rates of progression to AP/BC and fewer CML-related deaths compared with imatinib by 12 and 24 mo. Here, we report data with a minimum follow-up of 24 mo; however, efficacy and safety data based on considerably longer follow-up of ≥ 36 mo will be presented. As demonstrated in IRIS and other imatinib trials, most pts who progress on imatinib do so within the first 3 years of therapy. Thus, this 36-mo update of ENESTnd will be important to further verify the benefits of nilotinib in newly-diagnosed pts. Methods: 846 adult pts with newly-diagnosed Ph+ CML-CP were randomized to nilotinib 300 mg twice daily (BID) (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg once daily (QD) (n = 283). MMR, MR4, MR4.5, time to progression to AP/BC on treatment, progression-free survival (PFS) on treatment, and overall survival (OS) were evaluated. Results: By 24 mo, both doses of nilotinib demonstrated significantly higher rates of MMR, MR4, and MR4.5 vs imatinib (Table). Nilotinib-treated pts achieved median BCR-ABLIS levels of 0.09% (300 mg BID) and 0.10% (400 mg BID) by 12 mo, while this level of reduction was not observed before 24 mo on imatinib. More pts with CCyR achieved MMR at 12 and 24 mo with either dose of nilotinib vs imatinib (Table). Regardless of Sokal risk, rates of MMR and MR4.5 were higher for nilotinib at both doses vs imatinib (Table). Progression to AP/BC (excluding clonal evolution [CE]) on treatment was significantly lower for nilotinib vs imatinib (2 pts and 3 pts with nilotinib 300 mg BID [P = .0059] and 400 mg BID [P =.0196]), respectively vs 12 pts with imatinib). After achieving CCyR, 4 pts treated with imatinib progressed to AP/BC and 2 pts treated with nilotinib 400 mg BID progressed after achieving both CCyR and MMR (1 also achieved MR4). No pt who achieved MR4.5 progressed at any time. All but 1 pt who progressed to AP/BC on treatment were in the intermediate and high Sokal risk groups; 1 pt treated with nilotinib 400 mg BID progressed in the low Sokal risk group who had an E255V mutation at progression. When considering progression events of pts after discontinuation of treatment, an additional 7, 2, and 6 events (excluding CE) were observed with nilotinib 300 mg BID, nilotinib 400 mg BID and imatinib, respectively. Twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10 on 300 mg BID; n = 8 on 400 mg BID). At 24 mo, OS remained similar in all groups, but there were fewer CML-related deaths in both nilotinib 300 mg BID (5 pts) and nilotinib 400 mg BID (3 pts) arms vs imatinib (10 pts). Both drugs were well tolerated and few new adverse events (AEs) and lab abnormalities were observed between 12- and 24-mo of follow-up. Nilotinib 300 mg BID had the fewest discontinuations due to AEs/lab abnormalities (9% vs 13% and 10% with nilotinib 400 mg BID and imatinib, respectively). Conclusions: With a minimum follow-up of 24 mo, nilotinib continued to demonstrate superiority vs imatinib with faster and deeper molecular responses and a significantly decreased risk of progression. These data support the use of nilotinib as a standard of care option in newly-diagnosed adult pts with Ph+ CML-CP. Disclosures: Saglio: Novartis Pharmaceutical: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Pfizer: Consultancy. Off Label Use: Nilotinib is a safe and effective treatment for patients with CML. LeCoutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Nakamae:Novartis: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau. Flinn:nOVARTIS: Research Funding. Hochhaus:Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Gallagher:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: 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 Treatment Free Remission after Combination Therapy with Ruxolitinib Plus Tyrosine Kinase Inhibitors in Chronic Phase Chronic Myeloid Leukemia (CML)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2555-2555
Author(s):  
Kendra Sweet ◽  
Ehab L. Atallah ◽  
Jerry P. Radich ◽  
Mei-Jie Zhang ◽  
Eva Sahakian ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Advisory Committees ◽  
Treatment Free Remission ◽  
One Year

Abstract Background: Discontinuation of tyrosine kinase inhibitors (TKIs) is feasible in a subset of CML patients who have maintained a deep molecular response for at least two years. Numerous discontinuation trials have been performed and consistently show approximately 50% of patients relapse after stopping TKIs. A recent study examining rates of treatment free remission (TFR) after a second attempt at stopping TKIs found, with a median follow up time of 38.3 months, 64.3% of patients had a molecular relapse (defined as a loss of major molecular response (MMR)). At 12, 24 and 36 months, TFR rates were 48%, 42% and 35%, respectively. These data suggest some patients with a history of molecular relapse upon TKI cessation could successfully stop treatment on a subsequent attempt, yet the majority will relapse a second time. 'Complete eradication' of CML remains elusive in most patients likely as a result of minimal residual disease (MRD), which is the result of BCR-ABL independent drug resistance. More specifically, CML cells that reside in sanctuary sites such as the bone marrow adhere to fibronectin and demonstrate cell adhesion mediated drug resistance (CAM-DR). The bone marrow microenvironment contains many cytokines and growth factors capable of inducing STAT3-Y705 phosphorylation via the JAK-STAT pathway leading to protection against TKI-induced cell death. Inhibiting JAK2 and TYK2 leads to complete inhibition of pSTAT3-Y705, thereby implicating the role of activation of JAK2 and TYK2 in STAT3-Y705 phosphorylation and resistance towards BCR-ABL TKI-induced cell death. A phase I clinical trial combined ruxolitinib, which inhibits JAK2 and TYK2, plus nilotinib in chronic phase (CP) CML patients and found that ruxolitinib 15mg PO BID was safe and well tolerated with 4/10 patients achieving undetectable BCR-ABL1 transcripts by PCR. Study Design and Methods: This single arm phase II study (NCT03610971) will enroll 41 subjects from the H Jean Khoury Cure CML Consortium. Eligible subjects must have a confirmed diagnosis of CP-CML and have previously attempted to discontinue TKI therapy per NCCN guidelines and had molecular recurrence, defined as loss of MMR, and were restarted on TKI. This trial combines ruxolitinib 15mg BID plus BCR-ABL TKI (imatinib, dasatinib, nilotinib or bosutinib) for 12 28-day cycles in the combination treatment phase (CTP). RQ-PCR to measure BCR-ABL transcripts will be checked at screening and every three months during the CTP. In the event that a subject experiences intolerance to a TKI, has confirmed loss of MMR, or loss of MR4.5 (&gt;0.0032% IS) on two central PCR results, or discontinues ruxolitinib, the subject will be removed from CTP and enter into long term follow-up (LTFU). CTP phase will be followed by further RQ-PCR screening for the concurrent TFR phase. At this time ruxolitinib will be discontinued and any subject who has met the criteria for the TFR phase will be enrolled. During the TFR phase, subjects will discontinue their TKI and be monitored off treatment with RQ-PCR checked monthly for the first year, every six weeks for year two, and every 12 weeks during year three. Upon molecular recurrence, defined as loss of MMR, TKIs will be restarted. The primary endpoint is the 12-month TFR rate subsequent to completion of 12 cycles of combination therapy; however, subjects will remain in the TFR phase for three years. Therefore, the total duration of the trial will be approximately five years (one year on CTP + three years in the TFR phase + one-year LTFU). Study statistical design was calculated to yield a one-sided type I error rate of 0.025 and power of 65% when the true one-year relapse rate is 35%. This study will additionally assess patient-reported outcomes in conjunction with RQ-PCR testing. PROMIS and other measures will be self-administered through REDCap. Correlative studies will include comparing changes in pSTAT3 in K562 and KU812 cell lines using plasma from CML patients being treated with TKIs plus ruxolitinib, using the plasma inhibitory assay technique. Changes in pSTAT3 and pSTAT5 will be correlated with clinical response and rate of TFR. Additional correlatives include multiparameter flow-based assessment of the T-cell compartment (activity/polarization) as well as natural killer cell fractions in CML patients at various time points (TKIs alone, TKIs plus ruxolitinib and during TFR). Thus far, 14 patients have been enrolled. Disclosures Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Atallah: Amgen: Consultancy; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau. Radich: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Mauro: Pfizer: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sun Pharma / SPARC: Research Funding. Pinilla Ibarz: AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau. OffLabel Disclosure: Ruxolitinib is being used off-label in chronic myeloid leukemia

scholarly journals Myeloproliferative Neoplasms (MPN) Clonal Evolution Landscape and Its Impact on Patients' Prognosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 317-317
Author(s):  
Lin-Pierre Zhao ◽  
Marine Cazaux ◽  
Nabih Maslah ◽  
Rafael Daltro De Oliveira ◽  
Emmanuelle Verger ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Myeloproliferative Neoplasms ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Driver Mutation ◽  
Advisory Committees ◽  
Free Survival

Abstract Introduction: Although myeloproliferative neoplasms (MPN) are driven by three mutually exclusive driver mutations (JAK2, CALR and MPL), targeted deep sequencing studies identified multiple additional somatic mutations potentially impacting MPN evolution. Presence of a high molecular risk (HMR: ASXL1, EZH2, SRSF2 and IDH1/2) or a TP53 mutations has been associated with adverse prognosis. However, to date, the effect of clonal evolution (CEv) on MPN patients' outcome has not been evaluated, as most of the studies assessed mutational-based prognosis stratification from single baseline molecular genotyping. The objective of our study was to describe the clinical and molecular characteristics of patients with CEv in a large cohort of MPN patients and analyze its impact on patients' outcome. Methods: A total of 1538 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and January 2021. From this large retrospective cohort, we included in this study 446 patients who had at least 2 molecular analyses during the chronic phase of MPN, performed at diagnosis and/or during follow-up using next generation sequencing (NGS), targeting a panel of 36 genes involved in myeloid malignancies. Significant variants were retained with a sensitivity of 1%. CEv was defined as the acquisition of a new additional non-driver mutation between baseline and subsequent NGS evaluation. Statistical analyses were performed using the STATA software (STATA 17.0 for Mac Corporation, College Station, TX). Results: The median age at MPN diagnosis in our whole cohort was 51 years [IQR 41 - 60]. Our cohort included 167 (37%), 205 (46%) and 64 (14%) patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis (MF) respectively. With a median interval of 1.6 years [IQR 1.0 - 2.8] between the first and the second NGS analysis in the whole cohort, CEv occurred in 128 patients (29%). Patients with CEv were significantly older compared to patients without CEv (n=318) (p=0.03). MPN diagnosis, the type of driver mutation and complete blood counts at MPN diagnosis did not differ between the 2 groups. Eighty-one (63%) and 198 (62%) patients with or without CEv respectively had at least one additional non-driver mutation at baseline NGS (p=0.59), while the rate of HMR (n=25 (20%) versus n=79 (25%)) or TP53 (n=7 (5%) versus n=20 (6%)) mutations at baseline NGS did not differ between the 2 groups. Thirty six out of 128 (28%) of patients with CEv had more than 1 acquired mutation. Most recurrently acquired mutations involved the epigenetic regulators TET2 and DNMT3A that were mutated in respectively 33% and 25% of patients with CEv (Figure 1A). Moreover, 38% of CEv patients acquired HMR (ASXL1 (14%), EZH2 (6%), SRSF2 (3%), IDH1/2 (2%)) or TP53 (13%) mutations. After a median follow up of 10.8 years [IQR 6.6 - 17.2] in the whole cohort representing a total of 5635 patient years, 32 (7%) patients died, and 11 (2.5%) and 11 (2.5%) patients with at least 2 NGS performed during MPN chronic phase transformed respectively into secondary MF or myelodysplastic syndrome / acute myeloid leukemia (MDS/AML). Interestingly, CEv (HR 11.27, 95%CI [5.09; 24.96], p&lt;0.001) (Figure 1B), age at MPN diagnosis (HR 1.11, 95%CI [1.07; 1.15], p&lt;0.001) and the presence of HMR mutations at baseline NGS (HR 4.48, 95%CI [2.05; 9.77], p &lt;0.001) independently adversely impacted OS in a COX regression multivariate analysis. CEv also independently adversely impacted MDS/AML free survival (HR 13.15, 95%CI [3.88; 44.47], p&lt;0.001) and secondary MF free survival (HR 21.13, 95%CI [6.18; 72.20], p&lt;0.001) in a COX regression multivariate analysis. Conclusion: Our study on a large retrospective clinically and biologically annotated real-life cohort of MPN patients with long-term follow up shows that CEv independently adversely impacts OS, MDS/AML and secondary MF free survivals. CEv occurred in a clinically relevant proportion of MPN patients (28%) and was associated with patients' age. Acquired mutations mainly involved epigenetic regulators, HMR and TP53 genes. These results suggest that serial molecular monitoring using NGS could be routinely implemented in MPN patients follow up, to assess more accurately disease evolution and potentially update therapeutic management. Figure 1 Figure 1. Disclosures Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; ASTELLAS: Consultancy. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Benajiba: Gilead: Research Funding; Pfizer: Research Funding.

scholarly journals Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Franck E Nicolini ◽  
Vincent Alcazer ◽  
Pascale Cony-Makhoul ◽  
Stephanie Dulucq ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Front Line ◽  
Advisory Committees ◽  
Long Term Outcome

Nilotinib (NIL) 600 mg daily has demonstrated its superiority over Imatinib 400 mg daily in terms of response and incidence of deep molecular response in the front-line chronic phase (CP) CML setting. In this observational study we have retrospectively analyzed the outcome of in- and out-study 202 patients (pts) treated in this setting with NIL 600 mg front-line, in "real-life" conditions. All pts with newly diagnosed adult CP-CML receiving NIL 300 mg BID alone front-line between 10/2007 and 06/2020, were eligible for this study. Data were retrospectively collected according to the current French regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2003, 2006, and 2009 along treatment and to the recommendations from the French group of CML (D. Rea et al., Cancer 2018) in case of TFR. In this regard, a TKI was resumed if loss of MMR. All BCR-ABL1 assessments were performed in the 3 reference laboratories, standardised and expressed in % (IS) with ≥32,000 copies of ABL1 as control. The primary endpoints were the rate of molecular responses in the long-term and the (vascular) safety of Nilotinib. Secondary endpoints were the kinetics of molecular response, survival and safety of Nilotinib. Survival (OS, PFS & EFS) was defined according to ELN (J. Guilhot et al. Blood 2012). Two hundred and two patients were reported with 44% females and 56% males with a median age at diagnosis of 50.4 (17.5-83) years, and 26% of them had cardiovascular risk factors at onset (tobacco abuse 11%, hypercholesterolemia 9.3%, diabetes 1.45%, none with past history of cardiovascular events [CVE]). ELTS scores were high in 14%, intermediate in 31% and low in 55% of pts. Twenty-four (12%) pts harboured additional chromosomal abnormalities at diagnosis. The median follow-up after NIL initiation was 61.5 (1-147.5) months. At last follow-up 113 pts (55%) are not on NIL anymore for toxicities, TFR or resistance reasons. Twenty-eight (14%) pts present an arterial event on NIL (18% PAOD, 14% angina pectoralis, 7% myocardial infarction, 14% stroke, 47% others such as atrial fibrillation, cardiomyopathy...), that occurred after a median of 26 (0.6-98.5) months on NIL. Forty-six (22.5%) pts reached TFR criteria and stopped NIL after a median of 58.5 (27-126) months. The cumulative incidence (CI) rates of MMR at 1, 2 and 5 years were 64 (57-71)%, 79.4 (75.45-83.35)% and 95 (92-98.5)% respectively. For MR4, those were 35.5 (29-42)%, 60 (52-67)% and 82 (74.5-89)% respectively; and for MR4.5, were 14 (9-19)%, 31 (24-28)% and 62 (54-70.5)% respectively. The CI of sustained MR4.5 (i. e. patients eligible for TFR: MR4.5 ≥2 years) was observed in 30 (23-37)% at 3 years, 45.5 (36-55)% at 5 years and 52.5 (41.5-64)% at 6 years (Figure). The CI of patients entering TFR was 16.75 (10.5-23)% at 5 years and 51.94 (37.31-66.57)% at 10 years with a survival without MMR loss of 70.7 (58- 86)% at 1 year and 65.26 (50.6-84)% at 5 years. Nine (4.5%) pts progressed towards accelerated phase (4 pts) or BC (2 lymphoid, 3 myeloid) responsible for 5 deaths at latest follow-up. Among NIL resistant patients screened, 15 were harbouring ABL1 mutations (5 Y253H, 3 E255K, 3 T315I, 1 M244V, 1 G250E, 1 F359V, 1 V299L). Overall, 10 patients died (5 from CML, 5 from unrelated causes). The probability of OS was 95.75 [95%CI: 92.9-98.7]% at 2 years and 94.8 [91.5-98.3]% at 5 years, for PFS it was 94.92 [91.7-98.2]% at 2 years and 89.5 [84.7-94.6]% at 5 years, and EFS it was 78 [72.3-84]% at 2 years and 60.25 [53.3-68.1]% at 5 years. Regarding sustained MR4.5, univariate analysis showed that female gender (HR=2.46 [1.50-4.02], p&lt;0.001) and low ELTS (HR=0.41 [0.22-0.76], p&lt;0.004) had a significant impact, while multivariate analysis confirmed the role of these 2 factors (HR=2.31 [1.41- 3.79], p=0.001 and HR= 0.52 [0.30- 0.90], p=0.02) in addition to high ELTS (HR= 0.28 [0.14- 0.58], p&lt;0.001). Univariate and multivariate analyses demonstrated that only age impacted on the CI of CVE (HR= 1.07 [1.04-1.10], p&lt;0.001, and HR=1.07 [1.04-1.10], p&lt;0.001). NIL first-line efficiently limits progression of newly diagnosed CP-CML patients and provides high rates of sustained MR4.5, allowing TFR in a substantial proportion of pts. However, the onset of arterial occlusive events, especially in the elderly is a matter of concern in the choice of this compound at treatment initiation. Disclosures Nicolini: Incyte: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Sun Pharma Ltd: Consultancy. Cony-Makhoul:BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; BMS: Consultancy. Dulucq:Incyte: Speakers Bureau; Novartis: Speakers Bureau. Cayuela:Novartis: Speakers Bureau; Incyte: Speakers Bureau. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mahon:ARIAD: Honoraria; Pfizer: Honoraria; Novartis Pharma: Honoraria, Research Funding; BMS: Honoraria. Etienne:Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

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